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Li G, Gao J, Ding P, Gao Y. The role of endothelial cell-pericyte interactions in vascularization and diseases. J Adv Res 2025; 67:269-288. [PMID: 38246244 PMCID: PMC11725166 DOI: 10.1016/j.jare.2024.01.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2023] [Revised: 01/11/2024] [Accepted: 01/12/2024] [Indexed: 01/23/2024] Open
Abstract
BACKGROUND Endothelial cells (ECs) and pericytes (PCs) are crucial components of the vascular system, with ECs lining the inner layer of blood vessels and PCs surrounding capillaries to regulate blood flow and angiogenesis. Intercellular communication between ECs and PCs is vital for the formation, stability, and function of blood vessels. Various signaling pathways, such as the vascular endothelial growth factor/vascular endothelial growth factor receptor pathway and the platelet-derived growth factor-B/platelet-derived growth factor receptor-β pathway, play roles in communication between ECs and PCs. Dysfunctional communication between these cells is associated with various diseases, including vascular diseases, central nervous system disorders, and certain types of cancers. AIM OF REVIEW This review aimed to explore the diverse roles of ECs and PCs in the formation and reshaping of blood vessels. This review focused on the essential signaling pathways that facilitate communication between these cells and investigated how disruptions in these pathways may contribute to disease. Additionally, the review explored potential therapeutic targets, future research directions, and innovative approaches, such as investigating the impact of EC-PCs in novel systemic diseases, addressing resistance to antiangiogenic drugs, and developing novel antiangiogenic medications to enhance therapeutic efficacy. KEY SCIENTIFIC CONCEPTS OF REVIEW Disordered EC-PC intercellular signaling plays a role in abnormal blood vessel formation, thus contributing to the progression of various diseases and the development of resistance to antiangiogenic drugs. Therefore, studies on EC-PC intercellular interactions have high clinical relevance.
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Affiliation(s)
- Gan Li
- Department of Orthopaedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China; Institute of Microsurgery on Extremities, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China
| | - Junjie Gao
- Department of Orthopaedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China; Institute of Microsurgery on Extremities, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China; Shanghai Sixth People's Hospital Fujian, No. 16, Luoshan Section, Jinguang Road, Luoshan Street, Jinjiang City, Quanzhou, Fujian, China
| | - Peng Ding
- Department of Orthopaedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China; Institute of Microsurgery on Extremities, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China.
| | - Youshui Gao
- Department of Orthopaedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China; Institute of Microsurgery on Extremities, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China.
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Gilley P, Zhang K, Abdoli N, Sadri Y, Adhikari L, Fung KM, Qiu Y. Utilizing a Pathomics Biomarker to Predict the Effectiveness of Bevacizumab in Ovarian Cancer Treatment. Bioengineering (Basel) 2024; 11:678. [PMID: 39061760 PMCID: PMC11273783 DOI: 10.3390/bioengineering11070678] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2024] [Revised: 06/25/2024] [Accepted: 06/26/2024] [Indexed: 07/28/2024] Open
Abstract
The purpose of this investigation is to develop and initially assess a quantitative image analysis scheme that utilizes histopathological images to predict the treatment effectiveness of bevacizumab therapy in ovarian cancer patients. As a widely accessible diagnostic tool, histopathological slides contain copious information regarding underlying tumor progression that is associated with tumor prognosis. However, this information cannot be readily identified by conventional visual examination. This study utilizes novel pathomics technology to quantify this meaningful information for treatment effectiveness prediction. Accordingly, a total of 9828 features were extracted from segmented tumor tissue, cell nuclei, and cell cytoplasm, which were categorized into geometric, intensity, texture, and subcellular structure features. Next, the best performing features were selected as the input for SVM (support vector machine)-based prediction models. These models were evaluated on an open dataset containing a total of 78 patients and 288 whole slides images. The results indicated that the sufficiently optimized, best-performing model yielded an area under the receiver operating characteristic (ROC) curve of 0.8312. When examining the best model's confusion matrix, 37 and 25 cases were correctly predicted as responders and non-responders, respectively, achieving an overall accuracy of 0.7848. This investigation initially validated the feasibility of utilizing pathomics techniques to predict tumor responses to chemotherapy at an early stage.
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Affiliation(s)
- Patrik Gilley
- School of Electrical and Computer Engineering, University of Oklahoma, Norman, OK 73019, USA (N.A.)
| | - Ke Zhang
- School of Electrical and Computer Engineering, University of Oklahoma, Norman, OK 73019, USA (N.A.)
- Stephenson School of Biomedical Engineering, University of Oklahoma, Norman, OK 73019, USA
| | - Neman Abdoli
- School of Electrical and Computer Engineering, University of Oklahoma, Norman, OK 73019, USA (N.A.)
| | - Youkabed Sadri
- School of Electrical and Computer Engineering, University of Oklahoma, Norman, OK 73019, USA (N.A.)
| | - Laura Adhikari
- Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA (K.-M.F.)
| | - Kar-Ming Fung
- Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA (K.-M.F.)
| | - Yuchen Qiu
- School of Electrical and Computer Engineering, University of Oklahoma, Norman, OK 73019, USA (N.A.)
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Corrias G, Lai E, Ziranu P, Mariani S, Donisi C, Liscia N, Saba G, Pretta A, Persano M, Fanni D, Spanu D, Balconi F, Loi F, Deidda S, Restivo A, Pusceddu V, Puzzoni M, Solinas C, Massa E, Madeddu C, Gerosa C, Zorcolo L, Faa G, Saba L, Scartozzi M. Prediction of Response to Anti-Angiogenic Treatment for Advanced Colorectal Cancer Patients: From Biological Factors to Functional Imaging. Cancers (Basel) 2024; 16:1364. [PMID: 38611042 PMCID: PMC11011199 DOI: 10.3390/cancers16071364] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2024] [Revised: 03/24/2024] [Accepted: 03/27/2024] [Indexed: 04/14/2024] Open
Abstract
Colorectal cancer (CRC) is a leading tumor worldwide. In CRC, the angiogenic pathway plays a crucial role in cancer development and the process of metastasis. Thus, anti-angiogenic drugs represent a milestone for metastatic CRC (mCRC) treatment and lead to significant improvement of clinical outcomes. Nevertheless, not all patients respond to treatment and some develop resistance. Therefore, the identification of predictive factors able to predict response to angiogenesis pathway blockade is required in order to identify the best candidates to receive these agents. Unfortunately, no predictive biomarkers have been prospectively validated to date. Over the years, research has focused on biologic factors such as genetic polymorphisms, circulating biomarkers, circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), and microRNA. Moreover, research efforts have evaluated the potential correlation of molecular biomarkers with imaging techniques used for tumor assessment as well as the application of imaging tools in clinical practice. In addition to functional imaging, radiomics, a relatively newer technique, shows real promise in the setting of correlating molecular medicine to radiological phenotypes.
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Affiliation(s)
- Giuseppe Corrias
- Department of Radiology, University of Cagliari, 09042 Cagliari, Italy;
| | - Eleonora Lai
- Medical Oncology Unit, University Hospital and University of Cagliari, 09042 Cagliari, Italy; (E.L.); (P.Z.); (S.M.); (C.D.); (G.S.); (A.P.); (M.P.); (D.S.); (F.B.); (F.L.); (V.P.); (M.P.); (C.S.); (E.M.); (C.M.); (M.S.)
| | - Pina Ziranu
- Medical Oncology Unit, University Hospital and University of Cagliari, 09042 Cagliari, Italy; (E.L.); (P.Z.); (S.M.); (C.D.); (G.S.); (A.P.); (M.P.); (D.S.); (F.B.); (F.L.); (V.P.); (M.P.); (C.S.); (E.M.); (C.M.); (M.S.)
| | - Stefano Mariani
- Medical Oncology Unit, University Hospital and University of Cagliari, 09042 Cagliari, Italy; (E.L.); (P.Z.); (S.M.); (C.D.); (G.S.); (A.P.); (M.P.); (D.S.); (F.B.); (F.L.); (V.P.); (M.P.); (C.S.); (E.M.); (C.M.); (M.S.)
| | - Clelia Donisi
- Medical Oncology Unit, University Hospital and University of Cagliari, 09042 Cagliari, Italy; (E.L.); (P.Z.); (S.M.); (C.D.); (G.S.); (A.P.); (M.P.); (D.S.); (F.B.); (F.L.); (V.P.); (M.P.); (C.S.); (E.M.); (C.M.); (M.S.)
| | - Nicole Liscia
- Department of Medical Oncology, IRCCS San Raffaele Scientific Institute, Vita-Salute San Raffaele University, 20132 Milan, Italy;
| | - Giorgio Saba
- Medical Oncology Unit, University Hospital and University of Cagliari, 09042 Cagliari, Italy; (E.L.); (P.Z.); (S.M.); (C.D.); (G.S.); (A.P.); (M.P.); (D.S.); (F.B.); (F.L.); (V.P.); (M.P.); (C.S.); (E.M.); (C.M.); (M.S.)
| | - Andrea Pretta
- Medical Oncology Unit, University Hospital and University of Cagliari, 09042 Cagliari, Italy; (E.L.); (P.Z.); (S.M.); (C.D.); (G.S.); (A.P.); (M.P.); (D.S.); (F.B.); (F.L.); (V.P.); (M.P.); (C.S.); (E.M.); (C.M.); (M.S.)
| | - Mara Persano
- Medical Oncology Unit, University Hospital and University of Cagliari, 09042 Cagliari, Italy; (E.L.); (P.Z.); (S.M.); (C.D.); (G.S.); (A.P.); (M.P.); (D.S.); (F.B.); (F.L.); (V.P.); (M.P.); (C.S.); (E.M.); (C.M.); (M.S.)
| | - Daniela Fanni
- Division of Pathology, Department of Medical Sciences and Public Health, AOU Cagliari, University of Cagliari, 09124 Cagliari, Italy; (D.F.); (C.G.); (G.F.)
| | - Dario Spanu
- Medical Oncology Unit, University Hospital and University of Cagliari, 09042 Cagliari, Italy; (E.L.); (P.Z.); (S.M.); (C.D.); (G.S.); (A.P.); (M.P.); (D.S.); (F.B.); (F.L.); (V.P.); (M.P.); (C.S.); (E.M.); (C.M.); (M.S.)
| | - Francesca Balconi
- Medical Oncology Unit, University Hospital and University of Cagliari, 09042 Cagliari, Italy; (E.L.); (P.Z.); (S.M.); (C.D.); (G.S.); (A.P.); (M.P.); (D.S.); (F.B.); (F.L.); (V.P.); (M.P.); (C.S.); (E.M.); (C.M.); (M.S.)
| | - Francesco Loi
- Medical Oncology Unit, University Hospital and University of Cagliari, 09042 Cagliari, Italy; (E.L.); (P.Z.); (S.M.); (C.D.); (G.S.); (A.P.); (M.P.); (D.S.); (F.B.); (F.L.); (V.P.); (M.P.); (C.S.); (E.M.); (C.M.); (M.S.)
| | - Simona Deidda
- Colorectal Surgery Unit, A.O.U. Cagliari, Department of Surgical Science, University of Cagliari, 09042 Cagliari, Italy; (S.D.); (A.R.); (L.Z.)
| | - Angelo Restivo
- Colorectal Surgery Unit, A.O.U. Cagliari, Department of Surgical Science, University of Cagliari, 09042 Cagliari, Italy; (S.D.); (A.R.); (L.Z.)
| | - Valeria Pusceddu
- Medical Oncology Unit, University Hospital and University of Cagliari, 09042 Cagliari, Italy; (E.L.); (P.Z.); (S.M.); (C.D.); (G.S.); (A.P.); (M.P.); (D.S.); (F.B.); (F.L.); (V.P.); (M.P.); (C.S.); (E.M.); (C.M.); (M.S.)
| | - Marco Puzzoni
- Medical Oncology Unit, University Hospital and University of Cagliari, 09042 Cagliari, Italy; (E.L.); (P.Z.); (S.M.); (C.D.); (G.S.); (A.P.); (M.P.); (D.S.); (F.B.); (F.L.); (V.P.); (M.P.); (C.S.); (E.M.); (C.M.); (M.S.)
| | - Cinzia Solinas
- Medical Oncology Unit, University Hospital and University of Cagliari, 09042 Cagliari, Italy; (E.L.); (P.Z.); (S.M.); (C.D.); (G.S.); (A.P.); (M.P.); (D.S.); (F.B.); (F.L.); (V.P.); (M.P.); (C.S.); (E.M.); (C.M.); (M.S.)
| | - Elena Massa
- Medical Oncology Unit, University Hospital and University of Cagliari, 09042 Cagliari, Italy; (E.L.); (P.Z.); (S.M.); (C.D.); (G.S.); (A.P.); (M.P.); (D.S.); (F.B.); (F.L.); (V.P.); (M.P.); (C.S.); (E.M.); (C.M.); (M.S.)
| | - Clelia Madeddu
- Medical Oncology Unit, University Hospital and University of Cagliari, 09042 Cagliari, Italy; (E.L.); (P.Z.); (S.M.); (C.D.); (G.S.); (A.P.); (M.P.); (D.S.); (F.B.); (F.L.); (V.P.); (M.P.); (C.S.); (E.M.); (C.M.); (M.S.)
| | - Clara Gerosa
- Division of Pathology, Department of Medical Sciences and Public Health, AOU Cagliari, University of Cagliari, 09124 Cagliari, Italy; (D.F.); (C.G.); (G.F.)
| | - Luigi Zorcolo
- Colorectal Surgery Unit, A.O.U. Cagliari, Department of Surgical Science, University of Cagliari, 09042 Cagliari, Italy; (S.D.); (A.R.); (L.Z.)
| | - Gavino Faa
- Division of Pathology, Department of Medical Sciences and Public Health, AOU Cagliari, University of Cagliari, 09124 Cagliari, Italy; (D.F.); (C.G.); (G.F.)
| | - Luca Saba
- Department of Radiology, University of Cagliari, 09042 Cagliari, Italy;
| | - Mario Scartozzi
- Medical Oncology Unit, University Hospital and University of Cagliari, 09042 Cagliari, Italy; (E.L.); (P.Z.); (S.M.); (C.D.); (G.S.); (A.P.); (M.P.); (D.S.); (F.B.); (F.L.); (V.P.); (M.P.); (C.S.); (E.M.); (C.M.); (M.S.)
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Mäenpää N, Tiainen L, Hämäläinen M, Luukkaala T, Tanner M, Lahdenperä O, Vihinen P, Karihtala P, Kellokumpu-Lehtinen PL, Moilanen E, Jukkola A. Neuropilin-1 and placental growth factor as prognostic factors in metastatic breast cancer. BMC Cancer 2024; 24:331. [PMID: 38468231 DOI: 10.1186/s12885-024-12070-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2023] [Accepted: 02/28/2024] [Indexed: 03/13/2024] Open
Abstract
BACKGROUND Angiogenesis is crucial for tumor development, progression, and metastasizing. The most important regulator of angiogenesis is the vascular endothelial growth factor (VEGF) family, which is involved in multiple pathways in tumor microenvironment. The objective of this study was to investigate the prognostic value of the VEGF family in patients treated for metastatic breast cancer. The emphasis was on neuropilin-1 (NRP-1) and placental growth factor (PlGF). MATERIALS AND METHODS An analysis of eight members of the VEGF family was performed using baseline plasma samples of 65 patients treated for metastatic HER2 negative breast cancer in a phase II first-line bevacizumab plus chemotherapy trial. The patients were divided into two groups, high or low, according to the median for each VEGF family member. Progression-free survival (PFS) and overall survival (OS) were determined for each VEGF family member. RESULTS The patients with low plasma levels of NRP-1 and PlGF had a longer OS than those with high plasma levels [multivariable adjusted hazard ratios (HRs) 2.54 (95% confidence interval (CI) 1.11-5.82, p = 0.02) and 3.11 (95% CI 1.30-7.47, p = 0.01), respectively]. The patients with low levels of both NRP-1 and PlGF had a remarkably long OS with HR of 6.24, (95% CI 1.97-19.76, p = 0.002). In addition, high baseline NRP-1 level was associated with a significantly shorter PFS [multivariable adjusted HR 2.90 (95% CI 1.02-8.28, p = 0.04)] than that in the low-level group, and a high baseline vascular endothelial growth factor receptor-2 level was associated with a longer PFS [multivariable adjusted HR 0.43 (95% CI 0.19-0.98, p = 0.04)]. CONCLUSION Especially NRP-1 and PlGF have prognostic potential in metastatic breast cancer patients treated with a bevacizumab-taxane combination. Patients with low plasma levels of NRP-1 or PlGF have longer OS than patients with high levels. Patients with both low NRP-1 and PlGF levels appear to have excellent long-term survival. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT00979641, registration date 18/09/2009. The regional Ethics Committee: R08142M, registration date 18/11/2008.
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Affiliation(s)
- Niina Mäenpää
- Faculty of Medicine and Health Technology, Tampere University, FI-33014, Tampere, Finland.
- Department of Oncology, Tays Cancer Centre, Tampere University Hospital, FICAN Mid, Teiskontie 35, FI-33521, Tampere, Finland.
| | - Leena Tiainen
- Faculty of Medicine and Health Technology, Tampere University, FI-33014, Tampere, Finland
- Department of Oncology, Tays Cancer Centre, Tampere University Hospital, FICAN Mid, Teiskontie 35, FI-33521, Tampere, Finland
| | - Mari Hämäläinen
- The Immunopharmacology Research Group, Faculty of Medicine and Health Technology, Tampere University and Tampere University Hospital, Tampere University, 33014, Tampere, P.O. Box 100, Finland
| | - Tiina Luukkaala
- Research, Development and Innovation Center, Tampere University Hospital, Teiskontie 35, FI-33521, Tampere, Finland
- Health Sciences, Faculty of Social Sciences, Tampere University, FI-33521, Tampere, P.O. Box 2000, Finland
| | - Minna Tanner
- Department of Oncology, Tays Cancer Centre, Tampere University Hospital, FICAN Mid, Teiskontie 35, FI-33521, Tampere, Finland
| | - Outi Lahdenperä
- FICAN West Cancer Centre, Turku University Hospital, 20521, Turku, P.O. Box 52, Finland
| | - Pia Vihinen
- FICAN West Cancer Centre, Turku University Hospital, 20521, Turku, P.O. Box 52, Finland
| | - Peeter Karihtala
- Department of Oncology, Helsinki University Hospital Comprehensive Cancer Centre, University of Helsinki, FI-00029, Helsinki, P.O. Box 180, Finland
| | - Pirkko-Liisa Kellokumpu-Lehtinen
- Faculty of Medicine and Health Technology, Tampere University, FI-33014, Tampere, Finland
- Research, Development and Innovation Center, Tampere University Hospital, Teiskontie 35, FI-33521, Tampere, Finland
| | - Eeva Moilanen
- The Immunopharmacology Research Group, Faculty of Medicine and Health Technology, Tampere University and Tampere University Hospital, Tampere University, 33014, Tampere, P.O. Box 100, Finland
| | - Arja Jukkola
- Faculty of Medicine and Health Technology, Tampere University, FI-33014, Tampere, Finland
- Department of Oncology, Tays Cancer Centre, Tampere University Hospital, FICAN Mid, Teiskontie 35, FI-33521, Tampere, Finland
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Fan L, Wang ZH, Ma LX, Wu SY, Wu J, Yu KD, Sui XY, Xu Y, Liu XY, Chen L, Zhang WJ, Jin X, Xiao Q, Shui RH, Xiao Y, Wang H, Yang YS, Huang XY, Cao AY, Li JJ, Di GH, Liu GY, Yang WT, Hu X, Xia Y, Liang QN, Jiang YZ, Shao ZM. Optimising first-line subtyping-based therapy in triple-negative breast cancer (FUTURE-SUPER): a multi-cohort, randomised, phase 2 trial. Lancet Oncol 2024; 25:184-197. [PMID: 38211606 DOI: 10.1016/s1470-2045(23)00579-x] [Citation(s) in RCA: 14] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2023] [Revised: 11/03/2023] [Accepted: 11/06/2023] [Indexed: 01/13/2024]
Abstract
BACKGROUND Triple-negative breast cancers display heterogeneity in molecular drivers and immune traits. We previously classified triple-negative breast cancers into four subtypes: luminal androgen receptor (LAR), immunomodulatory, basal-like immune-suppressed (BLIS), and mesenchymal-like (MES). Here, we aimed to evaluate the efficacy and safety of subtyping-based therapy in the first-line treatment of triple-negative breast cancer. METHODS FUTURE-SUPER is an ongoing, open-label, randomised, controlled phase 2 trial being conducted at Fudan University Shanghai Cancer Center (FUSCC), Shanghai, China. Eligible participants were females aged 18-70 years, with an Eastern Cooperative Oncology Group performance status of 0-1, and histologically confirmed, untreated metastatic or recurrent triple-negative breast cancer. After categorising participants into five cohorts according to molecular subtype and genomic biomarkers, participants were randomly assigned (1:1) with a block size of 4, stratified by subtype, to receive, in 28-day cycles, nab-paclitaxel (100 mg/m2, intravenously on days 1, 8, and 15) alone (control group) or with a subtyping-based regimen (subtyping-based group): pyrotinib (400 mg orally daily) for the LAR-HER2mut subtype, everolimus (10 mg orally daily) for the LAR-PI3K/AKTmut and MES-PI3K/AKTmut subtypes, camrelizumab (200 mg intravenously on days 1 and 15) and famitinib (20 mg orally daily) for the immunomodulatory subtype, and bevacizumab (10 mg/kg intravenously on days 1 and 15) for the BLIS/MES-PI3K/AKTWT subtype. The primary endpoint was investigator-assessed progression-free survival for the pooled subtyping-based group versus the control group in the intention-to-treat population (all randomly assigned participants). Safety was analysed in all patients with safety records who received at least one dose of study drug. This study is registered with ClinicalTrials.gov (NCT04395989). FINDINGS Between July 28, 2020, and Oct 16, 2022, 139 female participants were enrolled and randomly assigned to the subtyping-based group (n=69) or control group (n=70). At the data cutoff (May 31, 2023), the median follow-up was 22·5 months (IQR 15·2-29·0). Median progression-free survival was significantly longer in the pooled subtyping-based group (11·3 months [95% CI 8·6-15·2]) than in the control group (5·8 months [4·0-6·7]; hazard ratio 0·44 [95% CI 0·30-0·65]; p<0·0001). The most common grade 3-4 treatment-related adverse events were neutropenia (21 [30%] of 69 in the pooled subtyping-based group vs 16 [23%] of 70 in the control group), anaemia (five [7%] vs none), and increased alanine aminotransferase (four [6%] vs one [1%]). Treatment-related serious adverse events were reported for seven (10%) of 69 patients in the subtyping-based group and none in the control group. No treatment-related deaths were reported in either group. INTERPRETATION These findings highlight the potential clinical benefits of using molecular subtype-based treatment optimisation in patients with triple-negative breast cancer, suggesting a path for further clinical investigation. Phase 3 randomised clinical trials assessing the efficacy of subtyping-based regimens are now underway. FUNDING National Natural Science Foundation of China, Natural Science Foundation of Shanghai, Shanghai Hospital Development Center, and Jiangsu Hengrui Pharmaceuticals. TRANSLATION For the Chinese translation of the abstract see Supplementary Materials section.
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Affiliation(s)
- Lei Fan
- Department of Breast Surgery, Fudan University Shanghai Cancer Center and Key Laboratory of Breast Cancer in Shanghai, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Zhong-Hua Wang
- Department of Breast Surgery, Fudan University Shanghai Cancer Center and Key Laboratory of Breast Cancer in Shanghai, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Lin-Xiaoxi Ma
- Department of Breast Surgery, Fudan University Shanghai Cancer Center and Key Laboratory of Breast Cancer in Shanghai, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Song-Yang Wu
- Department of Breast Surgery, Fudan University Shanghai Cancer Center and Key Laboratory of Breast Cancer in Shanghai, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Jiong Wu
- Department of Breast Surgery, Fudan University Shanghai Cancer Center and Key Laboratory of Breast Cancer in Shanghai, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Ke-Da Yu
- Department of Breast Surgery, Fudan University Shanghai Cancer Center and Key Laboratory of Breast Cancer in Shanghai, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Xin-Yi Sui
- Department of Breast Surgery, Fudan University Shanghai Cancer Center and Key Laboratory of Breast Cancer in Shanghai, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Ying Xu
- Department of Breast Surgery, Fudan University Shanghai Cancer Center and Key Laboratory of Breast Cancer in Shanghai, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Xi-Yu Liu
- Department of Breast Surgery, Fudan University Shanghai Cancer Center and Key Laboratory of Breast Cancer in Shanghai, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Li Chen
- Department of Breast Surgery, Fudan University Shanghai Cancer Center and Key Laboratory of Breast Cancer in Shanghai, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Wen-Juan Zhang
- Department of Breast Surgery, Fudan University Shanghai Cancer Center and Key Laboratory of Breast Cancer in Shanghai, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Xi Jin
- Department of Breast Surgery, Fudan University Shanghai Cancer Center and Key Laboratory of Breast Cancer in Shanghai, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Qin Xiao
- Department of Radiology, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Ruo-Hong Shui
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Yi Xiao
- Department of Breast Surgery, Fudan University Shanghai Cancer Center and Key Laboratory of Breast Cancer in Shanghai, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Han Wang
- Department of Breast Surgery, Fudan University Shanghai Cancer Center and Key Laboratory of Breast Cancer in Shanghai, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Yun-Song Yang
- Department of Breast Surgery, Fudan University Shanghai Cancer Center and Key Laboratory of Breast Cancer in Shanghai, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Xiao-Yan Huang
- Department of Breast Surgery, Fudan University Shanghai Cancer Center and Key Laboratory of Breast Cancer in Shanghai, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - A-Yong Cao
- Department of Breast Surgery, Fudan University Shanghai Cancer Center and Key Laboratory of Breast Cancer in Shanghai, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Jun-Jie Li
- Department of Breast Surgery, Fudan University Shanghai Cancer Center and Key Laboratory of Breast Cancer in Shanghai, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Gen-Hong Di
- Department of Breast Surgery, Fudan University Shanghai Cancer Center and Key Laboratory of Breast Cancer in Shanghai, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Guang-Yu Liu
- Department of Breast Surgery, Fudan University Shanghai Cancer Center and Key Laboratory of Breast Cancer in Shanghai, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Wen-Tao Yang
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Xin Hu
- Department of Breast Surgery, Fudan University Shanghai Cancer Center and Key Laboratory of Breast Cancer in Shanghai, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Yan Xia
- Department of Clinical Research & Development, Jiangsu Hengrui Pharmaceuticals, Shanghai, China
| | - Qian-Nan Liang
- Department of Clinical Research & Development, Jiangsu Hengrui Pharmaceuticals, Shanghai, China
| | - Yi-Zhou Jiang
- Department of Breast Surgery, Fudan University Shanghai Cancer Center and Key Laboratory of Breast Cancer in Shanghai, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
| | - Zhi-Ming Shao
- Department of Breast Surgery, Fudan University Shanghai Cancer Center and Key Laboratory of Breast Cancer in Shanghai, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
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6
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McLoughlin EC, Twamley B, O'Brien JE, Hannon Barroeta P, Zisterer DM, Meegan MJ, O'Boyle NM. Synthesis by diastereomeric resolution, biochemical evaluation and molecular modelling of chiral 3-hydroxyl b-lactam microtubule-targeting agents for the treatment of triple negative breast and chemoresistant colorectal cancers. Bioorg Chem 2023; 141:106877. [PMID: 37804699 DOI: 10.1016/j.bioorg.2023.106877] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Revised: 09/08/2023] [Accepted: 09/19/2023] [Indexed: 10/09/2023]
Abstract
The synthesis and biochemical activity of a series of chiral trans 3-hydroxyl β-lactams targeting tubulin is described. Synthesis of the series of enantiopure β-lactams was achieved using chiral derivatising reagent N-Boc-l-proline. The absolute configuration was determined as 3S,4S for (+) enantiomer 4EN1 and 3R,4R for (-) enantiomer 4EN2. Antiproliferative studies identified chiral 3S,4S b-lactams with subnanomolar IC50 values across a range of cancer cell lines, improving potency with respect to the corresponding racemates. Fluoro-substituted (+)-(3S,4S)-4-(3-fluoro-4-methoxyphenyl)-3-hydroxy-1-(3,4,5-trimethoxyphenyl)azetidin-2-one (27EN1) was determined as the lead eutomer with dual antiproliferative activity in triple negative breast cancer cells (TNBC), and combretastatin A-4 resistant HT-29 colorectal cancer cells. IC50 values were in the range of 0.26-0.7 nM across four cell lines. Tubulin polymerisation assays, confocal microscopy and molecular modelling studies indicated that 3S,4S eutomers are microtubule destabilisers, while 3R,4R distomers have lower potency as microtubule destabilisers. 27EN1 demonstrated anti-mitotic and pro-apoptotic activity in MDA-MB-231 and HT-29 cells in addition to selective toxicity toward MCF-7 breast cancer versus non-tumorigenic MCF-10-2A cells. The related 3S,4S β-lactam eutomer 4EN1 downregulated expression of key cell survival anti-apoptotic proteins Bcl-2 and Mcl-1 in MDA-MB-231 cells while 27EN1 downregulated Mcl-1 in HT-29 cells. Chiral β-lactam 27EN1 will be further developed for treatment of TNBC and CA-4 resistant colorectal cancers.
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Affiliation(s)
- Eavan C McLoughlin
- School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin, Panoz Institute and Trinity Biomedical Sciences Institute, 152-160 Pearse Street, Dublin 2, Ireland.
| | - Brendan Twamley
- School of Chemistry, Trinity College Dublin, Dublin 2, Ireland
| | - John E O'Brien
- School of Chemistry, Trinity College Dublin, Dublin 2, Ireland
| | - Patricia Hannon Barroeta
- School of Biochemistry and Immunology, Trinity College Dublin, Trinity Biomedical Sciences Institute, 152-160 Pearse Street, Dublin 2, Ireland
| | - Daniela M Zisterer
- School of Biochemistry and Immunology, Trinity College Dublin, Trinity Biomedical Sciences Institute, 152-160 Pearse Street, Dublin 2, Ireland
| | - Mary J Meegan
- School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin, Panoz Institute and Trinity Biomedical Sciences Institute, 152-160 Pearse Street, Dublin 2, Ireland
| | - Niamh M O'Boyle
- School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin, Panoz Institute and Trinity Biomedical Sciences Institute, 152-160 Pearse Street, Dublin 2, Ireland
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7
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Ilie MD, De Alcubierre D, Carretti AL, Jouanneau E, Raverot G. Therapeutic targeting of the pituitary tumor microenvironment. Pharmacol Ther 2023; 250:108506. [PMID: 37562699 DOI: 10.1016/j.pharmthera.2023.108506] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Revised: 07/28/2023] [Accepted: 08/07/2023] [Indexed: 08/12/2023]
Abstract
The tumor microenvironment (TME), the complex environment in which tumors develop, has been increasingly targeted for cancer treatment in recent years. Aggressive pituitary tumors and pituitary carcinomas have been so far targeted with immune-checkpoint inhibitors (28 cases, including a large cohort), and anti-angiogenic drugs (34 cases), specifically bevacizumab (30 cases), sunitinib (three cases), and apatinib (one case). Here, we reviewed all these cases, reporting tumor response, potential predictors of response, as well as adverse events. Given that the histological type could potentially influence treatment response, we present the existing data separately for each type. Briefly, under ICIs, complete response was noted in one case, partial response in a third of cases, stable disease in 10% of cases, while 54% of tumors progressed. Under BVZ monotherapy, most cases (57%) showed stable disease, while 36% of tumors progressed; partial response was reported in only one case. The three cases treated with sunitinib monotherapy progressed. Regarding predictive factors of response, the tumor type (aggressive pituitary tumor versus pituitary carcinoma) appears as the strongest predictor of response to ICIs. To date, no predictor of response to anti-angiogenic drugs in the treatment of pituitary carcinomas and aggressive pituitary tumors has been identified. The interest of BZV add-on to first- or second-line chemotherapy warrants further investigation. In addition, we discuss perspectives regarding the TME-targeting in aggressive pituitary tumors and pituitary carcinomas, including perspectives on immunotherapy, anti-angiogenic drugs, as well as on other TME components, namely stromal cells, extracellular matrix, and secreted molecules.
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Affiliation(s)
- Mirela-Diana Ilie
- Inserm U1052, CNRS UMR5286, Cancer Research Center of Lyon, Lyon, France; Lyon 1 University, Villeurbanne, France; Endocrinology Department, "C.I. Parhon" National Institute of Endocrinology, Bucharest, Romania
| | - Dario De Alcubierre
- Inserm U1052, CNRS UMR5286, Cancer Research Center of Lyon, Lyon, France; Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
| | - Anna Lucia Carretti
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy; Endocrinology Department, Reference Center for Rare Pituitary Diseases HYPO, "Groupement Hospitalier Est" Hospices Civils de Lyon, Bron, France
| | - Emmanuel Jouanneau
- Inserm U1052, CNRS UMR5286, Cancer Research Center of Lyon, Lyon, France; Lyon 1 University, Villeurbanne, France; Neurosurgery Department, Reference Center for Rare Pituitary Diseases HYPO, "Groupement Hospitalier Est" Hospices Civils de Lyon, Bron, France
| | - Gérald Raverot
- Inserm U1052, CNRS UMR5286, Cancer Research Center of Lyon, Lyon, France; Lyon 1 University, Villeurbanne, France; Endocrinology Department, Reference Center for Rare Pituitary Diseases HYPO, "Groupement Hospitalier Est" Hospices Civils de Lyon, Bron, France.
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8
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Song P, Rubin JM, Lowerison MR. Super-resolution ultrasound microvascular imaging: Is it ready for clinical use? Z Med Phys 2023; 33:309-323. [PMID: 37211457 PMCID: PMC10517403 DOI: 10.1016/j.zemedi.2023.04.001] [Citation(s) in RCA: 29] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2022] [Revised: 03/31/2023] [Accepted: 04/01/2023] [Indexed: 05/23/2023]
Abstract
The field of super-resolution ultrasound microvascular imaging has been rapidly growing over the past decade. By leveraging contrast microbubbles as point targets for localization and tracking, super-resolution ultrasound pinpoints the location of microvessels and measures their blood flow velocity. Super-resolution ultrasound is the first in vivo imaging modality that can image micron-scale vessels at a clinically relevant imaging depth without tissue destruction. These unique capabilities of super-resolution ultrasound provide structural (vessel morphology) and functional (vessel blood flow) assessments of tissue microvasculature on a global and local scale, which opens new doors for many enticing preclinical and clinical applications that benefit from microvascular biomarkers. The goal of this short review is to provide an update on recent advancements in super-resolution ultrasound imaging, with a focus on summarizing existing applications and discussing the prospects of translating super-resolution imaging to clinical practice and research. In this review, we also provide brief introductions of how super-resolution ultrasound works, how does it compare with other imaging modalities, and what are the tradeoffs and limitations for an audience who is not familiar with the technology.
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Affiliation(s)
- Pengfei Song
- Department of Electrical and Computer Engineering, University of Illinois Urbana-Champaign, United States; Beckman Institute for Advanced Science and Technology, University of Illinois Urbana-Champaign, United States; Department of Bioengineering, University of Illinois Urbana-Champaign, United States; Carle Illinois College of Medicine, University of Illinois Urbana-Champaign, United States.
| | - Jonathan M Rubin
- Department of Radiology, University of Michigan, Ann Arbor, United States
| | - Matthew R Lowerison
- Department of Electrical and Computer Engineering, University of Illinois Urbana-Champaign, United States; Beckman Institute for Advanced Science and Technology, University of Illinois Urbana-Champaign, United States
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9
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Zhou Q, Kong D, Li W, Shi Z, Liu Y, Sun R, Ma X, Qiu C, Liu Z, Hou Y, Jiang J. LncRNA HOXB-AS3 binding to PTBP1 protein regulates lipid metabolism by targeting SREBP1 in endometrioid carcinoma. Life Sci 2023; 320:121512. [PMID: 36858312 DOI: 10.1016/j.lfs.2023.121512] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2022] [Revised: 02/08/2023] [Accepted: 02/16/2023] [Indexed: 03/02/2023]
Abstract
Endometrial cancer (EC) is a malignant tumor with a high incidence in women, and the survival rate of high-risk patients decreases significantly after disease progression. The regulatory role of long non-coding RNAs (LncRNAs) in tumors has been widely appreciated, but there have been few studies in EC. To investigate the effect of HOXB-AS3 in EC, we used bioinformatics tools for prediction and collected clinical samples to detect the expression of HOXB-AS3. Colony formation assay, MTT assay, flow cytometry and apoptosis assay, and transwell assay were used to verify the role of HOXB-AS3 in EC. HOXB-AS3 was upregulated in EC, promoted the proliferation and invasive ability of EC cells, and inhibited apoptosis. In addition, the ROC curve illustrated its diagnostic value. We explored experiments via lentiviral transduction, FISH, Oil Red O staining, TC and FFA content detection, RNA-pulldown, RIP, and other mechanisms to reveal that HOXB-AS3 can bind to PTBP1 and co-regulate the expression of SREBP1, thereby regulating lipid metabolism in EC cells. To the best of our knowledge, this is the first study on HOXB-AS3 in disorders of lipid metabolism in EC. In addition, we believe HOXB-AS3 has the potential to be a neoplastic marker or a therapeutic target.
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Affiliation(s)
- Qing Zhou
- Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Jinan, Shandong, PR China; Department of Obstetrics and Gynecology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, PR China
| | - Deshui Kong
- Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Jinan, Shandong, PR China; Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, PR China
| | - Wenzhi Li
- Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Jinan, Shandong, PR China
| | - Zhengzheng Shi
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, PR China
| | - Yao Liu
- Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Jinan, Shandong, PR China
| | - Rui Sun
- Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Jinan, Shandong, PR China
| | - Xiaohong Ma
- Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Jinan, Shandong, PR China
| | - Chunping Qiu
- Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Jinan, Shandong, PR China
| | - Zhiming Liu
- Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Jinan, Shandong, PR China
| | - Yixin Hou
- Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Jinan, Shandong, PR China
| | - Jie Jiang
- Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Jinan, Shandong, PR China.
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10
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Wieser V, Tsibulak I, Reimer DU, Zeimet AG, Fiegl H, Hackl H, Marth C. An angiogenic tumor phenotype predicts poor prognosis in ovarian cancer. Gynecol Oncol 2023; 170:290-299. [PMID: 36758419 DOI: 10.1016/j.ygyno.2023.01.034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2022] [Revised: 01/26/2023] [Accepted: 01/27/2023] [Indexed: 02/09/2023]
Abstract
OBJECTIVE Epithelial ovarian cancer (OC) is the deadliest gynecological malignancy worldwide. Blocking angiogenesis with bevacizumab, an antibody targeting vascular endothelial growth factor (VEGF), shows efficacy in different lines of OC therapy. This study investigates the clinical impact of tumoral expression of angiogenesis-related genes and their association with bevacizumab response in OC in retrospective analysis of three independent cohorts. METHODS mRNA expression of seven angiogenic genes (VEGF, VEGFR2, PDGFA, PDGFB, PDGFRA, PDGFRB, KIT) was quantified in an inception OC cohort (n = 195) and a transcriptional tumor angiogenesis score from 0 to 3 was established and linked to progression-free survival (PFS) and overall survival (OS). This score was corroborated in an independent publicly available cohort from The Cancer Genome Atlas (TCGA, n = 582) and prediction of therapeutic efficacy of bevacizumab by the angiogenesis score was analyzed in the Gene Expression Omnibus (GEO) dataset GSE140082 (n = 380) from the ICON7-trial. RESULTS The tumor angiogenesis score prognosticated PFS and OS in patients with OC from the inception cohort (p < 0.001, respectively). Tumoral PDGFA expression (PFS: HR 2.46, p = 0.005; OS: HR 2.26, p = 0.011) and a high tumoral transcriptional angiogenesis score (PFS: HR 1.41, p = 0.018) were identified as independent predictors of clinical outcome. The transcriptional angiogenesis score exhibited a significant though smaller effect size on PFS in the TCGA cohort. However, in the ICON7-trial, the angiogenesis score was not associated with benefit of bevacizumab treatment. CONCLUSIONS Our study indicates that tumoral expression of angiogenic genes is unfavorable in OC. The established score could be used to identify patients who respond to targeted angiogenic therapies, a concept that warrants prospective controlled clinical trials.
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Affiliation(s)
- Verena Wieser
- Department of Obstetrics and Gynecology, Medical University of Innsbruck, 6020 Innsbruck, Austria.
| | - Irina Tsibulak
- Department of Obstetrics and Gynecology, Medical University of Innsbruck, 6020 Innsbruck, Austria
| | - Daniel Uwe Reimer
- Department of Obstetrics and Gynecology, Medical University of Innsbruck, 6020 Innsbruck, Austria
| | - Alain Gustave Zeimet
- Department of Obstetrics and Gynecology, Medical University of Innsbruck, 6020 Innsbruck, Austria
| | - Heidelinde Fiegl
- Department of Obstetrics and Gynecology, Medical University of Innsbruck, 6020 Innsbruck, Austria
| | - Hubert Hackl
- Biocenter, Institute of Bioinformatics, Medical University Innsbruck, 6020 Innsbruck, Austria
| | - Christian Marth
- Department of Obstetrics and Gynecology, Medical University of Innsbruck, 6020 Innsbruck, Austria
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11
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Zheng J, Wang X, Yu J, Zhan Z, Guo Z. IL-6, TNF-α and IL-12p70 levels in patients with colorectal cancer and their predictive value in anti-vascular therapy. Front Oncol 2022; 12:997665. [PMID: 36226059 PMCID: PMC9549173 DOI: 10.3389/fonc.2022.997665] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Accepted: 08/30/2022] [Indexed: 01/19/2023] Open
Abstract
We aimed to analyze the levels of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) and interleukin-12 (IL-12p70) in colorectal cancer and evaluate the predictive significance of clinical efficacy of patients with colorectal cancer treated with anti-vascular therapy combined with chemotherapy. A retrospective study of 162 patients with colorectal cancer in Fujian Medical University Hospital was conducted from January 2019 to December 2020. A comparative analysis of the levels of IL-6, TNF-α and IL-12p70 between the two groups were studied. The relationship between the levels and the clinical characteristics of patients was observed; the factors affecting the levels of IL-6, TNF-α, and IL-12p70 in colorectal cancer patients were analyzed, and the predictive validity of the efficacy of anti-vascular therapy was evaluated. We observed that the individual expression levels of IL-6, TNF-α and IL-12p70 in the patients with colorectal cancer are related to lymph node metastasis, TNM staging, and degree of differentiation (P<0.05); however, they are irrelevant to the age, sex, and tumor location of patients with colorectal cancer (P>0.05). The multiple stepwise regression analysis indicates that lymph node metastasis and TNM staging are independent risk factors that correlate with IL-6 and IL-12p70 levels in colorectal cancer patients (P<0.01). The degree of differentiation was found to be an independent risk factor connected to TNF- α levels of patients with colorectal cancer. The change of IL-12p70 level could predict the validity of anti-vascular treatment for advanced colorectal cancer. When evaluated for combined expression, IL-6 and IL-12p70 in patients with colorectal cancer closely related to lymph node metastasis and TNM staging. IL-12p70 can be used as a predictor of anti-vascular therapy with colorectal cancer.
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Affiliation(s)
- Jingxian Zheng
- Department of Medical Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, China
- Fujian Key Laboratory of Translational Cancer Medicine, Fujian Cancer Hospital, The Affiliated Cancer Hospital of Fujian Medical University, Fuzhou, China
- Fujian Provincial Key Laboratory of Tumor Biotherapy, Fujian Cancer Hospital, The Affiliated Cancer Hospital of Fujian Medical University, Fuzhou, China
| | - Xiaojie Wang
- Department of Medical Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, China
- Fujian Key Laboratory of Translational Cancer Medicine, Fujian Cancer Hospital, The Affiliated Cancer Hospital of Fujian Medical University, Fuzhou, China
- Fujian Provincial Key Laboratory of Tumor Biotherapy, Fujian Cancer Hospital, The Affiliated Cancer Hospital of Fujian Medical University, Fuzhou, China
| | - Jiami Yu
- Department of Medical Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, China
- Fujian Key Laboratory of Translational Cancer Medicine, Fujian Cancer Hospital, The Affiliated Cancer Hospital of Fujian Medical University, Fuzhou, China
- Fujian Provincial Key Laboratory of Tumor Biotherapy, Fujian Cancer Hospital, The Affiliated Cancer Hospital of Fujian Medical University, Fuzhou, China
| | - Zhouwei Zhan
- Department of Medical Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, China
- Fujian Key Laboratory of Translational Cancer Medicine, Fujian Cancer Hospital, The Affiliated Cancer Hospital of Fujian Medical University, Fuzhou, China
- Fujian Provincial Key Laboratory of Tumor Biotherapy, Fujian Cancer Hospital, The Affiliated Cancer Hospital of Fujian Medical University, Fuzhou, China
| | - Zengqing Guo
- Department of Medical Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, China
- Fujian Key Laboratory of Translational Cancer Medicine, Fujian Cancer Hospital, The Affiliated Cancer Hospital of Fujian Medical University, Fuzhou, China
- Fujian Provincial Key Laboratory of Tumor Biotherapy, Fujian Cancer Hospital, The Affiliated Cancer Hospital of Fujian Medical University, Fuzhou, China
- *Correspondence: Zengqing Guo,
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12
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Li B, Jiang C, Xu Y, Fan X, Yang L, Zou B, Fan B, Wang L. Genome-wide DNA methylation signature predict clinical benefit of bevacizumab in non-small cell lung cancer. BMC Cancer 2022; 22:828. [PMID: 35906610 PMCID: PMC9338664 DOI: 10.1186/s12885-022-09918-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Accepted: 07/19/2022] [Indexed: 11/17/2022] Open
Abstract
Background The efficacy of bevacizumab in non-small cell lung cancer (NSCLC) patients is unsatisfactory, and the selection of suitable patients is still challenging. Given the epigenetic modifications can contribute to an aberrant regulation of angiogenesis and microenvironment, we investigated DNA methylation profiles to determine clinical benefit of bevacizumab in NSCLC patients. Methods Genome-wide DNA methylation profiling was performed in NSCLC patients treated with chemotherapy in combination with bevacizumab. Patients were divided into better prognosis group (A group) and inferior prognosis group (B group) based on their survival. The difference of methylation patterns and respective functional enrichment analysis were performed between two groups. Prognostic DNA methylation signature for bevacizumab was established with the least absolute shrinkage and selection operator regression analyses. TISIDB database was further used to infer immunological relationship for prognostic related DNA methylation. Results Twenty patients were included in this study, and significantly distinct methylation patterns were observed between patients with different prognosis. Related genes of different methylation regions were significantly enriched in the biological process of cell projection assembly, neutrophil mediated immunity, and pathway of VEGFA-VEGFR2 signaling pathway, neutrophil degranulation. A 10-gene DNA methylation signature for prognosis prediction was established with the C-index of 0.76. And host genes of signature were found to be related to the abundance of ActCD4, Th1, ActCD8, NKT and neutrophil cells. Conclusion The 10-gene DNA methylation signature could serve as a novel biomarker to predict the clinical benefit of bevacizumab therapy and improve this anti-tumor approach for NSCLC patients. Supplementary Information The online version contains supplementary material available at 10.1186/s12885-022-09918-1.
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Affiliation(s)
- Butuo Li
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, 440 Jiyan Road, Jinan, 250117, Shandong, China
| | - Chao Jiang
- Department of Otorhinolaryngology Head and Neck Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
| | - Yiyue Xu
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, 440 Jiyan Road, Jinan, 250117, Shandong, China
| | - Xinyu Fan
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, 440 Jiyan Road, Jinan, 250117, Shandong, China
| | - Linlin Yang
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, 440 Jiyan Road, Jinan, 250117, Shandong, China
| | - Bing Zou
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, 440 Jiyan Road, Jinan, 250117, Shandong, China
| | - Bingjie Fan
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, 440 Jiyan Road, Jinan, 250117, Shandong, China
| | - Linlin Wang
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, 440 Jiyan Road, Jinan, 250117, Shandong, China.
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13
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Huang M, Lin Y, Wang C, Deng L, Chen M, Assaraf YG, Chen ZS, Ye W, Zhang D. New insights into antiangiogenic therapy resistance in cancer: Mechanisms and therapeutic aspects. Drug Resist Updat 2022; 64:100849. [PMID: 35842983 DOI: 10.1016/j.drup.2022.100849] [Citation(s) in RCA: 77] [Impact Index Per Article: 25.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Angiogenesis is a hallmark of cancer and is required for tumor growth and progression. Antiangiogenic therapy has been revolutionarily developing and was approved for the treatment of various types of cancer for nearly two decades, among which bevacizumab and sorafenib continue to be the two most frequently used antiangiogenic drugs. Although antiangiogenic therapy has brought substantial survival benefits to many cancer patients, resistance to antiangiogenic drugs frequently occurs during clinical treatment, leading to poor outcomes and treatment failure. Cumulative evidence has demonstrated that the intricate interplay among tumor cells, bone marrow-derived cells, and local stromal cells critically allows for tumor escape from antiangiogenic therapy. Currently, drug resistance has become the main challenge that hinders the therapeutic efficacies of antiangiogenic therapy. In this review, we describe and summarize the cellular and molecular mechanisms conferring tumor drug resistance to antiangiogenic therapy, which was predominantly associated with redundancy in angiogenic signaling molecules (e.g., VEGFs, GM-CSF, G-CSF, and IL17), alterations in biological processes of tumor cells (e.g., tumor invasiveness and metastasis, stemness, autophagy, metabolic reprogramming, vessel co-option, and vasculogenic mimicry), increased recruitment of bone marrow-derived cells (e.g., myeloid-derived suppressive cells, tumor-associated macrophages, and tumor-associated neutrophils), and changes in the biological functions and features of local stromal cells (e.g., pericytes, cancer-associated fibroblasts, and endothelial cells). We also review potential biomarkers to predict the response to antiangiogenic therapy in cancer patients, which mainly consist of imaging biomarkers, cellular and extracellular proteins, a certain type of bone marrow-derived cells, local stromal cell content (e.g., pericyte coverage) as well as serum or plasma biomarkers (e.g., non-coding RNAs). Finally, we highlight the recent advances in combination strategies with the aim of enhancing the response to antiangiogenic therapy in cancer patients and mouse models. This review introduces a comprehensive understanding of the mechanisms and biomarkers associated with the evasion of antiangiogenic therapy in cancer, providing an outlook for developing more effective approaches to promote the therapeutic efficacy of antiangiogenic therapy.
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Affiliation(s)
- Maohua Huang
- Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou, 510632, China; Integrated Chinese and Western Medicine Postdoctoral Research Station, Jinan University, Guangzhou, 510632, China
| | - Yuning Lin
- Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou, 510632, China
| | - Chenran Wang
- Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou, 510632, China
| | - Lijuan Deng
- Formula-Pattern Research Center, School of Traditional Chinese Medicine, Jinan University, Guangzhou, 510632, China
| | - Minfeng Chen
- Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou, 510632, China
| | - Yehuda G Assaraf
- The Fred Wyszkowski Cancer Research Laboratory, Department of Biology, Technion-Israel Institute of Technology, Haifa, 3200003, Israel
| | - Zhe-Sheng Chen
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, Institute for Biotechnology, St. John's University, NY 11439, USA.
| | - Wencai Ye
- Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou, 510632, China.
| | - Dongmei Zhang
- Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou, 510632, China.
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14
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Zhou YW, Long YX, Liu X, Liu JY, Qiu M. Tumor calcification is associated with better survival in metastatic colorectal cancer patients treated with bevacizumab plus chemotherapy. Future Oncol 2022; 18:2453-2464. [PMID: 35712899 DOI: 10.2217/fon-2021-1422] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Aims: The purpose was to investigate the correlation between calcification and outcome in metastatic colorectal cancer (mCRC) patients who received bevacizumab plus chemotherapy as the first-line treatment. Methods: A single retrospective cohort study was conducted with all diagnosed mCRC cases who received bevacizumab and chemotherapy as the first-line therapy. Results: Among all enrolled patients (n = 159), 31 had tumor calcification. The median overall survival and progression-free survival were significantly better in patients with tumor calcification than in those without calcification. A higher objective overall response rate was also observed in the tumor calcification group. On multivariate analysis, tumor calcification was independently associated with overall survival and progression-free survival. Conclusions: Tumor calcification was independently associated with improved survival in mCRC patients treated with bevacizumab plus chemotherapy.
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Affiliation(s)
- Yu-Wen Zhou
- Department of Biotherapy, Cancer Center, West China Hospital of Sichuan University, Chengdu, China
| | - Yi-Xiu Long
- Department of Biotherapy, Cancer Center, West China Hospital of Sichuan University, Chengdu, China
| | - Xia Liu
- Department of Colorectal Cancer Center, Cancer Center, West China Hospital of Sichuan University, Chengdu, China
| | - Ji-Yan Liu
- Department of Biotherapy, Cancer Center, West China Hospital of Sichuan University, Chengdu, China
| | - Meng Qiu
- Department of Colorectal Cancer Center, Cancer Center, West China Hospital of Sichuan University, Chengdu, China
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15
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Sharma D, Bisen S, Kaur G, Van Buren EC, Rao GN, Singh NK. IL-33 enhances Jagged1 mediated NOTCH1 intracellular domain (NICD) deubiquitination and pathological angiogenesis in proliferative retinopathy. Commun Biol 2022; 5:479. [PMID: 35589941 PMCID: PMC9120174 DOI: 10.1038/s42003-022-03432-7] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Accepted: 04/29/2022] [Indexed: 01/10/2023] Open
Abstract
Pathological retinal neovascularization (NV) is a clinical manifestation of various proliferative retinopathies, and treatment of NV using anti-VEGF therapies is not selective, as it also impairs normal retinal vascular growth and function. Here, we show that genetic deletion or siRNA-mediated downregulation of IL-33 reduces pathological NV in a murine model of oxygen-induced retinopathy (OIR) with no effect on the normal retinal repair. Furthermore, our fluorescent activated cell sorting (FACS) data reveals that the increase in IL-33 expression is in endothelial cells (ECs) of the hypoxic retina and conditional genetic deletion of IL-33 in retinal ECs reduces pathological NV. In vitro studies using human retinal microvascular endothelial cells (HRMVECs) show that IL-33 induces sprouting angiogenesis and requires NFkappaB-mediated Jagged1 expression and Notch1 activation. Our data also suggest that IL-33 enhances de-ubiquitination and stabilization of Notch1 intracellular domain via its interaction with BRCA1-associated protein 1 (BAP1) and Numb in HRMVECs and a murine model of OIR.
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Affiliation(s)
- Deepti Sharma
- Integrative Biosciences Center, Wayne State University, Detroit, MI, 48202, USA
- Department of Ophthalmology, Visual and Anatomical Sciences, Wayne State University School of Medicine, Detroit, MI, 48202, USA
| | - Shivantika Bisen
- Integrative Biosciences Center, Wayne State University, Detroit, MI, 48202, USA
- Department of Ophthalmology, Visual and Anatomical Sciences, Wayne State University School of Medicine, Detroit, MI, 48202, USA
| | - Geetika Kaur
- Integrative Biosciences Center, Wayne State University, Detroit, MI, 48202, USA
- Department of Ophthalmology, Visual and Anatomical Sciences, Wayne State University School of Medicine, Detroit, MI, 48202, USA
| | - Eric C Van Buren
- Department of Oncology, Wayne State University School of Medicine, Detroit, MI, 48201, USA
| | - Gadiparthi N Rao
- Department of Physiology, University of Tennessee Health Science Center, Memphis, TN, 38163, USA
| | - Nikhlesh K Singh
- Integrative Biosciences Center, Wayne State University, Detroit, MI, 48202, USA.
- Department of Ophthalmology, Visual and Anatomical Sciences, Wayne State University School of Medicine, Detroit, MI, 48202, USA.
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16
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Giuli MV, Mancusi A, Giuliani E, Screpanti I, Checquolo S. Notch signaling in female cancers: a multifaceted node to overcome drug resistance. CANCER DRUG RESISTANCE (ALHAMBRA, CALIF.) 2022; 4:805-836. [PMID: 35582386 PMCID: PMC8992449 DOI: 10.20517/cdr.2021.53] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Revised: 07/29/2021] [Accepted: 08/03/2021] [Indexed: 12/24/2022]
Abstract
Drug resistance is one of the main challenges in cancer therapy, including in the treatment of female-specific malignancies, which account for more than 60% of cancer cases among women. Therefore, elucidating the underlying molecular mechanisms is an urgent need in gynecological cancers to foster novel therapeutic approaches. Notably, Notch signaling, including either receptors or ligands, has emerged as a promising candidate given its multifaceted role in almost all of the hallmarks of cancer. Concerning the connection between Notch pathway and drug resistance in the afore-mentioned tumor contexts, several studies focused on the Notch-dependent regulation of the cancer stem cell (CSC) subpopulation or the induction of the epithelial-to-mesenchymal transition (EMT), both features implicated in either intrinsic or acquired resistance. Indeed, the present review provides an up-to-date overview of the published results on Notch signaling and EMT- or CSC-driven drug resistance. Moreover, other drug resistance-related mechanisms are examined such as the involvement of the Notch pathway in drug efflux and tumor microenvironment. Collectively, there is a long way to go before every facet will be fully understood; nevertheless, some small pieces are falling neatly into place. Overall, the main aim of this review is to provide strong evidence in support of Notch signaling inhibition as an effective strategy to evade or reverse resistance in female-specific cancers.
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Affiliation(s)
- Maria V Giuli
- Laboratory of Molecular Pathology, Department of Molecular Medicine, Sapienza University, Rome 00161, Italy
| | - Angelica Mancusi
- Laboratory of Molecular Pathology, Department of Molecular Medicine, Sapienza University, Rome 00161, Italy
| | - Eugenia Giuliani
- Scientific Direction, San Gallicano Dermatological Institute IRCCS, Rome 00144, Italy
| | - Isabella Screpanti
- Laboratory of Molecular Pathology, Department of Molecular Medicine, Sapienza University, Rome 00161, Italy
| | - Saula Checquolo
- Department of Medico-Surgical Sciences and Biotechnology, Sapienza University, Latina 04100, Italy.,Center for Life Nano Science@Sapienza, Istituto Italiano di Tecnologia, Rome 00161, Italy
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17
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VEGF-A, VEGFR1 and VEGFR2 single nucleotide polymorphisms and outcomes from the AGITG MAX trial of capecitabine, bevacizumab and mitomycin C in metastatic colorectal cancer. Sci Rep 2022; 12:1238. [PMID: 35075138 PMCID: PMC8786898 DOI: 10.1038/s41598-021-03952-y] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Accepted: 11/24/2021] [Indexed: 02/08/2023] Open
Abstract
The phase III MAX clinical trial randomised patients with metastatic colorectal cancer (mCRC) to receive first-line capecitabine chemotherapy alone or in combination with the anti-VEGF-A antibody bevacizumab (± mitomycin C). We utilised this cohort to examine whether single nucleotide polymorphisms (SNPs) in VEGF-A, VEGFR1, and VEGFR2 are predictive of efficacy outcomes with bevacizumab or the development of hypertension. Genomic DNA extracted from archival FFPE tissue for 325 patients (69% of the MAX trial population) was used to genotype 16 candidate SNPs in VEGF-A, VEGFR1, and VEGFR2, which were analysed for associations with efficacy outcomes and hypertension. The VEGF-A rs25648 ‘CC’ genotype was prognostic for improved PFS (HR 0.65, 95% CI 0.49 to 0.85; P = 0.002) and OS (HR 0.70, 95% CI 0.52 to 0.94; P = 0.019). The VEGF-A rs699947 ‘AA’ genotype was prognostic for shorter PFS (HR 1.32, 95% CI 1.002 to 1.74; P = 0.048). None of the analysed SNPs were predictive of bevacizumab efficacy outcomes. VEGFR2 rs11133360 ‘TT’ was associated with a lower risk of grade ≥ 3 hypertension (P = 0.028). SNPs in VEGF-A, VEGFR1 and VEGFR2 did not predict bevacizumab benefit. However, VEGF-A rs25648 and rs699947 were identified as novel prognostic biomarkers and VEGFR2 rs11133360 was associated with less grade ≥ 3 hypertension.
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18
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El-Qushayri AE, Benmelouka AY, Salman S, Nardone B. Melanoma and hypertension, is there an association? A U.S. population based study. Ital J Dermatol Venerol 2021; 157:270-274. [PMID: 34545727 DOI: 10.23736/s2784-8671.21.07089-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
BACKGROUND Melanoma is one of the three major types of skin cancer. In this study we aimed to investigate the association between melanoma and hypertension comorbidity. METHODS We performed a population based study using NHANES database during the period 1999-2004. Data were analyzed using SPSS version 24. RESULTS Data for 12446 individuals of which 146 had a diagnosis for melanoma were extracted. Melanoma group were older than the no melanoma group as 51% of the melanoma group were 60 years or elder; however 53.6% of the no melanoma group falls below 30 years old. Melanoma group had higher frequency of hypertension (37%) compared to the no melanoma group (22.5%). Logistic regression revealed that melanoma patients had higher odds of hypertension prevalence using the unadjusted model (odds ratio (OR): 2.03, 95% confidence interval (CI): 1.45-2.84, p <0.001). However, after controlling of all potential confounding factors the significance was lost (OR: 0.89, 95% CI: 0.61-1.3, p = 0.54). CONCLUSIONS There may be a possible association of melanoma with hypertension comorbidity. With the limitations we faced, we encourage further research to confirm the association of melanoma and hypertension comorbidity.
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Affiliation(s)
| | | | - Samar Salman
- Department of Dermatology and Venereology, Faculty of Medicine, Tanta University Hospital, Tanta University, Tanta, Egypt
| | - Beatrice Nardone
- Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
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19
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Zhang T, Zhang L, Gao Y, Wang Y, Liu Y, Zhang H, Wang Q, Hu F, Li J, Tan J, Wang DD, Gires O, Lin PP, Li B. Role of aneuploid circulating tumor cells and CD31 + circulating tumor endothelial cells in predicting and monitoring anti-angiogenic therapy efficacy in advanced NSCLC. Mol Oncol 2021; 15:2891-2909. [PMID: 34455700 PMCID: PMC8564645 DOI: 10.1002/1878-0261.13092] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2021] [Accepted: 08/23/2021] [Indexed: 12/18/2022] Open
Abstract
Prognosticating the efficacy of anti‐angiogenic therapy through longitudinal monitoring and early detection of treatment resistance in cancer patients remain highly challenging. In this study, co‐detection and comprehensive phenotypic and karyotypic molecular characterization of aneuploid circulating tumor cells (CTCs) and circulating tumor endothelial cells (CTECs) were conducted on non‐small cell lung cancer (NSCLC) patients receiving bevacizumab plus chemotherapy. Prognostic values of the cell‐based significant univariate risk factors identified by Cox regression analyses were progressively investigated. Subjects showing an increase in total post‐therapeutic platelet endothelial cell adhesion molecule‐1 (CD31)– CTCs and CD31+ CTECs exhibited a significantly reduced median progression‐free survival (mPFS) and overall survival. Further stratification analyses indicated that pretherapeutic patients bearing vimentin (Vim)+ CTECs (mesenchymal M‐type) at baseline revealed a significantly shortened mPFS compared with patients with Vim– CTECs. Post‐therapeutic patients harboring epithelial cell adhesion molecule (EpCAM)+ CTCs and CTECs (epithelial E‐type), regardless of Vim expression or not, showed a significantly reduced mPFS. Post‐therapeutic patients possessing de novo EpCAM+/Vim+ (hybrid E/M‐type) CTECs displayed the shortest mPFS. Patients harboring either pre‐ or post‐therapeutic EpCAM–/Vim– null CTECs (N‐type) exhibited a better response to therapy compared to patients harboring EpCAM+ and/or Vim+ CTECs. The presented results support the notion that baseline Vim+ CTECs and post‐therapeutic EpCAM+ CTCs and CTECs are predictive biomarkers for longitudinal monitoring of response to anti‐angiogenesis combination regimens in NSCLC patients.
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Affiliation(s)
- Tongmei Zhang
- Department of Medical Oncology, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, China
| | - Lina Zhang
- Department of Cellular and Molecular Biology, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, China
| | - Yuan Gao
- Department of Medical Oncology, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, China
| | - Ying Wang
- Department of Medical Oncology, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, China
| | - Yanxia Liu
- Department of Medical Oncology, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, China
| | - Hongmei Zhang
- Department of Medical Oncology, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, China
| | - Qunhui Wang
- Department of Medical Oncology, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, China
| | - Fanbin Hu
- Department of Medical Oncology, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, China
| | - Jie Li
- Department of Medical Oncology, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, China
| | - Jinjing Tan
- Department of Cellular and Molecular Biology, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, China
| | | | - Olivier Gires
- Department of Otorhinolaryngology, Head and Neck Surgery, University Hospital, LMU Munich, Germany
| | | | - Baolan Li
- Department of Medical Oncology, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, China
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20
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Avolio M, Trusolino L. Rational Treatment of Metastatic Colorectal Cancer: A Reverse Tale of Men, Mice, and Culture Dishes. Cancer Discov 2021; 11:1644-1660. [PMID: 33820776 DOI: 10.1158/2159-8290.cd-20-1531] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Revised: 01/04/2021] [Accepted: 02/01/2021] [Indexed: 11/16/2022]
Abstract
Stratification of colorectal cancer into subgroups with different response to therapy was initially guided by descriptive associations between specific biomarkers and treatment outcome. Recently, preclinical models based on propagatable patient-derived tumor samples have yielded an improved understanding of disease biology, which has facilitated the functional validation of correlative information and the discovery of novel response determinants, therapeutic targets, and mechanisms of tumor adaptation and drug resistance. We review the contribution of patient-derived models to advancing colorectal cancer characterization, discuss their influence on clinical decision-making, and highlight emerging challenges in the interpretation and clinical transferability of results obtainable with such approaches. SIGNIFICANCE: Association studies in patients with colorectal cancer have led to the identification of response biomarkers, some of which have been implemented as companion diagnostics for therapeutic decisions. By enabling biological investigation in a clinically relevant experimental context, patient-derived colorectal cancer models have proved useful to examine the causal role of such biomarkers in dictating drug sensitivity and are providing fresh knowledge on new actionable targets, dynamics of tumor evolution and adaptation, and mechanisms of drug resistance.
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Affiliation(s)
- Marco Avolio
- Department of Oncology, University of Torino, Candiolo, Torino, Italy.,Candiolo Cancer Institute - FPO IRCCS, Candiolo, Torino, Italy
| | - Livio Trusolino
- Department of Oncology, University of Torino, Candiolo, Torino, Italy. .,Candiolo Cancer Institute - FPO IRCCS, Candiolo, Torino, Italy
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21
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Carvalho B, Lopes JM, Silva R, Peixoto J, Leitão D, Soares P, Fernandes AC, Linhares P, Vaz R, Lima J. The role of c-Met and VEGFR2 in glioblastoma resistance to bevacizumab. Sci Rep 2021; 11:6067. [PMID: 33727583 PMCID: PMC7966794 DOI: 10.1038/s41598-021-85385-1] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Accepted: 02/24/2021] [Indexed: 02/06/2023] Open
Abstract
Dismal prognosis of glioblastoma (GBM) prompts for the identification of response predictors and therapeutic resistance mechanisms of current therapies. The authors investigated the impact of c-Met, HGF, VEGFR2 expression and microvessel density (MVD) in GBM patients submitted to second-line chemotherapy with bevacizumab. Immunohistochemical expression of c-Met, HGF, VEGFR2, and MVD was assessed in tumor specimens of GBM patients treated with bevacizumab, after progression under temozolomide. Survival analysis was evaluated according to the expression of the aforementioned biomarkers. c-Met overexpression was associated with a time-to-progression (TTP) after bevacizumab of 3 months (95% CI, 1.5-4.5) compared with a TTP of 7 months (95% CI, 4.6-9.4) in patients with low or no expression of c-Met (p = 0.05). VEGFR2 expression was associated with a TTP after bevacizumab of 3 months (95% CI, 1.8-4.2) compared with a TTP of 7 months (95% CI, 5.7-8.3) in patients with no tumoral expression of VEGFR2 (p = 0.009). Concomitant c-Met/VEGFR2 overexpression was associated with worse overall survival (13 months) compared with concomitant c-Met/VEGFR2 negative expression (19 months; p = 0.025). Our data support the hypothesis that c-Met and VEGFR2 overexpression have a role in the development of glioblastoma early resistance and might predict poorer responses to anti-angiogenic therapies.
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Affiliation(s)
- Bruno Carvalho
- Faculty of Medicine, University of Porto, Alameda Prof. Hernâni Monteiro, 4200-319, Porto, Portugal. .,Department of Neurosurgery, Centro Hospitalar Universitário S. João, Alameda Prof. Hernâni Monteiro, 4200-319, Porto, Portugal. .,Instituto de Investigação E Inovação Em Saúde (i3S), Porto, Portugal. .,Institute of Molecular Pathology and Immunology, University of Porto (Ipatimup), Porto, Portugal.
| | - José Manuel Lopes
- Faculty of Medicine, University of Porto, Alameda Prof. Hernâni Monteiro, 4200-319, Porto, Portugal.,Department of Pathology, Centro Hospitalar Universitário S. João, Alameda Prof. Hernâni Monteiro, 4200-319, Porto, Portugal.,Instituto de Investigação E Inovação Em Saúde (i3S), Porto, Portugal.,Institute of Molecular Pathology and Immunology, University of Porto (Ipatimup), Porto, Portugal
| | - Roberto Silva
- Faculty of Medicine, University of Porto, Alameda Prof. Hernâni Monteiro, 4200-319, Porto, Portugal.,Department of Pathology, Centro Hospitalar Universitário S. João, Alameda Prof. Hernâni Monteiro, 4200-319, Porto, Portugal
| | - Joana Peixoto
- Faculty of Medicine, University of Porto, Alameda Prof. Hernâni Monteiro, 4200-319, Porto, Portugal.,Instituto de Investigação E Inovação Em Saúde (i3S), Porto, Portugal.,Institute of Molecular Pathology and Immunology, University of Porto (Ipatimup), Porto, Portugal
| | - Dina Leitão
- Faculty of Medicine, University of Porto, Alameda Prof. Hernâni Monteiro, 4200-319, Porto, Portugal
| | - Paula Soares
- Faculty of Medicine, University of Porto, Alameda Prof. Hernâni Monteiro, 4200-319, Porto, Portugal.,Instituto de Investigação E Inovação Em Saúde (i3S), Porto, Portugal.,Institute of Molecular Pathology and Immunology, University of Porto (Ipatimup), Porto, Portugal
| | - Ana Catarina Fernandes
- Department of Oncology, Centro Hospitalar Universitário S. João, Alameda Prof. Hernâni Monteiro, 4200-319, Porto, Portugal
| | - Paulo Linhares
- Faculty of Medicine, University of Porto, Alameda Prof. Hernâni Monteiro, 4200-319, Porto, Portugal.,Department of Neurosurgery, Centro Hospitalar Universitário S. João, Alameda Prof. Hernâni Monteiro, 4200-319, Porto, Portugal.,Neurosciences Center-CUF Hospital, Estrada da Circunvalação 14341, 4100-180, Porto, Portugal
| | - Rui Vaz
- Faculty of Medicine, University of Porto, Alameda Prof. Hernâni Monteiro, 4200-319, Porto, Portugal.,Department of Neurosurgery, Centro Hospitalar Universitário S. João, Alameda Prof. Hernâni Monteiro, 4200-319, Porto, Portugal.,Neurosciences Center-CUF Hospital, Estrada da Circunvalação 14341, 4100-180, Porto, Portugal
| | - Jorge Lima
- Faculty of Medicine, University of Porto, Alameda Prof. Hernâni Monteiro, 4200-319, Porto, Portugal.,Instituto de Investigação E Inovação Em Saúde (i3S), Porto, Portugal.,Institute of Molecular Pathology and Immunology, University of Porto (Ipatimup), Porto, Portugal
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22
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Duco MR, Murdock JL, Reeves DJ. Vascular endothelial growth factor inhibitor induced hypertension: Retrospective analysis of the impact of blood pressure elevations on outcomes. J Oncol Pharm Pract 2021; 28:265-273. [PMID: 33430688 DOI: 10.1177/1078155220985915] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
BACKGROUND Vascular endothelial growth factor (VEGF) inhibitors are known to cause hypertension. The purpose of this study was to assess the impact of blood pressure (BP) elevations on outcomes in patients receiving VEGF inhibitors. METHODS This retrospective chart review analyzed patients receiving treatment with VEGF inhibitors. The primary endpoint was time to progression (TTP) in those with or without significant increase in BP (increase in systolic BP greater than 20 mm Hg or greater than 10 mm Hg increase in diastolic BP). Secondary endpoints included treatment interruption, therapy discontinuation due to documented adverse effect, and time to BP elevation. Subgroup analyses were completed in those receiving bevacizumab and oral tyrosine kinase inhibitors. RESULTS A total of 155 patients were included and 93 patients (60%) experienced a significant increase in BP. Median time to development of an elevated BP was 47 days. Patients with significant increases in BP had a longer median TTP compared to patients without (8.1 months vs 4.4 months, p = 0.002). No differences were present between groups in treatment interruption or discontinuation due to a documented adverse effect and outcomes were similar in those receiving bevacizumab and oral tyrosine kinase inhibitors. In the analysis of the impact of severity of BP elevations, those with severe BP elevations were more likely to have treatment interrupted but discontinuation rates were similar across groups. CONCLUSION Development of significant BP elevations may be a marker of therapeutic response to VEGF inhibitors and does not limit treatment duration, even in those with severe elevations.
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Affiliation(s)
- Marissa R Duco
- College of Pharmacy and Health Sciences, Butler University, Indianapolis, IN, USA
| | - Joshua L Murdock
- College of Pharmacy and Health Sciences, Butler University, Indianapolis, IN, USA
| | - David J Reeves
- College of Pharmacy and Health Sciences, Butler University, Indianapolis, IN, USA.,Franciscan Physician Network Oncology Hematology Specialists, Franciscan Health Indianapolis, Indianapolis, IN, USA
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23
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Osumi H, Shinozaki E, Ooki A, Wakatsuki T, Kamiimabeppu D, Sato T, Nakayama I, Ogura M, Takahari D, Chin K, Yamaguchi K. Early hypertension and neutropenia are predictors of treatment efficacy in metastatic colorectal cancer patients administered FOLFIRI and vascular endothelial growth factor inhibitors as second-line chemotherapy. Cancer Med 2021; 10:615-625. [PMID: 33347731 PMCID: PMC7877370 DOI: 10.1002/cam4.3638] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2020] [Revised: 11/11/2020] [Accepted: 11/16/2020] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Three vascular endothelial growth factor (VEGF) inhibitors, Bevacizumab (BEV), ramucirumab (RAM), and aflibercept (AFL), are widely used for metastatic colorectal cancer (mCRC) patients who are treated with second-line chemotherapy. The difference in outcome between the three drugs has not been evaluated. In contrast to epidermal growth factor receptor inhibitors, VEGF inhibitors have few candidate predictors of efficacy. METHODS Consecutive mCRC patients who were treated with second-line chemotherapy were retrospectively enrolled. Overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety were assessed. Subgroup analyses of prognostic and predictive efficacy markers were performed. RESULTS A total of 119 (41.2%), 107 (37.0%), and 63 patients (21.8%) were treated with FOLFIRI +BEV, RAM, or AFL, respectively. ORR, PFS, and OS showed no significant differences between three groups. However, the frequency of grade 3 or 4 adverse events (AEs) in the FOLFIRI +AFL group was significantly higher than that in the other groups (p < 0.001). Patients with grade 3 or 4 AEs, especially hypertension and neutropenia within the first four cycles of treatment had significantly longer PFS and OS than those without AEs, irrespective of treatment with VEGF inhibitors (p < 0.001). PFS in patients without prior BEV exposure was also significantly longer than that in patients with prior BEV exposure (p = 0.003). CONCLUSIONS Chemotherapeutic efficacy did not differ between the groups. Grade 3 or 4 AEs within the first four cycles of treatment and prior BEV exposure may be an effective predictor of treatment efficacy in mCRC patients administered VEGF inhibitors as second-line chemotherapy.
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Affiliation(s)
- Hiroki Osumi
- Department of GastroenterologyCancer Institute HospitalJapanese Foundation for Cancer ResearchTokyoJapan
| | - Eiji Shinozaki
- Department of GastroenterologyCancer Institute HospitalJapanese Foundation for Cancer ResearchTokyoJapan
| | - Akira Ooki
- Department of GastroenterologyCancer Institute HospitalJapanese Foundation for Cancer ResearchTokyoJapan
| | - Takeru Wakatsuki
- Department of GastroenterologyCancer Institute HospitalJapanese Foundation for Cancer ResearchTokyoJapan
| | - Daisaku Kamiimabeppu
- Department of GastroenterologyCancer Institute HospitalJapanese Foundation for Cancer ResearchTokyoJapan
| | - Taro Sato
- Department of GastroenterologyCancer Institute HospitalJapanese Foundation for Cancer ResearchTokyoJapan
| | - Izuma Nakayama
- Department of GastroenterologyCancer Institute HospitalJapanese Foundation for Cancer ResearchTokyoJapan
| | - Mariko Ogura
- Department of GastroenterologyCancer Institute HospitalJapanese Foundation for Cancer ResearchTokyoJapan
| | - Daisuke Takahari
- Department of GastroenterologyCancer Institute HospitalJapanese Foundation for Cancer ResearchTokyoJapan
| | - Keisho Chin
- Department of GastroenterologyCancer Institute HospitalJapanese Foundation for Cancer ResearchTokyoJapan
| | - Kensei Yamaguchi
- Department of GastroenterologyCancer Institute HospitalJapanese Foundation for Cancer ResearchTokyoJapan
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24
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Lu Y, Wu S, Cui C, Yu M, Wang S, Yue Y, Liu M, Sun Z. Gene Expression Along with Genomic Copy Number Variation and Mutational Analysis Were Used to Develop a 9-Gene Signature for Estimating Prognosis of COAD. Onco Targets Ther 2020; 13:10393-10408. [PMID: 33116619 PMCID: PMC7569059 DOI: 10.2147/ott.s255590] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2020] [Accepted: 08/19/2020] [Indexed: 12/13/2022] Open
Abstract
PURPOSE This study aims to systematically analyze multi-omics data to explore new prognosis biomarkers in colon adenocarcinoma (COAD). MATERIALS AND METHODS Multi-omics data of COAD and clinical information were obtained from The Cancer Genome Atlas (TCGA). Univariate Cox analysis was used to select genes which significantly related to the overall survival. GISTIC 2.0 software was used to identify significant amplification or deletion. Mutsig 2.0 software was used to identify significant mutation genes. The 9-gene signature was screened by random forest algorithm and Cox regression analysis. GSE17538 dataset was used as an external dataset to verify the predictive ability of 9-gene signature. qPCR was used to detect the expression of 9 genes in clinical specimens. RESULTS A total of 71 candidate genes are obtained by integrating genomic variation, mutation and prognostic data. Then, 9-gene signature was established, which includes HOXD12, RNF25, CBLN3, DOCK3, DNAJB13, PYGO2, CTNNA1, PTPRK, and NAT1. The 9-gene signature is an independent prognostic risk factor for COAD patients. In addition, the signature shows good predicting performance and clinical practicality in training set, testing set and external verification set. The results of qPCR based on clinical samples showed that the expression of HOXD12, RNF25, CBLN3, DOCK3, DNAJB13, and PYGO2 was increased in colon cancer tissues and the expression of CTNNA1, PTPRK, NAT1 was decreased in colon cancer tissues. CONCLUSION In this study, 9-gene signature is constructed as a new prognostic marker to predict the survival of COAD patients.
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Affiliation(s)
- Yiping Lu
- BioBank, The Affiliated Shengjing Hospital, China Medical University, Shenyang, Liaoning 110004, People's Republic of China
| | - Si Wu
- BioBank, The Affiliated Shengjing Hospital, China Medical University, Shenyang, Liaoning 110004, People's Republic of China
| | - Changwan Cui
- BioBank, The Affiliated Shengjing Hospital, China Medical University, Shenyang, Liaoning 110004, People's Republic of China
| | - Miao Yu
- BioBank, The Affiliated Shengjing Hospital, China Medical University, Shenyang, Liaoning 110004, People's Republic of China
| | - Shuang Wang
- BioBank, The Affiliated Shengjing Hospital, China Medical University, Shenyang, Liaoning 110004, People's Republic of China
| | - Yuanyi Yue
- BioBank, The Affiliated Shengjing Hospital, China Medical University, Shenyang, Liaoning 110004, People's Republic of China
| | - Miao Liu
- BioBank, The Affiliated Shengjing Hospital, China Medical University, Shenyang, Liaoning 110004, People's Republic of China
| | - Zhengrong Sun
- BioBank, The Affiliated Shengjing Hospital, China Medical University, Shenyang, Liaoning 110004, People's Republic of China
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25
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Izawa N, Shitara K, Yonesaka K, Yamanaka T, Yoshino T, Sunakawa Y, Masuishi T, Denda T, Yamazaki K, Moriwaki T, Okuda H, Kondoh C, Nishina T, Makiyama A, Baba H, Yamaguchi H, Nakamura M, Hyodo I, Muro K, Nakajima TE. Early Tumor Shrinkage and Depth of Response in the Second-Line Treatment for KRAS exon2 Wild-Type Metastatic Colorectal Cancer: An Exploratory Analysis of the Randomized Phase 2 Trial Comparing Panitumumab and Bevacizumab in Combination with FOLFIRI (WJOG6210G). Target Oncol 2020; 15:623-633. [PMID: 32960408 DOI: 10.1007/s11523-020-00750-w] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
BACKGROUND Predictive markers for the clinical outcomes of second-line treatment in patients with metastatic colorectal cancer (mCRC) remain unclear. OBJECTIVE This retrospective biomarker study was conducted to explore predictive markers for patients with KRAS exon 2 wild-type mCRC who were treated with FOLFIRI plus panitumumab (Pani) or bevacizumab (Bev) in the WJOG6210G trial. PATIENTS AND METHODS The associations of early tumor shrinkage (ETS), tumor location, and VEGF-D with progression-free survival (PFS) and overall survival (OS) were analyzed using a Cox proportional hazards model. Spearman's correlation coefficient was used to analyze the association of depth of response (DpR) with PFS and OS. Serum VEGF-D levels were measured in samples collected before treatment using magnetic bead panel Milliplex xMAP kits. RESULTS In total, 101 patients (Pani, n = 49; Bev, n = 52) were enrolled in this study. Patients with ETS had longer PFS (Pani: hazard ratio (HR) 0.40, P = 0.009; Bev: HR 0.078, P = 0.0002) and OS (Pani: HR 0.49, P = 0.044; Bev: HR 0.35, P = 0.048) than patients without ETS. The DpR was moderately correlated with PFS and OS in Pani (rs = 0.75, P < 0.001; rs = 0.60, P < 0.001) and Bev groups (rs = 0.68, P < 0.001; rs = 0.44, P = 0.002). No significant differences were observed in PFS and OS between the two treatment groups even if in left-sided tumors. No significant interaction between VEGF-D levels and treatment was observed in PFS and OS. CONCLUSIONS ETS and DpR serve as surrogate markers of PFS and OS in the second-line treatment with FOLFIRI plus targeted agent for mCRC.
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Affiliation(s)
- Naoki Izawa
- Department of Clinical Oncology, St. Marianna University School of Medicine, Kawasaki, Japan
| | - Kohei Shitara
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Kimio Yonesaka
- Department of Medical Oncology, Kindai University Faculty of Medicine, Osaka-sayama, Japan
| | - Takeharu Yamanaka
- Department of Biostatistics, Yokohama City University School of Medicine, Yokohama, Japan
| | - Takayuki Yoshino
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Yu Sunakawa
- Department of Clinical Oncology, St. Marianna University School of Medicine, Kawasaki, Japan
| | - Toshiki Masuishi
- Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya, Japan
| | - Tadamichi Denda
- Department of Gastroenterology, Chiba Cancer Center Hospital, Chiba, Japan
| | - Kentaro Yamazaki
- Division of Gastrointestinal Oncology, Shizuoka Cancer Center, Shimonagakubo, Japan
| | - Toshikazu Moriwaki
- Division of Gastroenterology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan
| | - Hiroyuki Okuda
- Department of Medical Oncology, Keiyukai Sapporo Hospital, Sapporo, Japan
| | - Chihiro Kondoh
- Department of Medical Oncology, Toranomon Hospital, Tokyo, Japan
| | - Tomohiro Nishina
- Department of Gastrointestinal Medical Oncology, National Hospital Organization Shikoku Cancer Center, Matsuyama, Japan
| | - Akitaka Makiyama
- Department of Hematology/Oncology, Japan Community Healthcare Organization Kyushu Hospital, Kita-Kyushu, Japan
- Cancer Center, Gifu University Hospital, Gifu, Japan
| | - Hideo Baba
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Hironori Yamaguchi
- Department of Gastrointestinal Surgery, Jichi Medical University, Shimotsuke, Japan
| | - Masato Nakamura
- Aizawa Comprehensive Cancer Center, Aizawa Hospital, Matsumoto, Japan
| | - Ichinosuke Hyodo
- Division of Gastroenterology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan
| | - Kei Muro
- Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya, Japan
| | - Takako Eguchi Nakajima
- Department of Clinical Oncology, St. Marianna University School of Medicine, Kawasaki, Japan.
- Kyoto Innovation Center for Next Generation Clinical Trials and iPS Cell Therapy (Ki-CONNECT), Kyoto University Hospital, 54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.
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26
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Aneuploid Circulating Tumor-Derived Endothelial Cell (CTEC): A Novel Versatile Player in Tumor Neovascularization and Cancer Metastasis. Cells 2020; 9:cells9061539. [PMID: 32599893 PMCID: PMC7349247 DOI: 10.3390/cells9061539] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2020] [Revised: 06/12/2020] [Accepted: 06/22/2020] [Indexed: 12/14/2022] Open
Abstract
Hematogenous and lymphogenous cancer metastases are significantly impacted by tumor neovascularization, which predominantly consists of blood vessel-relevant angiogenesis, vasculogenesis, vasculogenic mimicry, and lymphatic vessel-related lymphangiogenesis. Among the endothelial cells that make up the lining of tumor vasculature, a majority of them are tumor-derived endothelial cells (TECs), exhibiting cytogenetic abnormalities of aneuploid chromosomes. Aneuploid TECs are generated from “cancerization of stromal endothelial cells” and “endothelialization of carcinoma cells” in the hypoxic tumor microenvironment. Both processes crucially engage the hypoxia-triggered epithelial-to-mesenchymal transition (EMT) and endothelial-to-mesenchymal transition (EndoMT). Compared to the cancerization process, endothelialization of cancer cells, which comprises the fusion of tumor cells with endothelial cells and transdifferentiation of cancer cells into TECs, is the dominant pathway. Tumor-derived endothelial cells, possessing the dual properties of cancerous malignancy and endothelial vascularization ability, are thus the endothelialized cancer cells. Circulating tumor-derived endothelial cells (CTECs) are TECs shed into the peripheral circulation. Aneuploid CD31+ CTECs, together with their counterpart CD31- circulating tumor cells (CTCs), constitute a unique pair of cellular circulating tumor biomarkers. This review discusses a proposed cascaded framework that focuses on the origins of TECs and CTECs in the hypoxic tumor microenvironment and their clinical implications for tumorigenesis, neovascularization, disease progression, and cancer metastasis. Aneuploid CTECs, harboring hybridized properties of malignancy, vascularization and motility, may serve as a unique target for developing a novel metastasis blockade cancer therapy.
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27
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Indraccolo S, De Salvo GL, Verza M, Caccese M, Esposito G, Piga I, Del Bianco P, Pizzi M, Gardiman MP, Eoli M, Rudà R, Brandes AA, Ibrahim T, Rizzato S, Lolli I, Zagonel V, Lombardi G. Phosphorylated Acetyl-CoA Carboxylase Is Associated with Clinical Benefit with Regorafenib in Relapsed Glioblastoma: REGOMA Trial Biomarker Analysis. Clin Cancer Res 2020; 26:4478-4484. [PMID: 32518098 DOI: 10.1158/1078-0432.ccr-19-4055] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2019] [Revised: 04/21/2020] [Accepted: 06/05/2020] [Indexed: 11/16/2022]
Abstract
PURPOSE Preclinical studies show that antiangiogenic therapy exacerbates tumor glycolysis and activates liver kinase B1/AMP kinase (AMPK), a pathway involved in the regulation of tumor metabolism. We investigated whether certain metabolism-related in situ biomarkers could predict benefit to regorafenib in the phase II randomized REGOMA trial. PATIENTS AND METHODS IHC and digital pathology analysis were used to investigate the expression in glioblastoma (GBM) sections of monocarboxylate transporter 1 and 4 (MCT1 and MCT4), associated with OXPHOS and glycolysis, respectively, phosphorylated AMPK (pAMPK), and phosphorylated acetyl-CoA carboxylase (pACC), a canonical target of AMPK activity. The status of each biomarker was associated with clinical endpoints, including overall survival (OS) and progression-free survival (PFS) in patients with relapsed GBM treated either with regorafenib or lomustine. RESULTS Between November 2015 and February 2017, 119 patients were enrolled (n = 59 regorafenib and n = 60 lomustine) and stratified for surgery at recurrence, and baseline characteristics were balanced. Biomarker analysis was performed in 84 patients (71%), including 42 patients of the regorafenib arm and 42 patients of the lomustine arm. Among all markers analyzed, only pACC showed predictive value in terms of OS. In fact, median OS was 9.3 months [95% confidence interval (CI), 5.6-13.2] for regorafenib and 5.5 months (95% CI, 4.2-6.6) for lomustine for pACC-positive patients, HR, 0.37 (95% CI, 0.20-0.70); log rank P = 0.0013; test for interaction = 0.0453. No statistically significant difference was demonstrated for PFS according to pACC status. CONCLUSIONS We found that AMPK pathway activation is associated with clinical benefit from treatment with regorafenib in relapsed GBM.
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Affiliation(s)
- Stefano Indraccolo
- Immunology and Molecular Oncology Unit, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy.
| | - Gian Luca De Salvo
- Clinical Research Unit, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy
| | - Martina Verza
- Immunology and Molecular Oncology Unit, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy
| | - Mario Caccese
- Medical Oncology 1, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy
| | - Giovanni Esposito
- Immunology and Molecular Oncology Unit, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy
| | - Ilaria Piga
- Immunology and Molecular Oncology Unit, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy
| | - Paola Del Bianco
- Clinical Research Unit, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy
| | - Marco Pizzi
- Surgical Pathology and Cytopathology Unit, Department of Medicine-DIMED, University of Padova, Padova, Italy
| | - Marina Paola Gardiman
- Surgical Pathology and Cytopathology Unit, University Hospital of Padua, Padua, Italy
| | - Marica Eoli
- Molecular Neuro-Oncology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
| | - Roberta Rudà
- Department of Neuro-Oncology, University of Turin and City of Health and Science Hospital, Turin, Italy
| | - Alba Ariela Brandes
- Department of Medical Oncology, AUSL-IRCCS Scienze Neurologiche, Bologna, Italy
| | - Toni Ibrahim
- Osteoncology and Rare Tumors Center- Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy
| | - Simona Rizzato
- Department of Oncology, Azienda Sanitaria Universitaria Friuli Centrale, Udine, Italy
| | - Ivan Lolli
- Medical Oncology Unit-IRCCS Saverio de Bellis, Castellana Grotte, Bari, Italy
| | - Vittorina Zagonel
- Medical Oncology 1, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy
| | - Giuseppe Lombardi
- Medical Oncology 1, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy
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28
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Palmieri V, Lazaris A, Mayer TZ, Petrillo SK, Alamri H, Rada M, Jarrouj G, Park WY, Gao ZH, McDonald PP, Metrakos P. Neutrophils expressing lysyl oxidase-like 4 protein are present in colorectal cancer liver metastases resistant to anti-angiogenic therapy. J Pathol 2020; 251:213-223. [PMID: 32297656 DOI: 10.1002/path.5449] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2019] [Revised: 03/25/2020] [Accepted: 03/31/2020] [Indexed: 12/19/2022]
Abstract
Colorectal cancer liver metastases (CRCLM) that present with a replacement histopathological growth pattern (HGP) are resistant to neoadjuvant anti-angiogenic therapy. Surrogate biomarkers are not available to preoperatively identify patients with these tumors. Here we identify differentially expressed genes between CRCLM with a replacement HGP and those with a desmoplastic HGP using RNA sequencing. We demonstrate that LOXL4 is transcriptionally upregulated in replacement HGP CRCLM compared with desmoplastic HGP CRCLM and the adjacent normal liver. Interestingly, lysyl oxidase-like 4 (LOXL4) protein was expressed by neutrophils present in the tumor microenvironment in replacement HGP CRCLM. We further demonstrate that LOXL4 expression is higher in circulating neutrophils of cancer patients compared with healthy control patients and its expression can be induced by stimulation with lipopolysaccharide and TNF-α. Our study is the first to show the expression of LOXL4 in neutrophils and reveals the potential for LOXL4-expressing neutrophils to support the replacement HGP phenotype and to serve as a surrogate biomarker for this subtype of CRCLM. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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Affiliation(s)
| | - Anthoula Lazaris
- Research Institute of the McGill University Health Centre, Montreal, Canada
| | - Thomas Z Mayer
- Pulmonary Division, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Canada
| | | | - Hussam Alamri
- Department of Surgery, McGill University, Montreal, Canada
| | - Miran Rada
- Department of Surgery, McGill University, Montreal, Canada
| | - George Jarrouj
- Department of Anatomy and Cell Biology, McGill University, Montreal, Canada
| | - Woong-Yang Park
- Samsung Genome Institute, Samsung Medical Center, Seoul, Korea
| | - Zu-Hua Gao
- Research Institute of the McGill University Health Centre, Montreal, Canada
- Department of Pathology, McGill University, Montreal, Canada
| | - Patrick P McDonald
- Pulmonary Division, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Canada
| | - Peter Metrakos
- Research Institute of the McGill University Health Centre, Montreal, Canada
- Department of Surgery, McGill University, Montreal, Canada
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29
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Belardinilli F, Capalbo C, Malapelle U, Pisapia P, Raimondo D, Milanetti E, Yasaman M, Liccardi C, Paci P, Sibilio P, Pepe F, Bonfiglio C, Mezi S, Magri V, Coppa A, Nicolussi A, Gradilone A, Petroni M, Di Giulio S, Fabretti F, Infante P, Coni S, Canettieri G, Troncone G, Giannini G. Clinical Multigene Panel Sequencing Identifies Distinct Mutational Association Patterns in Metastatic Colorectal Cancer. Front Oncol 2020; 10:560. [PMID: 32457828 PMCID: PMC7221020 DOI: 10.3389/fonc.2020.00560] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2019] [Accepted: 03/27/2020] [Indexed: 12/12/2022] Open
Abstract
Extensive molecular characterization of human colorectal cancer (CRC) via Next Generation Sequencing (NGS) indicated that genetic or epigenetic dysregulation of a relevant, but limited, number of molecular pathways typically occurs in this tumor. The molecular picture of the disease is significantly complicated by the frequent occurrence of individually rare genetic aberrations, which expand tumor heterogeneity. Inter- and intratumor molecular heterogeneity is very likely responsible for the remarkable individual variability in the response to conventional and target-driven first-line therapies, in metastatic CRC (mCRC) patients, whose median overall survival remains unsatisfactory. Implementation of an extensive molecular characterization of mCRC in the clinical routine does not yet appear feasible on a large scale, while multigene panel sequencing of most commonly mutated oncogene/oncosuppressor hotspots is more easily achievable. Here, we report that clinical multigene panel sequencing performed for anti-EGFR therapy predictive purposes in 639 formalin-fixed paraffin-embedded (FFPE) mCRC specimens revealed previously unknown pairwise mutation associations and a high proportion of cases carrying actionable gene mutations. Most importantly, a simple principal component analysis directed the delineation of a new molecular stratification of mCRC patients in eight groups characterized by non-random, specific mutational association patterns (MAPs), aggregating samples with similar biology. These data were validated on a The Cancer Genome Atlas (TCGA) CRC dataset. The proposed stratification may provide great opportunities to direct more informed therapeutic decisions in the majority of mCRC cases.
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Affiliation(s)
| | - Carlo Capalbo
- Department of Molecular Medicine, University La Sapienza, Rome, Italy
| | | | - Pasquale Pisapia
- Department of Public Health, University Federico II, Naples, Italy
| | - Domenico Raimondo
- Department of Molecular Medicine, University La Sapienza, Rome, Italy
| | | | - Mahdavian Yasaman
- Department of Molecular Medicine, University La Sapienza, Rome, Italy
| | - Carlotta Liccardi
- Department of Molecular Medicine, University La Sapienza, Rome, Italy
| | - Paola Paci
- Institute for System Analysis and Computer Science "Antonio Ruberti", National Research Council, Rome, Italy
| | - Pasquale Sibilio
- Institute for System Analysis and Computer Science "Antonio Ruberti", National Research Council, Rome, Italy
| | - Francesco Pepe
- Department of Public Health, University Federico II, Naples, Italy
| | - Caterina Bonfiglio
- National Institute of Gastroenterology-Research Hospital, IRCCS "S. de Bellis", Bari, Italy
| | - Silvia Mezi
- Department of Radiological Oncological and Pathological Sciences, University La Sapienza, Rome, Italy
| | - Valentina Magri
- Department of Surgery Pietro Valdoni, Faculty of Medicine and Dentistry, Sapienza University of Rome, Rome, Italy
| | - Anna Coppa
- Department of Experimental Medicine, University La Sapienza, Rome, Italy
| | - Arianna Nicolussi
- Department of Experimental Medicine, University La Sapienza, Rome, Italy
| | - Angela Gradilone
- Department of Molecular Medicine, University La Sapienza, Rome, Italy
| | - Marialaura Petroni
- Center for Life Nano Science@Sapienza, Istituto Italiano di Tecnologia, Rome, Italy
| | - Stefano Di Giulio
- Department of Molecular Medicine, University La Sapienza, Rome, Italy
| | | | - Paola Infante
- Center for Life Nano Science@Sapienza, Istituto Italiano di Tecnologia, Rome, Italy
| | - Sonia Coni
- Department of Molecular Medicine, University La Sapienza, Rome, Italy
| | - Gianluca Canettieri
- Department of Molecular Medicine, University La Sapienza, Rome, Italy.,Pasteur Institute-Cenci Bolognetti Foundation, Rome, Italy
| | | | - Giuseppe Giannini
- Department of Molecular Medicine, University La Sapienza, Rome, Italy.,Pasteur Institute-Cenci Bolognetti Foundation, Rome, Italy
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30
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El Kaffas A, Hoogi A, Zhou J, Durot I, Wang H, Rosenberg J, Tseng A, Sagreiya H, Akhbardeh A, Rubin DL, Kamaya A, Hristov D, Willmann JK. Spatial Characterization of Tumor Perfusion Properties from 3D DCE-US Perfusion Maps are Early Predictors of Cancer Treatment Response. Sci Rep 2020; 10:6996. [PMID: 32332790 PMCID: PMC7181711 DOI: 10.1038/s41598-020-63810-1] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2019] [Accepted: 03/26/2020] [Indexed: 02/08/2023] Open
Abstract
There is a need for noninvasive repeatable biomarkers to detect early cancer treatment response and spare non-responders unnecessary morbidities and costs. Here, we introduce three-dimensional (3D) dynamic contrast enhanced ultrasound (DCE-US) perfusion map characterization as inexpensive, bedside and longitudinal indicator of tumor perfusion for prediction of vascular changes and therapy response. More specifically, we developed computational tools to generate perfusion maps in 3D of tumor blood flow, and identified repeatable quantitative features to use in machine-learning models to capture subtle multi-parametric perfusion properties, including heterogeneity. Models were developed and trained in mice data and tested in a separate mouse cohort, as well as early validation clinical data consisting of patients receiving therapy for liver metastases. Models had excellent (ROC-AUC > 0.9) prediction of response in pre-clinical data, as well as proof-of-concept clinical data. Significant correlations with histological assessments of tumor vasculature were noted (Spearman R > 0.70) in pre-clinical data. Our approach can identify responders based on early perfusion changes, using perfusion properties correlated to gold-standard vascular properties.
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Affiliation(s)
- Ahmed El Kaffas
- Department of Radiology, Molecular Imaging Program at Stanford, School of Medicine, Stanford University, Stanford, CA, USA. .,Department of Radiology, Integrative Biomedical Imaging Informatics at Stanford, School of Medicine, Stanford University, Stanford, CA, USA. .,Department of Radiology, Body Imaging, Stanford University, Stanford, CA, USA.
| | - Assaf Hoogi
- Department of Radiology, Integrative Biomedical Imaging Informatics at Stanford, School of Medicine, Stanford University, Stanford, CA, USA
| | - Jianhua Zhou
- Department of Radiology, Molecular Imaging Program at Stanford, School of Medicine, Stanford University, Stanford, CA, USA
| | - Isabelle Durot
- Department of Radiology, Molecular Imaging Program at Stanford, School of Medicine, Stanford University, Stanford, CA, USA
| | - Huaijun Wang
- Department of Radiology, Molecular Imaging Program at Stanford, School of Medicine, Stanford University, Stanford, CA, USA
| | - Jarrett Rosenberg
- Department of Radiology, Molecular Imaging Program at Stanford, School of Medicine, Stanford University, Stanford, CA, USA
| | - Albert Tseng
- Department of Radiology, Molecular Imaging Program at Stanford, School of Medicine, Stanford University, Stanford, CA, USA
| | - Hersh Sagreiya
- Department of Radiology, Integrative Biomedical Imaging Informatics at Stanford, School of Medicine, Stanford University, Stanford, CA, USA
| | - Alireza Akhbardeh
- Department of Radiology, Integrative Biomedical Imaging Informatics at Stanford, School of Medicine, Stanford University, Stanford, CA, USA
| | - Daniel L Rubin
- Department of Radiology, Integrative Biomedical Imaging Informatics at Stanford, School of Medicine, Stanford University, Stanford, CA, USA
| | - Aya Kamaya
- Department of Radiology, Molecular Imaging Program at Stanford, School of Medicine, Stanford University, Stanford, CA, USA.,Department of Radiology, Body Imaging, Stanford University, Stanford, CA, USA
| | - Dimitre Hristov
- Department of Radiation Oncology, School of Medicine, Stanford University, Stanford, CA, USA
| | - Jürgen K Willmann
- Department of Radiology, Molecular Imaging Program at Stanford, School of Medicine, Stanford University, Stanford, CA, USA.,Department of Radiology, Body Imaging, Stanford University, Stanford, CA, USA
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31
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Rezvani H, Mortazavizadeh SM, Allahyari A, Nekuee A, Najafi SN, Vahidfar M, Ghadyani M, Khosravi A, Qarib S, Sadeghi A, Esfandbod M, Rajaeinejad M, Rezvani A, Hajiqolami A, Payandeh M, Shazad B, Anjidani N, Meskinimood S, Alikhasi A, Karbalaeian M, Salari S. Efficacy and Safety of Proposed Bevacizumab Biosimilar BE1040V in Patients With Metastatic Colorectal Cancer: A Phase III, Randomized, Double-blind, Noninferiority Clinical Trial. Clin Ther 2020; 42:848-859. [PMID: 32334845 DOI: 10.1016/j.clinthera.2020.03.009] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2019] [Revised: 12/30/2019] [Accepted: 03/16/2020] [Indexed: 01/04/2023]
Abstract
PURPOSE The purpose of this study was to compare the efficacy and safety of a proposed bevacizumab biosimilar to those of the reference product in patients with metastatic colorectal cancer (mCRC). METHODS This Phase III, multicenter, randomized, double-blind (patient- and assessor-blind), active-controlled, 2-armed, parallel-group, noninferiority trial was conducted in patients with histologically verified colorectal cancer with evidence of at least 1 metastasis. Patients with mCRC were randomized 2:1 to receive 5 mg/kg IV of either study drug plus FOLFIRI-3 (with repeated irinotecan 100 mg/m2 60-min infusion on day 3) or the reference drug plus FOLFIRI-3 every 2 weeks for 1 year. Progression-free survival (PFS) was the primary end point, and overall survival, objective response rate, and time to treatment failure as well as safety and immunogenicity were secondary end points. The population assessable for PFS was per protocol, and the intention-to-treat population was used for sensitivity analysis. Safety was assessed based on reports of adverse events, laboratory test results, and vital sign measurements. FINDINGS A total of 126 patients were enrolled; PFS values in the biosimilar and reference arms were 232 days (7.7 months) and 210 days (7 months), respectively (P = 0.47). The hazard ratio of the biosimilar arm versus the reference arm was 0.79 in the per-protocol population (90% CI, 0.46-1.35; P = 0.47). The upper limit for the 2-sided 90% CI was lower than the margin of 1.44, indicating that the biosimilar drug was noninferior to the reference drug. The hazard ratio for overall survival in the intent-to-treat population was 0.99 (95% CI, 0.55-1.80; P = 0.99). The difference between other efficacy end points among the groups was not statistically significant. No significant difference was observed in the comparison of the two arms for safety. The antidrug antibody was positive in 1 patient in each arm. IMPLICATIONS The proposed biosimilar BE1040V was noninferior to the reference product in terms of efficacy in the treatment of mCRC, and tolerability was comparable between the 2 drugs. ClinicalTrials.gov identifier: NCT03288987.
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Affiliation(s)
- Hamid Rezvani
- Department of Medical Oncology, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | | | - Abolghasem Allahyari
- Division of Hematology and Medical Oncology, Emam Reza Hospital, Mashhad University of Medical Sciences, Mashhad, Iran
| | | | | | | | - Mojtaba Ghadyani
- Taleghani Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Adnan Khosravi
- Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Siroos Qarib
- Razi Hospital, Guilan University of Medical Sciences, Rasht, Iran
| | | | - Mohsen Esfandbod
- Hematology-Oncology and Stem Cell Transplantation Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | | | | | | | | | - Babak Shazad
- Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Nassim Anjidani
- Head of Medical Department, OrchidPharmed Company, Tehran, Iran
| | - Shahab Meskinimood
- Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Afsaneh Alikhasi
- Department of Radiology, Cancer Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Moein Karbalaeian
- Division of General Medicine of Medical School of Shaheed Sadoughi Medical School of Yazd University, Yazd, Iran
| | - Sina Salari
- Department of Medical Oncology, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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Caballero-Huertas M, Moraleda-Prados J, Joly S, Ribas L. Immune genes, IL1β and Casp9, show sexual dimorphic methylation patterns in zebrafish gonads. FISH & SHELLFISH IMMUNOLOGY 2020; 97:648-655. [PMID: 31830572 DOI: 10.1016/j.fsi.2019.12.013] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/02/2019] [Revised: 12/04/2019] [Accepted: 12/08/2019] [Indexed: 06/10/2023]
Abstract
There is crosstalk between the immune and reproductive systems in which sexual dimorphism is a common pattern in vertebrates. In recent years, epigenetics has emerged as a way to study the molecular mechanisms involved in gonadal development, those responsible for integrating environmental information that contribute to assigning a specific sexual phenotype (either an ovary or a testis). The knowledge of epigenetic mechanisms in certain molecular processes allows the development of epigenetic markers. In fish gonads, the existence of reproduction-immune system interactions is known, although the epigenetic mechanisms involved are far from clear. Here, we used the zebrafish (Danio rerio) as a model to study the DNA methylation patterns in gonads of two well-known innate immune genes: IL1β and Casp9. DNA methylation levels were studied by a candidate gene approach at single nucleotide resolution and gene expression analyses were also carried out. Results showed that there was clear sexual dimorphism in the DNA methylation levels of the two immune genes studied, being significantly higher in the testes when compared to the ovaries. In summary, and although further research is needed, this paper presents sexual dimorphic methylation patterns of two immune-related genes, thus sex-biased differences in methylation profiles should considered when analyzing immune responses in fish. Data showed here can help to develop epimarkers with forthcoming applications in livestock and fish farming production, for example, in immune fish diseases or sexual control programs as epigenetic molecular tools to predict environmental pressure in the gonads.
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Affiliation(s)
- M Caballero-Huertas
- Institute of Marine Sciences, Spanish National Research Council (ICM-CSIC), Passeig Marítim de la Barceloneta, 37-49, 08003, Barcelona, Spain
| | - J Moraleda-Prados
- Institute of Marine Sciences, Spanish National Research Council (ICM-CSIC), Passeig Marítim de la Barceloneta, 37-49, 08003, Barcelona, Spain
| | - S Joly
- Institute of Marine Sciences, Spanish National Research Council (ICM-CSIC), Passeig Marítim de la Barceloneta, 37-49, 08003, Barcelona, Spain
| | - L Ribas
- Institute of Marine Sciences, Spanish National Research Council (ICM-CSIC), Passeig Marítim de la Barceloneta, 37-49, 08003, Barcelona, Spain.
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Karn T, Meissner T, Weber KE, Solbach C, Denkert C, Engels K, Fasching PA, Sinn BV, Schrader I, Budczies J, Marmé F, Müller V, Holtrich U, Gerber B, Schem C, Young BM, Hanusch C, Stickeler E, Huober J, van Mackelenbergh M, Leyland-Jones B, Fehm T, Nekljudova V, Untch M, Loibl S. A Small Hypoxia Signature Predicted pCR Response to Bevacizumab in the Neoadjuvant GeparQuinto Breast Cancer Trial. Clin Cancer Res 2020; 26:1896-1904. [PMID: 31932495 DOI: 10.1158/1078-0432.ccr-19-1954] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2019] [Revised: 11/19/2019] [Accepted: 01/08/2020] [Indexed: 11/16/2022]
Abstract
PURPOSE In breast cancer, bevacizumab increased pCR rate but not long-term survival and no predictive markers are available to identify patients with long-term benefit from the drug. EXPERIMENTAL DESIGN We profiled 289 pretherapeutic formalin-fixed, paraffin-embedded (FFPE) biopsies of HER2-negative patients from the GeparQuinto trial of neoadjuvant chemotherapy ± bevacizumab by exome-capture RNA-sequencing (RNA-seq). In a prospectively planned study, we tested molecular signatures for response prediction. IHC validation was performed using tissue microarrays. RESULTS We found strong agreement of molecular and pathologic parameters as hormone receptors, grading, and lymphocyte infiltration in 221 high-quality samples. Response rates (49.3% pCR overall) were higher in basal-like (68.9%) and HER2-enriched (45.5%) than in luminal B (35.7%), luminal A (17.9%), and normal-like (20.0%) subtypes. T-cell (OR = 1.60; 95% confidence interval, 1.21-2.12; P = 0.001), proliferation (OR = 2.88; 95% CI, 2.00-4.15; P < 0.001), and hypoxia signatures (OR = 1.92; 95% CI, 1.41-2.60; P < 0.001) significantly predicted pCR in univariate analysis. In a prespecified multivariate logistic regression, a small hypoxia signature predicted pCR (OR = 2.40; 95% CI, 1.28-4.51; P = 0.006) with a significant interaction with bevacizumab treatment (P = 0.020). IHC validation using NDRG1 as marker revealed highly heterogenous expression within tissue leading to profound loss of sensitivity in TMA analysis, still a significant predictive value for pCR was detected (P = 0.025). CONCLUSIONS Exome-capture RNA-seq characterizes small FFPE core biopsies by reliably detecting factors as for example ER status, grade, and tumor-infiltrating lymphocytes levels. Beside molecular subtypes and immune signatures, a small hypoxia signature predicted pCR to bevacizumab, which could be validated by IHC. The signature can have important applications for bevacizumab treatment in different cancer types and might also have a role for novel combination therapies of bevacizumab with immune checkpoint inhibition.
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Affiliation(s)
- Thomas Karn
- Goethe University Hospital Frankfurt, Frankfurt, Germany.
| | | | | | | | | | - Knut Engels
- Goethe University Hospital Frankfurt, Frankfurt, Germany
| | - Peter A Fasching
- Department of Gynecology and Obstetrics, University Hospital Erlangen, Comprehensive Cancer Center Erlangen-EMN, Friedrich-Alexander University Erlangen-Nuremberg, Germany
| | | | - Iris Schrader
- Gynäkologisch-Onkologische Praxis Hannover, Hannover, Germany
| | | | | | - Volkmar Müller
- University Hospital Hamburg-Eppendorf, Hamburg-Eppendorf, Germany
| | - Uwe Holtrich
- Goethe University Hospital Frankfurt, Frankfurt, Germany
| | | | | | | | | | | | | | | | | | - Tanja Fehm
- University Hospital Tübingen, Tübingen, Germany
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Balikova I, Postelmans L, Pasteels B, Coquelet P, Catherine J, Efendic A, Hosoda Y, Miyake M, Yamashiro K, Thienpont B, Lambrechts D. Genetic biomarkers in the VEGF pathway predicting response to anti-VEGF therapy in age-related macular degeneration. BMJ Open Ophthalmol 2019; 4:e000273. [PMID: 31909188 PMCID: PMC6936450 DOI: 10.1136/bmjophth-2019-000273] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2019] [Revised: 10/18/2019] [Accepted: 11/11/2019] [Indexed: 11/17/2022] Open
Abstract
OBJECTIVE Age-related macular degeneration (ARMD) is a leading cause of visual impairment. Intravitreal injections of anti-vascular endothelial growth factor (VEGF) are the standard treatment for wet ARMD. There is however, variability in patient responses, suggesting patient-specific factors influencing drug efficacy. We tested whether single nucleotide polymorphisms (SNPs) in genes encoding VEGF pathway members contribute to therapy response. METHODS AND ANALYSIS A retrospective cohort of 281 European wet ARMD patients treated with anti-VEGF was genotyped for 138 tagging SNPs in the VEGF pathway. Per patient, we collected best corrected visual acuity at baseline, after three loading injections and at 12 months. We also registered the injection number and changes in retinal morphology after three loading injections (central foveal thickness (CFT), intraretinal cysts and serous neuroepithelium detachment). Changes in CFT after 3 months were our primary outcome measure. Association of SNPs to response was assessed by binomial logistic regression. Replication was attempted by associating visual acuity changes to genotypes in an independent Japanese cohort. RESULTS Association with treatment response was detected for seven SNPs, including in FLT4 (rs55667289: OR=0.746, 95% CI 0.63 to 0.88, p=0.0005) and KDR (rs7691507: OR=1.056, 95% CI 1.02 to 1.10, p=0.005; and rs2305945: OR=0.963, 95% CI 0.93 to 1.00, p=0.0472). Only association with rs55667289 in FLT4 survived multiple testing correction. This SNP was unavailable for testing in the replication cohort. Of six SNPs tested for replication, one was significant although not after multiple testing correction. CONCLUSION Identifying genetic variants that define treatment response can help to develop individualised therapeutic approaches for wet ARMD patients and may point towards new targets in non-responders.
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Affiliation(s)
- Irina Balikova
- Department of
Ophthalmology, Ghent University Hospital, Ghent
University, Ghent,
Belgium
- Ophthalmology, University Hospital Brugmann, Université
Libre de Bruxelles, Brussels,
Belgium
| | - Laurence Postelmans
- Ophthalmology, University Hospital Brugmann, Université
Libre de Bruxelles, Brussels,
Belgium
| | - Brigitte Pasteels
- Ophthalmology, University Hospital Brugmann, Université
Libre de Bruxelles, Brussels,
Belgium
| | - Pascale Coquelet
- Ophthalmology, University Hospital Brugmann, Université
Libre de Bruxelles, Brussels,
Belgium
| | - Janet Catherine
- Ophthalmology, University Hospital Brugmann, Université
Libre de Bruxelles, Brussels,
Belgium
| | - Azra Efendic
- Ophthalmology, University Hospital Brugmann, Université
Libre de Bruxelles, Brussels,
Belgium
| | - Yoshikatsu Hosoda
- Department of
Ophthalmology and Visual Sciences, Kyoto University Graduate
School of Medicine, Kyoto,
Japan
| | - Masahiro Miyake
- Department of
Ophthalmology and Visual Sciences, Kyoto University Graduate
School of Medicine, Kyoto,
Japan
| | - Kenji Yamashiro
- Department of
Ophthalmology and Visual Sciences, Kyoto University Graduate
School of Medicine, Kyoto,
Japan
- Department of
Ophthalmology, Otsu Red Cross Hospital,
Otsu, Japan
| | | | - Bernard Thienpont
- Laboratory of
Translational Genetics, Department of Human Genetics, KU
Leuven, Leuven,
Belgium
- Laboratory of Functional
Epigenetics, Department of Human Genetics, KU
Leuven, Leuven,
Belgium
| | - Diether Lambrechts
- Laboratory of
Translational Genetics, Department of Human Genetics, KU
Leuven, Leuven,
Belgium
- VIB Center for Cancer Biology,
Leuven, Belgium
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Chen WZ, Jiang JX, Yu XY, Xia WJ, Yu PX, Wang K, Zhao ZY, Chen ZG. Endothelial cells in colorectal cancer. World J Gastrointest Oncol 2019; 11:946-956. [PMID: 31798776 PMCID: PMC6883186 DOI: 10.4251/wjgo.v11.i11.946] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2019] [Revised: 08/18/2019] [Accepted: 09/26/2019] [Indexed: 02/05/2023] Open
Abstract
The dependence of tumor growth on neovascularization has become an important aspect of cancer biology. Tumor angiogenesis is one of the key mechanisms of tumorigenesis, growth and metastasis. The key events involved in this process are endothelial cell proliferation, migration, and vascular formation. Recent studies have revealed the importance of tumor-associated endothelial cells (TECs) in the development and progression of colorectal cancer (CRC), including epithelial proliferation, stem cell maintenance, angiogenesis, and immune remodeling. Decades of research have identified that the molecular basis of tumor angiogenesis includes vascular endothelial growth factors (VEGFs) and their receptor family, which are the main targets of antiangiogenesis therapy. VEGFs and their receptors play key roles in the pathology of angiogenesis, and their overexpression indicates poor prognosis in CRC. This article reviews the characteristics of the tumor vasculature and the role of TECs in different stages of CRC and immune remodeling. We also discuss the biological effects of VEGFs and their receptor family as angiogenesis regulators and emphasize the clinical implications of TECs in clinical treatment.
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Affiliation(s)
- Wu-Zhen Chen
- Department of Surgical Oncology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310000, Zhejiang Province, China
- Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, Hangzhou, China
| | - Jing-Xin Jiang
- Department of Surgical Oncology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310000, Zhejiang Province, China
- Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, Hangzhou, China
| | - Xiu-Yan Yu
- Department of Surgical Oncology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310000, Zhejiang Province, China
- Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, Hangzhou, China
| | - Wen-Jie Xia
- Department of Breast Surgery, Zhejiang Provincial People’s Hospital, Hangzhou 310000, Zhejiang Province, China
| | - Peng-Xin Yu
- Department of Surgical Oncology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310000, Zhejiang Province, China
- Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, Hangzhou, China
| | - Ke Wang
- Department of Surgical Oncology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310000, Zhejiang Province, China
- Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, Hangzhou, China
| | - Zhi-Yong Zhao
- Department of Administrative Office, the First People’s Hospital of Jiande, Hangzhou 310000, Zhejiang Province, China
| | - Zhi-Gang Chen
- Department of Surgical Oncology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310000, Zhejiang Province, China
- Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, Hangzhou, China
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Perez IE, Taveras Alam S, Hernandez GA, Sancassani R. Cancer Therapy-Related Cardiac Dysfunction: An Overview for the Clinician. CLINICAL MEDICINE INSIGHTS-CARDIOLOGY 2019; 13:1179546819866445. [PMID: 31384135 PMCID: PMC6664629 DOI: 10.1177/1179546819866445] [Citation(s) in RCA: 115] [Impact Index Per Article: 19.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2019] [Accepted: 07/02/2019] [Indexed: 12/28/2022]
Abstract
Cancer therapy-related cardiac dysfunction (CTRCD) is one of the most feared and
undesirable side effects of chemotherapy, occurring in approximately 10% of the
patients. It can be classified as direct (dose-dependent vs dose-independent) or
indirect, either case being potentially permanent or reversible. Risk
assessment, recognition, and prevention of CTRCD are crucial.
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Affiliation(s)
- Irving E Perez
- Department of Cardiovascular Disease, Jackson Memorial Hospital, University of Miami Hospital, Miami, FL, USA
| | - Sara Taveras Alam
- Section of Hematology-Oncology, Department of Medicine, Baylor College of Medicine, Houston, TX, USA
| | - Gabriel A Hernandez
- Department of Cardiovascular Disease, Jackson Memorial Hospital, University of Miami Hospital, Miami, FL, USA
| | - Rhea Sancassani
- Department of Cardiovascular Disease, Jackson Memorial Hospital, University of Miami Hospital, Miami, FL, USA
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37
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Yeung AWK, Abdel-Daim MM, Abushouk AI, Kadonosono K. A literature analysis on anti-vascular endothelial growth factor therapy (anti-VEGF) using a bibliometric approach. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2019; 392:393-403. [PMID: 30826857 DOI: 10.1007/s00210-019-01629-y] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/15/2018] [Accepted: 02/06/2019] [Indexed: 12/24/2022]
Abstract
We performed the current study to assess the citation performance of research works on anti-vascular endothelial growth factor (anti-VEGF) therapy. We searched Web of Science (WoS) to identify relevant publications and analyze them with reference to their publication year, journal title, citation count, WoS category, and article type. The bibliometric software (VOSviewer) was used for citation analyses of countries and journals and to generate a term map that visualizes the recurring terms appearing in the titles and abstracts of published articles. The literature search resulted in 7364 articles, with a mean citation count of 26.2. Over half of them (50.2%) were published during the past 5 years. Original articles constituted the majority (67.8%). The publications were mainly classified into WoS categories of ophthalmology (43.2%) and oncology (20.6%). The most prolific ophthalmology and cancer journals were Investigative Ophthalmology & Visual Science (7.3%) and Cancer Research (1.4%), respectively. The correlation between journal impact factor and citation count was weak to moderate (for journals with impact factor up to 5 and 10, respectively), and open-access articles had significantly more citations than non-open-access articles (p < 0.001). The frequently targeted tumors by anti-VEGF therapy included metastatic colorectal cancer (196; 49.2 citations per article (CPA)), breast cancers (167; 37.2 CPA), and renal cell carcinoma (122; 38.2 CPA). The frequently targeted eye pathologies were age-related macular degeneration (828; 18.2 CPA), diabetic macular edema (466; 10.8 CPA), and diabetic retinopathy (358; 31.9 CPA). These results indicate that anti-VEGF therapy has a wide range of applications and its publications are highly cited.
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Affiliation(s)
- Andy Wai Kan Yeung
- Oral and Maxillofacial Radiology, Applied Oral Sciences, Faculty of Dentistry, The University of Hong Kong, Hong Kong S.A.R., China.
| | - Mohamed M Abdel-Daim
- Pharmacology Department, Faculty of Veterinary Medicine, Suez Canal University, Ismailia, 41522, Egypt.
- Department of Ophthalmology and Micro-Technology, Yokohama City University, Yokohama, Japan.
| | | | - Kazuaki Kadonosono
- Department of Ophthalmology and Micro-Technology, Yokohama City University, Yokohama, Japan
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Efficacy and Safety of Neoadjuvant Treatment with Bevacizumab, Liposomal Doxorubicin, Cyclophosphamide and Paclitaxel Combination in Locally/Regionally Advanced, HER2-Negative, Grade III at Premenopausal Status Breast Cancer: A Phase II Study. Clin Drug Investig 2019; 38:639-648. [PMID: 29744672 DOI: 10.1007/s40261-018-0655-z] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
BACKGROUND In the era of personalized therapy, targeted treatment in specific patient populations is mandated. OBJECTIVE We evaluated the efficacy and safety of neoadjuvant treatment on locally advanced breast cancer (LABC) with a monoclonal agent against vascular endothelial growth factor (VEGF), bevacizumab plus chemotherapy combination of liposomal doxorubicin, cyclophosphamide and paclitaxel (PLAC-B). METHODS Patients enrolled were at premenopausal status and characterized by human epidermal growth factor receptor 2 (HER2)-negative, hormone-receptor positive (estrogen receptor/progesterone receptor-positive [ER/PR+]) or triple-negative (TNBC), LABC (T > 3 cm), with high-grade ductal carcinoma. Patients had to have a measurable disease and Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0, with adequate hematologic, renal, and hepatic function. Patients received intravenous liposomal doxorubicin 30 mg/m2, cyclophosphamide 600 mg/m2, paclitaxel 120 mg/m2, and bevacizumab 8 mg/kg on day 1 of 15-day cycles for four cycles (four administrations as neoadjuvant treatment). The primary endpoint was complete clinical (cCR) and pathologic (pCR) response rates, while secondary endpoints included safety, breast-conserving surgery (BCS) conversion rate, and disease-free survival (DFS). RESULTS Sixty-two women were enrolled; 20 were ER/PR+ and 42 had TNBC. All underwent surgery, six received mastectomy, and 56 (90.3%) received BCS, with an equal conversion rate from initial indication for mastectomy. cCR was 25.8%. pCR in the breast and axilla occurred in 24 patients (38.7%). pCR was 42.9% for TNBC and 30% for ER/PR+. Hematologic adverse events (AEs) included neutropenia (74.2% total; 22.6% grade 3 [G3]) and febrile neutropenia (6.5% G3); non-hematologic G3 AEs included nausea (6.5%), mucositis (9.7%), and infection (3.2%), all of which were managed without negative sequelae. Over a 3-year follow-up, all patients were alive and DFS was 87.1%. CONCLUSION PLAC-B as neoadjuvant treatment of this subpopulation with TNBC and ER/PR+ patients is effective and safe. Further studies are necessitated.
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Hacker U, Lordick F. Anti-angiogenics in Gastroesophageal Cancer. TUMOR ANGIOGENESIS 2019:395-414. [DOI: 10.1007/978-3-319-33673-2_17] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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40
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Sánchez Ramírez J, Bequet-Romero M, Morera Díaz Y, Hernández-Bernal F, de la Torre Santos A, Selman-Housein Bernal KH, Martín Bauta Y, Bermúdez Badell CH, Limonta Fernández M, Ayala Avila M. Evaluation of methodologies to determine the effect of specific active immunotherapy on VEGF levels in phase I clinical trial patients with advanced solid tumors. Heliyon 2018; 4:e00906. [PMID: 30426104 PMCID: PMC6223189 DOI: 10.1016/j.heliyon.2018.e00906] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2018] [Revised: 08/16/2018] [Accepted: 10/29/2018] [Indexed: 02/07/2023] Open
Abstract
Two phase I clinical trials were conducted to evaluate, among other parameters, the humoral response elicited by a vascular endothelial growth factor (VEGF)-based therapeutic vaccine in cancer patients with advanced solid tumors. VEGF reduction was studied using an indirect methodology named as “Platelet VEGF”. This methodology is based on the estimation of VEGF within platelets by subtracting the plasma VEGF level from the serum level and dividing this by the platelet count, and then this latter expression is additionally corrected by the hematocrit. However, there is broad debate, whether serum or plasma VEGF or platelet-derived VEGF measurements is the most appropriate strategy to study the changes that occur on ligand bioavailability when patients are submitted to a VEGF-based immunotherapy. The current research is a retrospective study evaluating the changes on VEGF levels in serum and plasma as well as platelet-derived measurements. Changes in VEGF levels were related with the humoral response seen in cancer patients after an active immunotherapy with a VEGF-based vaccine. The present study indicates that “Platelet VEGF” is the most reliable methodology to investigate the effect of VEGF-based immunotherapies on ligand bioavailability. “Platelet VEGF” was associated with those groups of individuals that exhibited the best specific humoral response and the variation of “Platelet VEGF” showed the strongest negative correlation with VEGF-specific IgG antibody levels. This methodology will be very useful for the investigation of this VEGF-based vaccine in phase II clinical trials and could be applied to immunotherapies directed to other growth factors that are actively sequestered by platelets.
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Affiliation(s)
- Javier Sánchez Ramírez
- Department of Pharmaceuticals, Center for Genetic Engineering and Biotechnology, Playa, Havana, Cuba
| | - Mónica Bequet-Romero
- Department of Pharmaceuticals, Center for Genetic Engineering and Biotechnology, Playa, Havana, Cuba
| | - Yanelys Morera Díaz
- Department of Pharmaceuticals, Center for Genetic Engineering and Biotechnology, Playa, Havana, Cuba
| | | | | | | | - Yenima Martín Bauta
- Department of Clinical Research, Center for Genetic Engineering and Biotechnology, Playa, Havana, Cuba
| | - Cimara H Bermúdez Badell
- Department of Clinical Research, Center for Genetic Engineering and Biotechnology, Playa, Havana, Cuba
| | - Miladys Limonta Fernández
- Department of Pharmaceuticals, Center for Genetic Engineering and Biotechnology, Playa, Havana, Cuba
| | - Marta Ayala Avila
- Department of Pharmaceuticals, Center for Genetic Engineering and Biotechnology, Playa, Havana, Cuba
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41
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Schuster C, Akslen LA, Stokowy T, Straume O. Predictive value of angiogenic proteins in patients with metastatic melanoma treated with bevacizumab monotherapy. JOURNAL OF PATHOLOGY CLINICAL RESEARCH 2018; 5:53-62. [PMID: 30225999 PMCID: PMC6317286 DOI: 10.1002/cjp2.116] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/08/2018] [Revised: 09/11/2018] [Accepted: 09/13/2018] [Indexed: 01/23/2023]
Abstract
The incidence of malignant melanoma is rising worldwide and survival for metastatic disease is still poor. Recently, new treatment options have become available. Still, predictive biomarkers are needed to optimise treatment for this patient group. In this study, we investigated the predictive value of 60 angiogenic factors in patients with metastatic melanoma treated with the anti-vascular endothelial growth factor A antibody bevacizumab. Thirty-five patients were included in a clinical phase II trial and baseline serum samples were analysed by multiplex protein array. High-serum concentration of Activin A was significantly associated with objective response (OR) to treatment (p = 0.014). Candidate proteins that indicated a borderline association with treatment response were further investigated by immunohistochemistry. Strong expression of Activin A, interleukin-1β, and urokinase-type plasminogen activator receptor in metastases was significantly associated with OR (p = 0.011, p = 0.003, and p = 0.007, respectively), as well as with markers of activated angiogenesis, such as higher number of proliferating vessels and the presence of glomeruloid microvascular proliferations. Our findings indicate that these proteins may be potential predictive markers for treatment with bevacizumab monotherapy.
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Affiliation(s)
- Cornelia Schuster
- Centre for Cancer Biomarkers CCBIO, Department of Clinical Medicine, University of Bergen, Bergen, Norway.,Department of Oncology and Medical Physics, Haukeland University Hospital, Bergen, Norway
| | - Lars A Akslen
- Centre for Cancer Biomarkers CCBIO, Department of Clinical Medicine, University of Bergen, Bergen, Norway.,Department of Pathology, Haukeland University Hospital, Bergen, Norway
| | - Tomasz Stokowy
- Department of Clinical Science, University of Bergen, Bergen, Norway.,Computational Biology Unit, Department of Informatics, University of Bergen, Bergen, Norway
| | - Oddbjørn Straume
- Centre for Cancer Biomarkers CCBIO, Department of Clinical Medicine, University of Bergen, Bergen, Norway.,Department of Oncology and Medical Physics, Haukeland University Hospital, Bergen, Norway
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Colombo M, Rizzuto MA, Pacini C, Pandolfi L, Bonizzi A, Truffi M, Monieri M, Catrambone F, Giustra M, Garbujo S, Fiandra L, Corsi F, Prosperi D, Mazzucchelli S. Half-Chain Cetuximab Nanoconjugates Allow Multitarget Therapy of Triple Negative Breast Cancer. Bioconjug Chem 2018; 29:3817-3832. [PMID: 30350574 DOI: 10.1021/acs.bioconjchem.8b00667] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
The use of therapeutic monoclonal antibodies (mAbs) has revolutionized cancer treatment. The conjugation of mAbs to nanoparticles has been broadly exploited to improve the targeting efficiency of drug nanocarriers taking advantage of high binding efficacy and target selectivity of antibodies for specific cell receptors. However, the therapeutic implications of nanoconjugation have been poorly considered. In this study, half-chain fragments of the anti-EGFR mAb cetuximab were conjugated to colloidal nanoparticles originating stable nanoconjugates that were investigated as surrogates of therapeutic mAbs in triple negative breast cancer (TNBC). Three TNBC cell lines were selected according to EGFR expression, which regulates activation of MAPK/ERK and PI3K/Akt pathways, and to distinctive molecular profiling including KRAS, PTEN, and BRCA1 mutations normally associated with diverse sensitivity to treatment with cetuximab. The molecular mechanisms of action of nanoconjugated half-chain mAb, including cell targeting, interference with downstream signaling pathways, proliferation, cell cycle, and apoptosis, along with triggering of ADCC response, were investigated in detail in sensitive and resistant TNBC cells. We found that half-chain mAb nanoconjugation was able to enhance the therapeutic efficacy and improve the target selectivity against sensitive, but unexpectedly also resistant, TNBC cells. Viability assays and signaling transduction modulation suggested a role of BRCA1 mutation in TNBC resistance to cetuximab alone, whereas its effect could be circumvented using half-chain cetuximab nanoconjugates, suggesting that nanoconjugation not only improved the antibody activity but also exerted different mechanisms of action. Our results provide robust evidence of the potential of half-chain antibody nanoconjugates in the treatment of TNBC, which could offer a new paradigm for therapeutic antibody administration, potentially allowing improved curative efficiency and reduced minimal effective dosages in both sensitive and resistant tumors.
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Affiliation(s)
- Miriam Colombo
- NanoBioLab, Dipartimento di Biotecnologie e Bioscienze , Università di Milano-Bicocca , Piazza della Scienza 2 , 20126 Milano , Italy
| | - Maria Antonietta Rizzuto
- NanoBioLab, Dipartimento di Biotecnologie e Bioscienze , Università di Milano-Bicocca , Piazza della Scienza 2 , 20126 Milano , Italy
| | - Chiara Pacini
- NanoBioLab, Dipartimento di Biotecnologie e Bioscienze , Università di Milano-Bicocca , Piazza della Scienza 2 , 20126 Milano , Italy
| | - Laura Pandolfi
- NanoBioLab, Dipartimento di Biotecnologie e Bioscienze , Università di Milano-Bicocca , Piazza della Scienza 2 , 20126 Milano , Italy
| | - Arianna Bonizzi
- Nanomedicine Laboratory , ICS Maugeri S.p.A. SB , via S. Maugeri 10 , 27100 Pavia , Italy
| | - Marta Truffi
- Department of Biomedical and Clinical Sciences "L. Sacco" , University of Milano , via G. B. Grassi 74 , 20157 Milano , Italy
| | - Matteo Monieri
- Department of Biomedical and Clinical Sciences "L. Sacco" , University of Milano , via G. B. Grassi 74 , 20157 Milano , Italy
| | - Francesco Catrambone
- NanoBioLab, Dipartimento di Biotecnologie e Bioscienze , Università di Milano-Bicocca , Piazza della Scienza 2 , 20126 Milano , Italy.,Department of Biomedical and Clinical Sciences "L. Sacco" , University of Milano , via G. B. Grassi 74 , 20157 Milano , Italy
| | - Marco Giustra
- NanoBioLab, Dipartimento di Biotecnologie e Bioscienze , Università di Milano-Bicocca , Piazza della Scienza 2 , 20126 Milano , Italy
| | - Stefania Garbujo
- NanoBioLab, Dipartimento di Biotecnologie e Bioscienze , Università di Milano-Bicocca , Piazza della Scienza 2 , 20126 Milano , Italy
| | - Luisa Fiandra
- NanoBioLab, Dipartimento di Biotecnologie e Bioscienze , Università di Milano-Bicocca , Piazza della Scienza 2 , 20126 Milano , Italy
| | - Fabio Corsi
- Department of Biomedical and Clinical Sciences "L. Sacco" , University of Milano , via G. B. Grassi 74 , 20157 Milano , Italy.,Nanomedicine Laboratory , ICS Maugeri S.p.A. SB , via S. Maugeri 10 , 27100 Pavia , Italy.,Surgery Department, Breast Unit , ICS Maugeri S.p.A. SB , via S. Maugeri 10 , 27100 Pavia , Italy
| | - Davide Prosperi
- NanoBioLab, Dipartimento di Biotecnologie e Bioscienze , Università di Milano-Bicocca , Piazza della Scienza 2 , 20126 Milano , Italy.,Nanomedicine Laboratory , ICS Maugeri S.p.A. SB , via S. Maugeri 10 , 27100 Pavia , Italy
| | - Serena Mazzucchelli
- Department of Biomedical and Clinical Sciences "L. Sacco" , University of Milano , via G. B. Grassi 74 , 20157 Milano , Italy
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Jiang C, Huang YH, Lu JB, Yang YZ, Rao HL, Zhang B, He WZ, Xia LP. Perivascular cell coverage of intratumoral vasculature is a predictor for bevacizumab efficacy in metastatic colorectal cancer. Cancer Manag Res 2018; 10:3589-3597. [PMID: 30271207 PMCID: PMC6149904 DOI: 10.2147/cmar.s172261] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Purpose Tumor vessels supported by perivascular cells have been implicated in the failure of some anti-angiogenic agents. The relationship between perivascular cell coverage (PC) and bevacizumab efficacy in metastatic colorectal cancer (mCRC) was analyzed. Patients and methods A total of 284 consecutive mCRC patients who received first-line chemotherapy with or without bevacizumab from 2007-2014 in Sun Yat-Sen University Cancer Center were analyzed. Immunohistochemical double-stain for the perivascular cell marker alpha-smooth muscle actin and endothelial cell (cluster of differentiation 31) was performed to characterize the intratumoral microvascular density. Multispectral image capturing and computerized image analyses were used to quantify the microvessels supported by the perivascular cells. The patients were divided into high and low PC group according to a median cutoff value of 0.55. Results No significant differences in overall survival (OS) and progression-free survival (PFS) were noted between the high and low PC group. In the low PC group, the patients with bevacizumab treatment had favorable OS (P=0.03), but without PFS benefit. In the high PC group, neither OS nor PFS was significantly different between the B+C and C subgroup. Tumors with perineural invasion had high PC (P=0.03). Conclusion The data showed that a low PC value could be a predictor for bevacizumab benefit.
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Affiliation(s)
- Chang Jiang
- VIP Region, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong 510060, People's Republic of China,
| | - Yu-Hua Huang
- Department of Pathology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong 510060, People's Republic of China
| | - Jia-Bin Lu
- Department of Pathology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong 510060, People's Republic of China
| | - Yuan-Zhong Yang
- Department of Pathology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong 510060, People's Republic of China
| | - Hui-Lan Rao
- Department of Pathology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong 510060, People's Republic of China
| | - Bei Zhang
- VIP Region, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong 510060, People's Republic of China,
| | - Wen-Zhuo He
- VIP Region, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong 510060, People's Republic of China,
| | - Liang-Ping Xia
- VIP Region, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong 510060, People's Republic of China,
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Earl HM, Hiller L, Dunn JA, Blenkinsop C, Grybowicz L, Vallier AL, Gounaris I, Abraham JE, Hughes-Davies L, McAdam K, Chan S, Ahmad R, Hickish T, Rea D, Caldas C, Bartlett JMS, Cameron DA, Provenzano E, Thomas J, Hayward RL. Disease-free and overall survival at 3.5 years for neoadjuvant bevacizumab added to docetaxel followed by fluorouracil, epirubicin and cyclophosphamide, for women with HER2 negative early breast cancer: ARTemis Trial. Ann Oncol 2018; 28:1817-1824. [PMID: 28459938 PMCID: PMC5834079 DOI: 10.1093/annonc/mdx173] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Background The ARTemis trial previously reported that addition of neoadjuvant bevacizumab (Bev) to docetaxel (D) followed by fluorouracil, epirubicin and cyclophosphamide (D-FEC) in HER2 negative breast cancer improved the pathological complete response (pCR) rate. We present disease-free survival (DFS) and overall survival (OS) with central pathology review. Patients and methods Patients were randomized to 3 cycles of D followed by 3 cycles of FEC (D-FEC), ±4 cycles of Bev (Bev + D-FEC). DFS and OS were analyzed by treatment and by central pathology reviewed pCR and Residual Cancer Burden (RCB) class. Results A total of 800 patients were randomized [median follow-up 3.5 years (IQR 3.2–4.4)]. DFS and OS were similar across treatment arms [DFS hazard ratio (HR)=1.18 (95% CI 0.89–1.57), P = 0.25; OS HR = 1.26 (95% CI 0.90–1.76), P = 0.19). Both local pathology report review and central histopathology review confirmed a significant improvement in DFS and OS for patients who achieved a pCR [DFS HR = 0.38 (95% CI 0.23–0.63), P < 0.001; OS HR = 0.43 (95% CI 0.24–0.75), P = 0.003]. However, significant heterogeneity was observed (P = 0.02); larger improvements in DFS were obtained with a pCR achieved with D-FEC than a pCR achieved with Bev + D-FEC. As RCB class increased, significantly worse DFS and OS was observed (P for trend <0.0001), which effect was most marked in the ER negative group. Conclusions The addition of short course neoadjuvant Bev to standard chemotherapy did not demonstrate a DFS or OS benefit. Achieving a pCR with D-FEC is associated with improved DFS and OS but not when pCR is achieved with Bev + D-FEC. At the present time therefore, Bev is not recommended in early breast cancer. ClinicalTrials.gov number NCT01093235.
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Affiliation(s)
- H M Earl
- Department of Oncology, University of Cambridge, Cambridge.,NIHR Cambridge Biomedical Research Centre, Cambridge.,Cambridge Breast Cancer Research Unit, Cambridge University Hospitals NHS Foundation Trust, Cambridge
| | - L Hiller
- Warwick Clinical Trials Unit, University of Warwick, Coventry
| | - J A Dunn
- Warwick Clinical Trials Unit, University of Warwick, Coventry
| | - C Blenkinsop
- Warwick Clinical Trials Unit, University of Warwick, Coventry
| | - L Grybowicz
- Cambridge Clinical Trials Unit - Cancer Theme, Cambridge University Hospitals NHS Foundation Trust, Cambridge
| | - A-L Vallier
- Cambridge Clinical Trials Unit - Cancer Theme, Cambridge University Hospitals NHS Foundation Trust, Cambridge
| | - I Gounaris
- Department of Oncology, Queen Elizabeth Hospital King's Lynn NHS Foundation Trust, King's Lynn.,Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge
| | - J E Abraham
- Department of Oncology, University of Cambridge, Cambridge.,NIHR Cambridge Biomedical Research Centre, Cambridge.,Cambridge Breast Cancer Research Unit, Cambridge University Hospitals NHS Foundation Trust, Cambridge
| | - L Hughes-Davies
- Department of Oncology, University of Cambridge, Cambridge.,Department of Oncology, Cambridge University Hospitals NHS Foundation Trust, Cambridge
| | - K McAdam
- Department of Oncology, Cambridge University Hospitals NHS Foundation Trust, Cambridge.,Department of Oncology, Peterborough and Stamford Hospitals NHS Foundation Trust, Peterborough
| | - S Chan
- Department of Oncology, Nottingham City Hospital, Nottingham
| | - R Ahmad
- Department of Oncology, West Middlesex University Hospital, Isleworth
| | - T Hickish
- Department of Oncology, Poole Hospital NHS Foundation Trust/Bournemouth University, Poole
| | - D Rea
- Cancer Research UK Clinical Trials Unit, University of Birmingham, Edgbaston, UK
| | - C Caldas
- Department of Oncology, University of Cambridge, Cambridge.,NIHR Cambridge Biomedical Research Centre, Cambridge.,Cambridge Breast Cancer Research Unit, Cambridge University Hospitals NHS Foundation Trust, Cambridge.,Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge
| | - J M S Bartlett
- Ontario Institute for Cancer Research, MaRS Centre, Toronto, Canada.,Cancer Research Centre, University of Edinburgh, IGMM, Western General Hospital, Edinburgh
| | - D A Cameron
- Cancer Research Centre, University of Edinburgh, IGMM, Western General Hospital, Edinburgh
| | - E Provenzano
- NIHR Cambridge Biomedical Research Centre, Cambridge.,Department of Histopathology, Cambridge University Hospitals NHS Foundation Trust, Cambridge
| | - J Thomas
- Department of Pathology, University of Edinburgh, Edinburgh, UK
| | - R L Hayward
- Cancer Research Centre, University of Edinburgh, IGMM, Western General Hospital, Edinburgh
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45
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Zhang H, Shen G, Zhang S, Du F, Cao Y, Jiang J, Zheng F, Ma X, Wang Z, Ren D, Ahmad R, Zhao F, Zhao J. Novel fluoropyrimidine-based chemotherapy for advanced well-differentiated neuroendocrine tumors: a clinical update. Expert Opin Pharmacother 2018; 19:795-807. [PMID: 29693454 DOI: 10.1080/14656566.2018.1465928] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
INTRODUCTION Patients with advanced well-differentiated neuroendocrine tumors (NETs) who have bulky and/or symptomatic and/or rapidly progressive disease require chemotherapy treatment. AREAS COVERED This review summarizes the accumulating evidence for treatment with fluorouracil-based chemotherapy in well-differentiated NETs. The main clinical studies, toxicity and predictors of fluorouracil- based chemotherapy regimens in well-differentiated NETs are discussed, along with the current issues, future research directions and therapeutic prospects. EXPERT OPINION Somatostatin analogs may control symptoms of hormone excess and tumor growth in patients with well-differentiated metastatic NETs, and biological therapies may improve progression-free survival for these patients. However, chemotherapy leads to higher objective response rates and symptom control by reducing tumor bulk. The low response rate and significant toxicities of conventional chemotherapy regimens limit their widespread use. Fortunately, some novel fluoropyrimidine-based treatment including fluorouracil, capecitabine, or S-1 based chemotherapy with or without antiangiogenic agents have been investigated in recent years. These treatments showed significant efficacy and less toxicity in pancreatic and non-pancreatic metastatic well-differentiated NETs. Additionally, non-pancreatic well-differentiated NETs have also achieved similar tumor response or survival comparable to pancreatic NETs. Moreover, some predictors of response to these treatment regimens have been evaluated.
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Affiliation(s)
- Heling Zhang
- a Affiliated Hospital of Qinghai University , Xining , China
| | - Guoshuang Shen
- a Affiliated Hospital of Qinghai University , Xining , China
| | - Shuisheng Zhang
- b Department of Medical Oncology , National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College , Beijing , China
| | - Feng Du
- c Peking University Cancer Hospital and Institute , Beijing , China
| | - Yang Cao
- d The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou , China
| | - Jun Jiang
- a Affiliated Hospital of Qinghai University , Xining , China
| | - Fangchao Zheng
- a Affiliated Hospital of Qinghai University , Xining , China
| | - Xinfu Ma
- a Affiliated Hospital of Qinghai University , Xining , China
| | - Ziyi Wang
- a Affiliated Hospital of Qinghai University , Xining , China
| | - Dengfen Ren
- a Affiliated Hospital of Qinghai University , Xining , China
| | - Raees Ahmad
- a Affiliated Hospital of Qinghai University , Xining , China
| | - Fuxin Zhao
- a Affiliated Hospital of Qinghai University , Xining , China
| | - Jiuda Zhao
- a Affiliated Hospital of Qinghai University , Xining , China
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A predictive value of von Willebrand factor for early response to Bevacizumab therapy in recurrent glioma. J Neurooncol 2018; 138:527-535. [PMID: 29594657 DOI: 10.1007/s11060-018-2820-x] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2018] [Accepted: 03/02/2018] [Indexed: 01/13/2023]
Abstract
Bevacizumab (BV), a neutralizing monoclonal antibody against the vascular endothelial growth factor ligand, is recognized as a potent anti-angiogenic agent with antitumor activity. The aim of this single-center, retrospective, longitudinal study was to investigate the possible predictive value of baseline demographic, clinical and laboratory parameters for early 3-month response to BV therapy in patients with recurrent glioma. Forty-nine patients with recurrent glioma received BV at 10 mg/kg intravenously every 3 weeks alone or in association with chemotherapy were included in this study. Blood samples were collected from all patients before the first (baseline), the second and the third administration of BV. After 3 months of BV therapy, patients with partial response were defined as responders whereas patients with stable or progressive disease were defined as non-responders. The median overall follow-up was 8 months (range 1-73), the median overall survival (OS) was 8 months (95% CI 6-10) and the median progression free survival (PFS) was 4 months (95% CI 3-5). Thirty-five % of patients were responders and showed significantly lower von Willebrand factor (VWF) levels than non-responders at all sample times (p < .02 for all). Also, on multivariate analysis the baseline VWF value was the only predictor for an early response to BV therapy. Furthermore, D-dimer and prothrombin fragment 1+2 were predictive factors for OS while Karnofsky performance status resulted predictive for PFS. VWF antigen value is a possible predictive biomarker for an early 3-month response to BV therapy in recurrent glioma.
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47
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Targeting the pro-angiogenic forms of VEGF or inhibiting their expression as anti-cancer strategies. Oncotarget 2018; 8:9174-9188. [PMID: 27999187 PMCID: PMC5354723 DOI: 10.18632/oncotarget.13942] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2016] [Accepted: 12/05/2016] [Indexed: 12/20/2022] Open
Abstract
Tumor growth relies on oxygen and blood supply depending on neo-vascularization. This process is mediated by the Vascular Endothelial Growth Factor (VEGF) in many tumors. This paradigm has led to the development of specific therapeutic approaches targeting VEGF or its receptors. Despite their promising effects, these strategies have not improved overall survival of patients suffering from different cancers compared to standard therapies. We hypothesized that the existence of anti-angiogenic forms of VEGF VEGFxxxb which are still present in many tumors limit the therapeutic effects of the anti-VEGF antibodies bevacizumab/Avastin (BVZ). To test this hypothesis, we generated renal cell carcinoma cells (RCC) expressing VEGF165b. The incidence of tumors xenografts generated in nude mice and their growth were inferior to those obtained with control cells. Whereas BVZ had no effect on control tumors, it slowed-down the growth of tumor generated with VEGF165b expressing cells. A prophylactic immunization against the domain discriminating VEGF from VEGFxxxb isoforms inhibited the growth of tumor generated with two different syngenic tumor cell lines (melanoma (B16 cells) and RCC (RENCA cells)). Purified immunoglobulins from immunized mice also slowed-down tumor growth of human RCC xenografts in nude mice, producing a potent effect compared to BVZ in this model. Furthermore, down-regulating the serine-arginine-rich splicing factor 1 (SRSF1) or masking SRSF1 binding sites by 2'O-Methyl RNA resulted in the increase of the VEGFxxxb/VEGF ratio. Therefore, a vaccine approach, specific antibodies against pro-angiogenic forms of VEGF, or increasing the VEGFxxxb/VEGF ratio may represent new prophylactic or pro-active anti-cancer strategies.
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48
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Noonan SA, Morrissey ME, Martin P, Biniecka M, Ó'Meachair S, Maguire A, Tosetto M, Nolan B, Hyland J, Sheahan K, O'Donoghue D, Mulcahy H, Fennelly D, O'Sullivan J. Tumour vasculature immaturity, oxidative damage and systemic inflammation stratify survival of colorectal cancer patients on bevacizumab treatment. Oncotarget 2018. [PMID: 29535825 PMCID: PMC5828217 DOI: 10.18632/oncotarget.24276] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Despite treatment of patients with metastatic colorectal cancer (mCRC) with bevacizumab plus chemotherapy, response rates are modest and there are no biomarkers available that will predict response. The aim of this study was to assess if markers associated with three interconnected cancer-associated biological processes, specifically angiogenesis, inflammation and oxidative damage, could stratify the survival outcome of this cohort. Levels of angiogenesis, inflammation and oxidative damage markers were assessed in pre-bevacizumab resected tumour and serum samples of mCRC patients by dual immunofluorescence, immunohistochemistry and ELISA. This study identified that specific markers of angiogenesis, inflammation and oxidative damage stratify survival of patients on this anti-angiogenic treatment. Biomarkers of immature tumour vasculature (% IMM, p=0.026, n=80), high levels of oxidative damage in the tumour epithelium (intensity of 8-oxo-dG in nuclear and cytoplasmic compartments, p=0.042 and 0.038 respectively, n=75) and lower systemic pro-inflammatory cytokines (IL6 and IL8, p=0.053 and 0.049 respectively, n=61) significantly stratify with median overall survival (OS). In summary, screening for a panel of biomarkers for high levels of immature tumour vasculature, high levels of oxidative DNA damage and low levels of systemic pro-inflammatory cytokines may be beneficial in predicting enhanced survival outcome following bevacizumab treatment for mCRC.
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Affiliation(s)
- Sinead A Noonan
- Centre for Colorectal Disease, St. Vincent's University Hospital, University College Dublin, Dublin, Ireland
| | - Maria E Morrissey
- Trinity Translational Medicine Institute (TTMI), Department of Surgery, Trinity College Dublin, St James's Hospital, Dublin, Ireland
| | - Petra Martin
- Centre for Colorectal Disease, St. Vincent's University Hospital, University College Dublin, Dublin, Ireland
| | - Monika Biniecka
- Education and Research Centre, St. Vincent's University Hospital, University College Dublin, Dublin, Ireland
| | - Shane Ó'Meachair
- Centre for Health Decision Science (CHeDS), School of Computer Science and Statistics, Trinity College Dublin, Dublin, Ireland
| | - Aoife Maguire
- Department of Histopathology, St. James's Hospital, Dublin, Ireland
| | - Miriam Tosetto
- Centre for Colorectal Disease, St. Vincent's University Hospital, University College Dublin, Dublin, Ireland
| | - Blathnaid Nolan
- Centre for Colorectal Disease, St. Vincent's University Hospital, University College Dublin, Dublin, Ireland
| | - John Hyland
- Centre for Colorectal Disease, St. Vincent's University Hospital, University College Dublin, Dublin, Ireland
| | - Kieran Sheahan
- Centre for Colorectal Disease, St. Vincent's University Hospital, University College Dublin, Dublin, Ireland
| | - Diarmuid O'Donoghue
- Centre for Colorectal Disease, St. Vincent's University Hospital, University College Dublin, Dublin, Ireland
| | - Hugh Mulcahy
- Centre for Colorectal Disease, St. Vincent's University Hospital, University College Dublin, Dublin, Ireland
| | - David Fennelly
- Centre for Colorectal Disease, St. Vincent's University Hospital, University College Dublin, Dublin, Ireland
| | - Jacintha O'Sullivan
- Trinity Translational Medicine Institute (TTMI), Department of Surgery, Trinity College Dublin, St James's Hospital, Dublin, Ireland
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Histopathological investigation of glioblastomas resected under bevacizumab treatment. Oncotarget 2018; 7:52423-52435. [PMID: 27244880 PMCID: PMC5239563 DOI: 10.18632/oncotarget.9387] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2016] [Accepted: 05/09/2016] [Indexed: 12/20/2022] Open
Abstract
To date, no clinical observations have been reported for histopathological changes in human gliomas under antiangiogenic treatment. We collected six glioblastomas resected under bevacizumab treatment. Histopathological investigation was performed by hematoxilyn-eosin staining and immunohistochemistry for CD34, VEGF, VEGFR1/2, HIF-1α, CA9, and nestin as compared to eleven control glioblastomas to assess the differences in histological features, microvessel density, expression of VEGF and its receptors, tumor oxygenation, and status of glioma stem-like cells. In the six tumors resected under bevacizumab, microvascular proliferation was absent, and microvessel density had significantly decreased compared with that of the controls. The expressions of VEGF and its receptors were downregulated in two cases of partial response. HIF-1α or CA9 expression was decreased in five of the six tumors, whereas the decreased expression of these markers was noted in only one of the 11 control glioblastomas. The expression of nestin significantly decreased in the six tumors compared with that of the controls, with the remaining nestin-positive cells being relatively concentrated around vessels. We provide the first clinicopathological evidence that antiangiogenic therapy induces the apparent normalization of vascular structure, decrease of microvessel density, and improvement of tumor oxygenation in glioblastomas. These in situ observations will help to optimize therapy.
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50
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Serzan MT, Weinberg BA, Salem ME. Second-Line Therapy for Advanced Colorectal Cancer: EGFR vs. Continuation of VEGF Inhibition. CURRENT COLORECTAL CANCER REPORTS 2017. [DOI: 10.1007/s11888-017-0388-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
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