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Shah FH, Nam YS, Bang JY, Hwang IS, Kim DH, Ki M, Lee HW. Targeting vascular endothelial growth receptor-2 (VEGFR-2): structural biology, functional insights, and therapeutic resistance. Arch Pharm Res 2025:10.1007/s12272-025-01545-1. [PMID: 40341988 DOI: 10.1007/s12272-025-01545-1] [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: 08/23/2024] [Accepted: 04/22/2025] [Indexed: 05/11/2025]
Abstract
Angiogenesis, the process of new blood vessel formation, is a fundamental physiological process implicated in several pathological disorders. The vascular endothelial growth factors (VEGFs) and their receptors (VEGFRs) are crucial for angiogenesis and vasculogenesis. Among them, the tyrosine kinase receptor VEGFR-2 is primarily expressed in endothelial cells (ECs). These cells regulate various physiological responses, including differentiation, cell proliferation, migration, and survival, by binding to VEGF mitogens. Vascular Endothelial Growth Factor Receptor 2 (VEGFR-2) is a key regulator of this process, making it a prime target for therapeutic intervention. Several drugs targeting VEGFR-2 have been approved and are currently utilized to halt the pathological axis of VEGF-VEGFR. This review will focus on the recent developments in the molecular structure and function of VEGFR-2, the molecular mechanism of VEGFR-2 activation, and its downstream signaling pathway. It will also discuss therapies and experimental drugs approved to inhibit the function of VEGFR-2 and the resistance mechanism.
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Affiliation(s)
- Fahad Hassan Shah
- College of Pharmacy, Chosun University, Gwangju, Republic of Korea
- Institute of Well-Aging Medicare & Chosun University G-LAMP Project Group, Chosun University, Gwangju, Republic of Korea
| | - Yoon Seok Nam
- College of Pharmacy, Chosun University, Gwangju, Republic of Korea
- Institute of Well-Aging Medicare & Chosun University G-LAMP Project Group, Chosun University, Gwangju, Republic of Korea
| | - Jun Young Bang
- College of Pharmacy, Chosun University, Gwangju, Republic of Korea
- Institute of Well-Aging Medicare & Chosun University G-LAMP Project Group, Chosun University, Gwangju, Republic of Korea
| | - In Seo Hwang
- Department of Pharmacy, College of Pharmacy, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul, Korea
| | - Dae Hong Kim
- College of Pharmacy, Chosun University, Gwangju, Republic of Korea
- Institute of Well-Aging Medicare & Chosun University G-LAMP Project Group, Chosun University, Gwangju, Republic of Korea
| | - Minkyoung Ki
- College of Pharmacy, Chosun University, Gwangju, Republic of Korea
- Institute of Well-Aging Medicare & Chosun University G-LAMP Project Group, Chosun University, Gwangju, Republic of Korea
| | - Heon-Woo Lee
- Institute of Well-Aging Medicare & Chosun University G-LAMP Project Group, Chosun University, Gwangju, Republic of Korea.
- Department of Pharmacy, College of Pharmacy, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul, Korea.
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Zhou Y, Tao L, Qiu J, Xu J, Yang X, Zhang Y, Tian X, Guan X, Cen X, Zhao Y. Tumor biomarkers for diagnosis, prognosis and targeted therapy. Signal Transduct Target Ther 2024; 9:132. [PMID: 38763973 PMCID: PMC11102923 DOI: 10.1038/s41392-024-01823-2] [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: 06/05/2023] [Revised: 03/07/2024] [Accepted: 04/02/2024] [Indexed: 05/21/2024] Open
Abstract
Tumor biomarkers, the substances which are produced by tumors or the body's responses to tumors during tumorigenesis and progression, have been demonstrated to possess critical and encouraging value in screening and early diagnosis, prognosis prediction, recurrence detection, and therapeutic efficacy monitoring of cancers. Over the past decades, continuous progress has been made in exploring and discovering novel, sensitive, specific, and accurate tumor biomarkers, which has significantly promoted personalized medicine and improved the outcomes of cancer patients, especially advances in molecular biology technologies developed for the detection of tumor biomarkers. Herein, we summarize the discovery and development of tumor biomarkers, including the history of tumor biomarkers, the conventional and innovative technologies used for biomarker discovery and detection, the classification of tumor biomarkers based on tissue origins, and the application of tumor biomarkers in clinical cancer management. In particular, we highlight the recent advancements in biomarker-based anticancer-targeted therapies which are emerging as breakthroughs and promising cancer therapeutic strategies. We also discuss limitations and challenges that need to be addressed and provide insights and perspectives to turn challenges into opportunities in this field. Collectively, the discovery and application of multiple tumor biomarkers emphasized in this review may provide guidance on improved precision medicine, broaden horizons in future research directions, and expedite the clinical classification of cancer patients according to their molecular biomarkers rather than organs of origin.
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Affiliation(s)
- Yue Zhou
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Lei Tao
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Jiahao Qiu
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Jing Xu
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Xinyu Yang
- West China School of Pharmacy, Sichuan University, Chengdu, 610041, China
| | - Yu Zhang
- West China School of Pharmacy, Sichuan University, Chengdu, 610041, China
- School of Medicine, Tibet University, Lhasa, 850000, China
| | - Xinyu Tian
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Xinqi Guan
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Xiaobo Cen
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
- National Chengdu Center for Safety Evaluation of Drugs, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Yinglan Zhao
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China.
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Boland PM, Ebos JML, Attwood K, Mastri M, Fountzilas C, Iyer RV, Banker C, Goey AKL, Bies R, Ma WW, Fakih M. A phase I/II study of nintedanib and capecitabine for refractory metastatic colorectal cancer. JNCI Cancer Spectr 2024; 8:pkae017. [PMID: 38697618 PMCID: PMC11065487 DOI: 10.1093/jncics/pkae017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2023] [Revised: 12/29/2023] [Accepted: 02/26/2024] [Indexed: 05/05/2024] Open
Abstract
BACKGROUND Nintedanib is a tyrosine kinase inhibitor with efficacy in bevacizumab-resistant colorectal cancer models. This phase I/II study evaluated the recommended phase II dose and efficacy of nintedanib and capecitabine in refractory metastatic colorectal cancer. METHODS Key eligibility criteria included refractory metastatic colorectal cancer and ECOG performance status of 1 or lower. The primary endpoint was 18-week progression-free survival (PFS). A 1-sided binomial test (at α = .1) compared the observed 18-week PFS with a historic control of .25. RESULTS Forty-two patients were enrolled, including 39 at the recommended phase II dose. The recommended phase II dose was established to be nintedanib 200 mg by mouth twice daily and capecitabine 1000 mg/m2 by mouth twice daily. The protocol was evaluated for efficacy in 36 patients. The 18-week PFS was 42% (15/36 patients; P = .0209). Median PFS was 3.4 mo. Median overall survival was 8.9 mo. Sixteen (44%) patients experienced a grade 3/4 adverse event, most commonly fatigue (8%), palmoplantar erythrodysesthesia (8%), aspartate aminotransferase elevation (6%), asthenia (6%), pulmonary embolus (6%), and dehydration (6%). Osteopontin levels at cycle 1, day 1 and cycle 3, day 1 as well as ΔCCL2 levels correlated to disease control at 18 weeks. CONCLUSIONS The combination of nintedanib and capecitabine is well tolerated. Clinical efficacy appears to be superior to regorafenib or tipiracil hydrochloride monotherapy. Further investigation of similar combinations is warranted. CLINICALTRIALS.GOV IDENTIFIER NCT02393755.
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Affiliation(s)
- Patrick M Boland
- Department of Medical Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA
- Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - John M L Ebos
- Department of Cancer Genetics and Genomics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Kristopher Attwood
- Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Michalis Mastri
- Department of Cancer Genetics and Genomics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Christos Fountzilas
- Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Renuka V Iyer
- Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Christopher Banker
- Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Andrew K L Goey
- Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Robert Bies
- Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, NY, USA
| | - Wen Wee Ma
- Department of Hematology and Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Marwan Fakih
- Department of Medicine, City of Hope Comprehensive Cancer Center, Duarte, CA, USA
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Egidi MJ, Krug S, Haybaeck J, Michl P, Griesmann H. Anti-angiogenic therapy using the multi-tyrosine kinase inhibitor Regorafenib enhances tumor progression in a transgenic mouse model of ß-cell carcinogenesis. Br J Cancer 2023; 129:1225-1237. [PMID: 37620408 PMCID: PMC10575939 DOI: 10.1038/s41416-023-02389-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2022] [Revised: 07/12/2023] [Accepted: 07/31/2023] [Indexed: 08/26/2023] Open
Abstract
BACKGROUND Pancreatic neuroendocrine tumors (PNETs) represent a distinct hypervascularized tumor entity, often diagnosed at metastatic stage. Therapeutic efficacy of anti-angiogenic multi-kinase inhibitors is frequently limited by primary or acquired resistance in vivo. This study aimed to characterize the molecular mode of action as well as resistance mechanisms to the anti-angiogenic multi-tyrosine kinase inhibitor (TKI) Regorafenib in vitro and in vivo. METHODS In vitro, human and murine pancreatic neuroendocrine cell lines were comparatively treated with Regorafenib and other TKIs clinically used in PNETs. Effects on cell viability and proliferation were analyzed. In vivo, transgenic RIP1Tag2 mice were treated with Regorafenib at two different time periods during carcinogenesis and its impact on angiogenesis and tumor progression was evaluated. RESULTS Compared to the established TKI therapies with Sunitinib and Everolimus, Regorafenib showed the strongest effects on cell viability and proliferation in vitro, but was unable to induce apoptosis. Unexpectedly and in contrast to these in vitro findings, Regorafenib enhanced proliferation during early tumor development in RIP1Tag2 mice and had no significant effect in late tumor progression. In addition, invasiveness was increased at both time points. Mechanistically, we could identify an upregulation of the pro-survival protein Bcl-2, the induction of the COX2-PGE2-pathway as well as the infiltration of CSF1R positive immune cells into the tumors as potential resistance mechanisms following Regorafenib treatment. DISCUSSION Our data identify important tumor cell-autonomous and stroma-dependent mechanisms of resistance to antiangiogenic therapies.
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Affiliation(s)
- Maren Juliane Egidi
- Clinic for Internal Medicine I, Martin-Luther University Halle/Wittenberg, Ernst-Grube-Straße 40, D 06120, Halle, Germany
| | - Sebastian Krug
- Clinic for Internal Medicine I, Martin-Luther University Halle/Wittenberg, Ernst-Grube-Straße 40, D 06120, Halle, Germany
- Department of Internal Medicine IV, Heidelberg University Hospital, Heidelberg, Germany
| | - Johannes Haybaeck
- Department of Pathology, Neuropathology, and Molecular Pathology, Medical University of Innsbruck, Innsbruck, Austria
- Diagnostic & Research Center for Molecular Biomedicine, Institute of Pathology, Medical University of Graz, Graz, Austria
| | - Patrick Michl
- Clinic for Internal Medicine I, Martin-Luther University Halle/Wittenberg, Ernst-Grube-Straße 40, D 06120, Halle, Germany.
- Department of Internal Medicine IV, Heidelberg University Hospital, Heidelberg, Germany.
| | - Heidi Griesmann
- Clinic for Internal Medicine I, Martin-Luther University Halle/Wittenberg, Ernst-Grube-Straße 40, D 06120, Halle, Germany
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Liu X, Huangfu Y, Wang J, Kong P, Tian W, Liu P, Fang C, Li S, Nie Y, Feng Z, Huang P, Shi S, Zhang C, Dong A, Wang W. Supramolecular Polymer-Nanomedicine Hydrogel Loaded with Tumor Associated Macrophage-Reprogramming polyTLR7/8a Nanoregulator for Enhanced Anti-Angiogenesis Therapy of Orthotopic Hepatocellular Carcinoma. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2023; 10:e2300637. [PMID: 37229748 PMCID: PMC10401096 DOI: 10.1002/advs.202300637] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Revised: 04/07/2023] [Indexed: 05/27/2023]
Abstract
Anti-angiogenic therapies targeting inhibition of vascular endothelial growth factor (VEGF) pathway show clinical benefit in hypervascular hepatocellular carcinoma (HCC) tumors. However, HCC expresses massive pro-angiogenic factors in the tumor microenvironment (TME) in response to anti-angiogenic therapy, recruiting tumor-associated macrophages (TAMs), leading to revascularization and tumor progression. To regulate cell types in TME and promote the therapeutic efficiency of anti-angiogenic therapy, a supramolecular hydrogel drug delivery system (PLDX-PMI) co-assembled by anti-angiogenic nanomedicines (PCN-Len nanoparticles (NPs)) and oxidized dextran (DX), and loaded with TAMs-reprogramming polyTLR7/8a nanoregulators (p(Man-IMDQ) NRs) is developed for orthotopic liver cancer therapy. PCN-Len NPs target tyrosine kinases of vascular endothelial cells and blocked VEGFR signaling pathway. p(Man-IMDQ) NRs repolarize pro-angiogenic M2-type TAMs into anti-angiogenic M1-type TAMs via mannose-binding receptors, reducing the secretion of VEGF, which further compromised the migration and proliferation of vascular endothelial cells. On highly malignant orthotopic liver cancer Hepa1-6 model, it is found that a single administration of the hydrogel formulation significantly decreases tumor microvessel density, promotes tumor vascular network maturation, and reduces M2-subtype TAMs, thereby effectively inhibiting tumor progression. Collectively, findings in this work highlight the great significance of TAMs reprogramming in enhancing anti-angiogenesis treatment for orthotopic HCC, and provides an advanced hydrogel delivery system-based synergistic approach for tumor therapy.
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Affiliation(s)
- Xiang Liu
- Department of Polymer Science and EngineeringKey Laboratory of Systems Bioengineering (Ministry of Education)School of Chemical Engineering and TechnologyTianjin UniversityTianjin300072P. R. China
| | - Yini Huangfu
- Department of Polymer Science and EngineeringKey Laboratory of Systems Bioengineering (Ministry of Education)School of Chemical Engineering and TechnologyTianjin UniversityTianjin300072P. R. China
| | - Jingrong Wang
- Tianjin Key Laboratory of Biomaterial ResearchInstitute of Biomedical EngineeringChinese Academy of Medical Sciences and Peking Union Medical CollegeTianjin300192P. R. China
| | - Pengxu Kong
- Department of Structural Heart DiseaseFuwai HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing100037P. R. China
| | - Weijun Tian
- Department of General SurgeryTianjin Medical University General HospitalTianjin300052P. R. China
| | - Peng Liu
- Department of General SurgeryTianjin Medical University General HospitalTianjin300052P. R. China
| | - Chuang Fang
- Department of General SurgeryTianjin Medical University General HospitalTianjin300052P. R. China
| | - Shuangyang Li
- Department of Polymer Science and EngineeringKey Laboratory of Systems Bioengineering (Ministry of Education)School of Chemical Engineering and TechnologyTianjin UniversityTianjin300072P. R. China
| | - Yu Nie
- Department of Gastrointestinal OncologyShandong Cancer Hospital and InstituteShandong First Medical University and Shandong Academy of Medical SciencesJinanShandong250117P. R. China
| | - Zujian Feng
- Tianjin Key Laboratory of Biomaterial ResearchInstitute of Biomedical EngineeringChinese Academy of Medical Sciences and Peking Union Medical CollegeTianjin300192P. R. China
| | - Pingsheng Huang
- Tianjin Key Laboratory of Biomaterial ResearchInstitute of Biomedical EngineeringChinese Academy of Medical Sciences and Peking Union Medical CollegeTianjin300192P. R. China
| | - Shengbin Shi
- Department of Gastrointestinal OncologyShandong Cancer Hospital and InstituteShandong First Medical University and Shandong Academy of Medical SciencesJinanShandong250117P. R. China
| | - Chuangnian Zhang
- Tianjin Key Laboratory of Biomaterial ResearchInstitute of Biomedical EngineeringChinese Academy of Medical Sciences and Peking Union Medical CollegeTianjin300192P. R. China
| | - Anjie Dong
- Department of Polymer Science and EngineeringKey Laboratory of Systems Bioengineering (Ministry of Education)School of Chemical Engineering and TechnologyTianjin UniversityTianjin300072P. R. China
- Frontiers Science Center for Synthetic BiologyKey Laboratory of Systems Bioengineering (MOE)Tianjin UniversityTianjin300072P. R. China
| | - Weiwei Wang
- Tianjin Key Laboratory of Biomaterial ResearchInstitute of Biomedical EngineeringChinese Academy of Medical Sciences and Peking Union Medical CollegeTianjin300192P. R. China
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Bazarbashi S, Alzahrani A, Aljubran A, Elshenawy M, Gad AM, Maraiki F, Alzannan N, Elhassan T, Badran A. Combining Sunitinib and Bevacizumab for the Management of Advanced Renal Cell Carcinoma: A Phase I/II Trial. Oncologist 2023; 28:e254-e262. [PMID: 36648325 PMCID: PMC10166178 DOI: 10.1093/oncolo/oyac261] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2022] [Accepted: 11/18/2022] [Indexed: 01/18/2023] Open
Abstract
BACKGROUND Tyrosine kinase inhibitors remain a cornerstone in managing metastatic clear cell renal cell carcinoma (RCC). The 4 weeks on/2 weeks off intermittent sunitinib schedule could result in rebound angiogenesis and tumor progression in the 2-week rest period. We propose using bevacizumab during this period for continuous antiangiogenic effects. METHOD This was a phase I/II study of patients with advanced clear cell RCC. Sunitinib was given 50 mg daily on a 4-week on/2-week off schedule. Bevacizumab was given on day 29 of each sunitinib cycle. The bevacizumab starting dose was 5 mg/kg, and the dose was escalated to 10 mg if there was no dose-limiting toxicity. The primary endpoints were response rate and progression-free survival (PFS). RESULTS Twenty-five patients were recruited. The study was closed prematurely because of poor accrual. No dose-limiting toxicity was observed with 5 mg bevacizumab. One patient achieved a complete response, and 12 achieved a partial response (52% response rate). At a median follow-up of 42.2 months (95%, confidence interval (CI) 32.9 to 51.4), the median PFS duration was 16.5 months (95% CI 4.1-28.8), and the median overall survival time was 33.3 months (95% CI 19.4-47.3). Twenty-two patients (88%) had at least one grade 3 or 4 toxicity; the most common were thrombocytopenia (32%), lymphopenia (32%), hypertension (28%), and fatigue (24%). CONCLUSION Continuous angiogenesis blockade by adding bevacizumab to the sunitinib on/off regimen for advanced RCC yields significant antitumor activity with manageable increased toxicity.
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Affiliation(s)
- Shouki Bazarbashi
- Medical Oncology, Oncology Center, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
| | - Ahmed Alzahrani
- Medical Oncology, Oncology Center, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
| | - Ali Aljubran
- Medical Oncology, Oncology Center, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
| | - Mahmoud Elshenawy
- Medical Oncology, Oncology Center, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
- Clinical Oncology and Nuclear Medicine Department, Faculty of Medicine, Menoufia University, Shebin El Kom, Egypt
| | - Ahmed Mostafa Gad
- Medical Oncology, Oncology Center, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
- Clinical Oncology and Nuclear Medicine Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Fatima Maraiki
- Department of Pharmacy, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
| | - Noura Alzannan
- Research Unit, Oncology Center, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
| | - Tusneem Elhassan
- Research Unit, Oncology Center, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
| | - Ahmed Badran
- Medical Oncology, Oncology Center, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
- Clinical Oncology and Nuclear Medicine Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt
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Circulating Biomarkers in Patients With Locally Advanced or Metastatic Renal Cell Carcinoma Treated With Everolimus in the Pre-nephrectomy Setting. Clin Oncol (R Coll Radiol) 2023; 35:e245-e255. [PMID: 36526521 DOI: 10.1016/j.clon.2022.11.012] [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: 05/05/2022] [Revised: 09/28/2022] [Accepted: 11/18/2022] [Indexed: 12/23/2022]
Abstract
Many drugs are available in renal cell carcinoma (RCC), yet clinicians are still looking for predictive biomarkers of disease recurrence or progression supporting more personalised treatments. An assessment of circulating biomarkers over time was carried out in this French, open-label, single-arm, multicentre trial conducted in 25 patients with either locally advanced (n = 14) or metastatic RCC (n = 11) who received everolimus (10 mg daily) for 6 weeks prior to nephrectomy (NEORAD, NCT01715935). Circulating biomarkers, including circulating tumour cells, haematopoietic and endothelial cells, plasma angiogenesis and inflammatory markers were quantified at baseline, upon everolimus and post-nephrectomy. We assessed tumour burden, objective response rate upon RECIST1.1, disease-free survival (DFS) and progression-free survival (PFS). The correlation between circulating biomarkers was evaluated with multiple factor analysis and biomarker association with DFS/PFS by Cox regression. No objective response rate was obtained before nephrectomy. Upon everolimus, neutrophils, platelets and sVEGFR2 significantly decreased. We did not find any association between circulating biomarkers and DFS/PFS, but patients with the highest tumour burden at baseline had significantly higher plasma levels of interleukin-6, an inflammatory circulating biomarker, and lower levels of sVEGFR2, related to angiogenesis. Further understanding of the link between these circulating biomarkers could help to optimise drug combinations in RCC.
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Jeon H, Byun J, Kang H, Kim K, Lee E, Kim JH, Hong CK, Song SW, Kim YH, Chong S, Kim JH, Nam SJ, Park JE, Lee S. Proteomic analysis predicts anti-angiogenic resistance in recurred glioblastoma. J Transl Med 2023; 21:69. [PMID: 36732815 PMCID: PMC9893563 DOI: 10.1186/s12967-023-03936-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2022] [Accepted: 01/27/2023] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND Recurrence is common in glioblastoma multiforme (GBM) because of the infiltrative, residual cells in the tumor margin. Standard therapy for GBM consists of surgical resection followed by chemotherapy and radiotherapy, but the median survival of GBM patients remains poor (~ 1.5 years). For recurrent GBM, anti-angiogenic treatment is one of the common treatment approaches. However, current anti-angiogenic treatment modalities are not satisfactory because of the resistance to anti-angiogenic agents in some patients. Therefore, we sought to identify novel prognostic biomarkers that can predict the therapeutic response to anti-angiogenic agents in patients with recurrent glioblastoma. METHODS We selected patients with recurrent GBM who were treated with anti-angiogenic agents and classified them into responders and non-responders to anti-angiogenic therapy. Then, we performed proteomic analysis using liquid-chromatography mass spectrometry (LC-MS) with formalin-fixed paraffin-embedded (FFPE) tissues obtained from surgical specimens. We conducted a gene-ontology (GO) analysis based on protein abundance in the responder and non-responder groups. Based on the LC-MS and GO analysis results, we identified potential predictive biomarkers for anti-angiogenic therapy and validated them in recurrent glioblastoma patients. RESULTS In the mass spectrometry-based approach, 4957 unique proteins were quantified with high confidence across clinical parameters. Unsupervised clustering analysis highlighted distinct proteomic patterns (n = 269 proteins) between responders and non-responders. The GO term enrichment analysis revealed a cluster of genes related to immune cell-related pathways (e.g., TMEM173, FADD, CD99) in the responder group, whereas the non-responder group had a high expression of genes related to nuclear replisome (POLD) and damaged DNA binding (ERCC2). Immunohistochemistry of these biomarkers showed that the expression levels of TMEM173 and FADD were significantly associated with the overall survival and progression-free survival of patients with recurrent GBM. CONCLUSIONS The candidate biomarkers identified in our protein analysis may be useful for predicting the clinical response to anti-angiogenic agents in patients with recurred GBM.
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Affiliation(s)
- Hanwool Jeon
- grid.413967.e0000 0001 0842 2126Translational Biomedical Research Group, Asan Institute for Life Sciences, Asan Medical Center, Seoul, Republic of Korea ,grid.267370.70000 0004 0533 4667Department of Neurological Surgery, Brain Tumor Center, Asan Medical Center, University of Ulsan College of Medicine 88, Olympic-ro 43-gil, Songpa-gu, Seoul, Republic of Korea ,grid.267370.70000 0004 0533 4667Bio-Medical Institute of Technology, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Joonho Byun
- grid.267370.70000 0004 0533 4667Department of Neurological Surgery, Brain Tumor Center, Asan Medical Center, University of Ulsan College of Medicine 88, Olympic-ro 43-gil, Songpa-gu, Seoul, Republic of Korea
| | - Hayeong Kang
- grid.267370.70000 0004 0533 4667Department of Neurological Surgery, Brain Tumor Center, Asan Medical Center, University of Ulsan College of Medicine 88, Olympic-ro 43-gil, Songpa-gu, Seoul, Republic of Korea
| | - Kyunggon Kim
- grid.413967.e0000 0001 0842 2126Asan Institute for Life Sciences, Asan Medical Center, Seoul, Republic of Korea
| | - Eunyeup Lee
- grid.413967.e0000 0001 0842 2126Translational Biomedical Research Group, Asan Institute for Life Sciences, Asan Medical Center, Seoul, Republic of Korea ,grid.267370.70000 0004 0533 4667Department of Neurological Surgery, Brain Tumor Center, Asan Medical Center, University of Ulsan College of Medicine 88, Olympic-ro 43-gil, Songpa-gu, Seoul, Republic of Korea ,grid.267370.70000 0004 0533 4667Bio-Medical Institute of Technology, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Jeong Hoon Kim
- grid.267370.70000 0004 0533 4667Department of Neurological Surgery, Brain Tumor Center, Asan Medical Center, University of Ulsan College of Medicine 88, Olympic-ro 43-gil, Songpa-gu, Seoul, Republic of Korea
| | - Chang Ki Hong
- grid.267370.70000 0004 0533 4667Department of Neurological Surgery, Brain Tumor Center, Asan Medical Center, University of Ulsan College of Medicine 88, Olympic-ro 43-gil, Songpa-gu, Seoul, Republic of Korea
| | - Sang Woo Song
- grid.267370.70000 0004 0533 4667Department of Neurological Surgery, Brain Tumor Center, Asan Medical Center, University of Ulsan College of Medicine 88, Olympic-ro 43-gil, Songpa-gu, Seoul, Republic of Korea
| | - Young-Hoon Kim
- grid.267370.70000 0004 0533 4667Department of Neurological Surgery, Brain Tumor Center, Asan Medical Center, University of Ulsan College of Medicine 88, Olympic-ro 43-gil, Songpa-gu, Seoul, Republic of Korea
| | - Sangjoon Chong
- grid.267370.70000 0004 0533 4667Department of Neurological Surgery, Brain Tumor Center, Asan Medical Center, University of Ulsan College of Medicine 88, Olympic-ro 43-gil, Songpa-gu, Seoul, Republic of Korea
| | - Jae Hyun Kim
- grid.267370.70000 0004 0533 4667Department of Neurological Surgery, Brain Tumor Center, Asan Medical Center, University of Ulsan College of Medicine 88, Olympic-ro 43-gil, Songpa-gu, Seoul, Republic of Korea
| | - Soo Jeong Nam
- grid.267370.70000 0004 0533 4667Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Ji Eun Park
- grid.267370.70000 0004 0533 4667Department of Radiology and Research Institute of Radiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Seungjoo Lee
- Translational Biomedical Research Group, Asan Institute for Life Sciences, Asan Medical Center, Seoul, Republic of Korea. .,Department of Neurological Surgery, Brain Tumor Center, Asan Medical Center, University of Ulsan College of Medicine 88, Olympic-ro 43-gil, Songpa-gu, Seoul, Republic of Korea. .,Bio-Medical Institute of Technology, University of Ulsan College of Medicine, Seoul, Republic of Korea.
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9
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Renal Carcinoma and Angiogenesis: Therapeutic Target and Biomarkers of Response in Current Therapies. Cancers (Basel) 2022; 14:cancers14246167. [PMID: 36551652 PMCID: PMC9776425 DOI: 10.3390/cancers14246167] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2022] [Revised: 12/05/2022] [Accepted: 12/09/2022] [Indexed: 12/15/2022] Open
Abstract
Due to the aberrant hypervascularization and the high immune infiltration of renal tumours, current therapeutic regimens of renal cell carcinoma (RCC) target angiogenic or immunosuppressive pathways or both. Tumour angiogenesis plays an essential role in tumour growth and immunosuppression. Indeed, the aberrant vasculature promotes hypoxia and can also exert immunosuppressive functions. In addition, pro-angiogenic factors, including VEGF-A, have an immunosuppressive action on immune cells. Despite the progress of treatments in RCC, there are still non responders or acquired resistance. Currently, no biomarkers are used in clinical practice to guide the choice between the different available treatments. Considering the role of angiogenesis in RCC, angiogenesis-related markers are interesting candidates. They have been studied in the response to antiangiogenic drugs (AA) and show interest in predicting the response. They have been less studied in immunotherapy alone or combined with AA. In this review, we will discuss the role of angiogenesis in tumour growth and immune escape and the place of angiogenesis-targeted biomarkers to predict response to current therapies in RCC.
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10
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Circulating Angiogenic Markers in Gastroenteropancreatic Neuroendocrine Neoplasms: A Systematic Review. Curr Issues Mol Biol 2022; 44:4001-4014. [PMID: 36135186 PMCID: PMC9497497 DOI: 10.3390/cimb44090274] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2022] [Revised: 08/26/2022] [Accepted: 08/30/2022] [Indexed: 11/30/2022] Open
Abstract
Background: Neuroendocrine neoplasms are a heterogeneous group of tumors that raise challenges in terms of diagnosis, treatment and monitoring. Despite continuous efforts, no biomarker has showed satisfying accuracy in predicting outcome or response to treatment. Methods: We conducted a systematic review to determine relevant circulating biomarkers for angiogenesis in neuroendocrine tumors. We searched three databases (Pubmed, Embase, Web of Science) using the keywords “neuroendocrine” and “biomarkers”, plus specific biomarkers were searched by full and abbreviated name. From a total of 2448 publications, 11 articles met the eligibility criteria. Results: VEGF is the most potent and the most studied angiogenic molecule, but results were highly controversial. Placental growth factor, Angiopoietin 2 and IL-8 were the most consistent markers in predicting poor outcome and aggressive disease behavior. Conclusions: There is no robust evidence so far to sustain the use of angiogenic biomarkers in routine practice, although the results show promising leads.
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11
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Khbouz B, Lallemand F, Cirillo A, Rowart P, Legouis D, Sounni NE, Noël A, De Tullio P, de Seigneux S, Jouret F. Kidney-targeted irradiation triggers renal ischaemic preconditioning in mice. Am J Physiol Renal Physiol 2022; 323:F198-F211. [PMID: 35796462 DOI: 10.1152/ajprenal.00005.2022] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Renal ischemia/reperfusion (I/R) causes acute kidney injury (AKI). Ischemic preconditioning (IPC) attenuates I/R-associated AKI. Whole-body irradiation induces renal IPC in mice. Still, the mechanisms remain largely unknown. Furthermore, the impact of kidney-centered irradiation on renal resistance against I/R has not been studied. Renal irradiation (8.5Gy) was done in male 8-12-week-old C57bl/6 mice using Small Animal Radiation Therapy (SmART) device. Left renal I/R was performed by clamping the renal pedicles for 30 minutes, with simultaneous right nephrectomy, at 7, 14, and 28 days post-irradiation. The renal reperfusion lasted 48 hours. Following I/R, blood urea nitrogen (BUN) and creatinine (SCr) levels were lower in pre-irradiated mice compared to controls, so was the histological Jablonski score of AKI. The metabolomics signature of renal I/R was attenuated in pre-irradiated mice. The numbers of PCNA-, CD11b-, and F4-80-positive cells in the renal parenchyma post-I/R were reduced in pre-irradiated versus control groups. Such an IPC was significantly observed as early as D14 post-irradiation. RNA-Seq showed an up-regulation of angiogenesis- and stress response-related signaling pathways in irradiated non-ischemic kidneys at D28. RT-qPCR confirmed the increased expression of VEGF, ALK5, HO1, PECAM1, NOX2, HSP70, and HSP27 in irradiated kidneys compared to controls. In addition, irradiated kidneys showed an increased CD31-positive vascular area compared to controls. A 14-day gavage of irradiated mice with the anti-angiogenic drug Sunitinib before I/R abrogated the irradiation-induced IPC at both functional and structural levels. Our observations suggest that kidney-centered irradiation activates pro-angiogenic pathways and induces IPC, with preserved renal function and attenuated inflammation post-I/R.
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Affiliation(s)
- Badr Khbouz
- Groupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA), Cardiovascular Sciences, University of Liège, Liège, Belgium.,Division of Nephrology, CHU of Liège, University of Liège, Liège, Belgium
| | - François Lallemand
- Cyclotron Research Center, University of Liège, Liège, Belgium.,Division of Radiotherapy, CHU of Liège, University of Liège, Liège, Belgium
| | - Arianna Cirillo
- Center for Interdisciplinary Research on Medicines (CIRM), Metabolomics group, University of Liège, Liège, Belgium
| | - Pascal Rowart
- Groupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA), Cardiovascular Sciences, University of Liège, Liège, Belgium.,Department of Pharmacology and Chemical Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, United States
| | - David Legouis
- Division of Intensive Care, Department of Acute Medicine, Geneva University Hospitals, Geneva, Switzerland.,Laboratory of Nephrology, Department of Medicine and Cell Physiology, University Hospital and University of Geneva, Geneva, Switzerland
| | - Nor Eddine Sounni
- Groupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA), Cancer Sciences, University of Liège, Liège, Belgium
| | - Agnès Noël
- Groupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA), Cancer Sciences, University of Liège, Liège, Belgium
| | - Pascal De Tullio
- Center for Interdisciplinary Research on Medicines (CIRM), Metabolomics group, University of Liège, Liège, Belgium
| | - Sophie de Seigneux
- Laboratory of Nephrology, Department of Medicine and Cell Physiology, University Hospital and University of Geneva, Geneva, Switzerland
| | - Francois Jouret
- Groupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA), Cardiovascular Sciences, University of Liège, Liège, Belgium.,Division of Nephrology, CHU of Liège, University of Liège, Liège, Belgium
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12
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Fu Z, Li H, Xue P, Yu H, Yang S, Tao C, Li W, Wang Y, Zhang J, Wang Y. Implantable Bioresponsive Hydrogel Prevents Local Recurrence of Breast Cancer by Enhancing Radiosensitivity. Front Bioeng Biotechnol 2022; 10:881544. [PMID: 35497337 PMCID: PMC9039615 DOI: 10.3389/fbioe.2022.881544] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Accepted: 03/14/2022] [Indexed: 12/04/2022] Open
Abstract
Breast cancer is one of the most common types of cancer. Patients are often concerned about regional recurrence after breast cancer surgery. Radiotherapy plays a vital role in reducing recurrence and prolonging the survival of patients undergoing breast-conserving surgery and high-risk mastectomy. However, 8–15% of patients still have disease progression due to radiation resistance. Therefore, new strategies for combination radiotherapy sensitization must be investigated. In this study, an implantable drug loading system, sunitinib nanoparticles @ matrix metalloproteinases -response hydrogel (NSMRH), uses enzyme-sensitive hydrogel as a carrier to load sunitinib nanoparticles, was identified. The releasing profile demonstrated that sunitinib nanoparticles may be continuously released from the hydrogels. Functional experiments revealed that, when paired with NSMRH, radiation may significantly inhibit tumor cell proliferation, migration, and invasion in vitro. Further animal experiments showed that NSMRH combined with radiotherapy could more effectively control the recurrence of subcutaneous xenograft tumors, prolong the survival time, and have no obvious toxicity in nude mice. Finally, by studying the molecular mechanism of NSMRH, it was hypothesized that in breast cancer cells, NSMRH cooperated with sensitized radiotherapy, mainly due to significantly blocking the G2/M phase, reducing the DNA repair efficiency, inhibiting tumor angiogenesis, promoting apoptosis, and reversing the abnormal expression of platelet-derived growth factor receptor alpha (PDGFRA) after radiotherapy. These findings suggest that NSMRH’s radiation sensitization and anti-tumor activity may aid in the development of a novel method in future clinical applications.
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Affiliation(s)
- Zhiguang Fu
- Department of Tumor Radiotherapy, Air Force Medical Center, PLA, Beijing, China
- Department of Stomatology, The First Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Hongqi Li
- Department of Tumor Radiotherapy, Air Force Medical Center, PLA, Beijing, China
| | - Peng Xue
- Department of Stomatology, The First Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Hanying Yu
- Department of Stomatology, The First Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Shuo Yang
- Department of Stomatology, The First Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Cheng Tao
- College of Chemical Engineering, Beijing University of Chemical Technology, Beijing, China
| | - Wei Li
- College of Chemical Engineering, Beijing University of Chemical Technology, Beijing, China
| | - Yingjie Wang
- Department of Tumor Radiotherapy, Air Force Medical Center, PLA, Beijing, China
- *Correspondence: Yingjie Wang, ; Jianjun Zhang, ; Yu Wang,
| | - Jianjun Zhang
- College of Chemical Engineering, Beijing University of Chemical Technology, Beijing, China
- *Correspondence: Yingjie Wang, ; Jianjun Zhang, ; Yu Wang,
| | - Yu Wang
- Department of Oncology, Air Force Medical Center, PLA, Beijing, China
- *Correspondence: Yingjie Wang, ; Jianjun Zhang, ; Yu Wang,
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13
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Song S, Bai M, Li X, Gong S, Yang W, Lei C, Tian H, Si M, Hao X, Guo T. Early Predictive Value of Circulating Biomarkers for Sorafenib in Advanced Hepatocellular Carcinoma. Expert Rev Mol Diagn 2022; 22:361-378. [PMID: 35234564 DOI: 10.1080/14737159.2022.2049248] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
INTRODUCTION Sorafenib is currently the first-line therapeutic regimen for patients with advanced hepatocellular carcinoma (HCC). However, many patients did not experience any benefit and suffered extreme adverse events and heavy economic burden. Thus, the early identification of patients who are most likely to benefit from sorafenib is needed. AREAS COVERED This review focused on the clinical application of circulating biomarkers (including conventional biomarkers, immune biomarkers, genetic biomarkers, and some novel biomarkers) in advanced HCC patients treated with sorafenib. An online search on PubMed, Web of Science, Embase, and Cochrane Library was conducted from the inception to Aug 15, 2021. Studies investigating the predictive or prognostic value of these biomarkers were included. EXPERT OPINION The distinction of patients who may benefit from sorafenib treatment is of utmost importance. The predictive roles of circulating biomarkers could solve this problem. Many biomarkers can be obtained by liquid biopsy, which is a less or non-invasive approach. The short half-life of sorafenib could reflect the dynamic changes of tumor progression and monitor the treatment response. Circulating biomarkers obtained from liquid biopsy resulted as a promising assessment method in HCC, allowing for better treatment decisions in the near future.
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Affiliation(s)
- Shaoming Song
- The First Clinical Medical College of Lanzhou University, Lanzhou, China.,Department of General Surgery, Gansu Provincial Hospital, Lanzhou, China
| | - Mingzhen Bai
- The First Clinical Medical College of Lanzhou University, Lanzhou, China
| | - Xiaofei Li
- Department of General Surgery, Gansu Provincial Hospital, Lanzhou, China
| | - Shiyi Gong
- Department of General Surgery, Gansu Provincial Hospital, Lanzhou, China.,School of Basic Medical Sciences, Evidence-Based Medicine Center, Lanzhou University, Lanzhou, China
| | - Wenwen Yang
- The First Clinical Medical College of Lanzhou University, Lanzhou, China.,School of Basic Medical Sciences, Evidence-Based Medicine Center, Lanzhou University, Lanzhou, China
| | - Caining Lei
- Department of General Surgery, Gansu Provincial Hospital, Lanzhou, China.,School of Basic Medical Sciences, Evidence-Based Medicine Center, Lanzhou University, Lanzhou, China
| | - Hongwei Tian
- The First Clinical Medical College of Lanzhou University, Lanzhou, China.,Department of General Surgery, Gansu Provincial Hospital, Lanzhou, China.,Key Laboratory of Molecular Diagnostics, and Precision Medicine of Surgical Oncology in Gansu Province, Lanzhou, China
| | - Moubo Si
- Department of General Surgery, Gansu Provincial Hospital, Lanzhou, China.,Key Laboratory of Molecular Diagnostics, and Precision Medicine of Surgical Oncology in Gansu Province, Lanzhou, China
| | - Xiangyong Hao
- Department of General Surgery, Gansu Provincial Hospital, Lanzhou, China.,Key Laboratory of Molecular Diagnostics, and Precision Medicine of Surgical Oncology in Gansu Province, Lanzhou, China
| | - Tiankang Guo
- The First Clinical Medical College of Lanzhou University, Lanzhou, China.,Key Laboratory of Molecular Diagnostics, and Precision Medicine of Surgical Oncology in Gansu Province, Lanzhou, China
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14
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Chen C, Cui P, Zhao K, Niu G, Hou S, Zhao D, Zeng H. Down Syndrome Candidate Region 1 Isoform 1L regulated tumor growth by targeting both angiogenesis and tumor cells. Microvasc Res 2022; 140:104305. [PMID: 34958805 PMCID: PMC9295909 DOI: 10.1016/j.mvr.2021.104305] [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: 06/24/2021] [Revised: 12/13/2021] [Accepted: 12/13/2021] [Indexed: 11/26/2022]
Abstract
Angiogenesis is critical for solid tumor growth beyond its minimal size. Previously, we reported that Down Syndrome Candidate Region 1 isoform 1L (DSCR1-1L) was one of the most up-regulated genes in endothelial cells induced by VEGF and histamine, and regulated endothelial cell proliferation, migration and angiogenesis. However, it was not known whether DSCR1-1L played a role in tumor growth. In this study, we found that DSCR1-1L shRNAs significantly inhibited the growth of transplanted melanoma in mice and its associated tumoral angiogenesis. In the gain of function assay, overexpression of DSCR1-1L cDNA in mouse endothelium is sufficient to significantly increase the tumor initiation induced by carcinogen, the growth of xenografted tumor, and the tumor metastasis in our endothelially-expressed DSCR1-1L transgenic mice, in which angiogenesis was induced. It was the first time to find that DSCR1-1L was also expressed in various tumor cells. DSCR1-1L shRNAs inhibited, but overexpression of DSCR1-1L cDNA increased, the tumor cell proliferation and migration. Most recently, we reported that DSCR1-1L modulated angiogenesis by down-regulation of VE-cadherin expression. Here, we found that DSCR1-1L down-regulated the expression of E-cadherin. Hence, DSCR1-1L is an excellent therapeutic target for cancers by regulation of both the endothelial and tumor cells through down-regulating (V)E-cadherin. DSCR1-1L shRNAs have the potential to be developed for clinical application.
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Affiliation(s)
- Chen Chen
- Center for Vascular Biology Research and Division of Gastroenterology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA; Department of Surgery of Breast and Thyroid, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, China
| | - Pengfei Cui
- Center for Vascular Biology Research and Division of Gastroenterology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA; Pancreatic Disease Institute, Department of General Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, China
| | - Kevin Zhao
- Center for Vascular Biology Research and Division of Gastroenterology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA
| | - Gengming Niu
- Center for Vascular Biology Research and Division of Gastroenterology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA; Department of General Surgery, Huashan Hospital, Fudan University, Shanghai 200040, China
| | - Shiqiang Hou
- Center for Vascular Biology Research and Division of Gastroenterology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA; Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Dezheng Zhao
- Center for Vascular Biology Research and Division of Gastroenterology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA
| | - Huiyan Zeng
- Center for Vascular Biology Research and Division of Gastroenterology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.
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15
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Adachi Y, Kamiyama H, Ichikawa K, Fukushima S, Ozawa Y, Yamaguchi S, Goda S, Kimura T, Kodama K, Matsuki M, Miyano SW, Yokoi A, Kato Y, Funahashi Y. Inhibition of FGFR Reactivates IFNγ Signaling in Tumor Cells to Enhance the Combined Antitumor Activity of Lenvatinib with Anti-PD-1 Antibodies. Cancer Res 2022; 82:292-306. [PMID: 34753772 PMCID: PMC9397636 DOI: 10.1158/0008-5472.can-20-2426] [Citation(s) in RCA: 98] [Impact Index Per Article: 32.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2020] [Revised: 01/13/2021] [Accepted: 11/05/2021] [Indexed: 01/07/2023]
Abstract
Combination therapies consisting of immune checkpoint inhibitors plus anti-VEGF therapy show enhanced antitumor activity and are approved treatments for patients with renal cell carcinoma (RCC). The immunosuppressive roles of VEGF in the tumor microenvironment are well studied, but those of FGF/FGFR signaling remain largely unknown. Lenvatinib is a receptor tyrosine kinase inhibitor that targets both VEGFR and FGFR. Here, we examine the antitumor activity of anti-PD-1 mAb combined with either lenvatinib or axitinib, a VEGFR-selective inhibitor, in RCC. Both combination treatments showed greater antitumor activity and longer survival in mouse models versus either single agent treatment, whereas anti-PD-1 mAb plus lenvatinib had enhanced antitumor activity compared with anti-PD-1 mAb plus axitinib. Flow cytometry analysis showed that lenvatinib decreased the population of tumor-associated macrophages and increased that of IFNγ-positive CD8+ T cells. Activation of FGFR signaling inhibited the IFNγ-stimulated JAK/STAT signaling pathway and decreased expression of its target genes, including B2M, CXCL10, and PD-L1. Furthermore, inhibition of FGFR signaling by lenvatinib restored the tumor response to IFNγ stimulation in mouse and human RCC cell lines. These preclinical results reveal novel roles of tumor FGFR signaling in the regulation of cancer immunity through inhibition of the IFNγ pathway, and the inhibitory activity of lenvatinib against FGFRs likely contributes to the enhanced antitumor activity of combination treatment comprising lenvatinib plus anti-PD-1 mAb. SIGNIFICANCE: FGFR pathway activation inhibits IFNγ signaling in tumor cells, and FGFR inhibition with lenvatinib enhances antitumor immunity and the activity of anti-PD-1 antibodies.
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Affiliation(s)
- Yusuke Adachi
- Corresponding Authors: Yusuke Adachi, Tsukuba Research Laboratories, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba, Ibaraki 3002635, Japan. Phone: 81-29-847-7098; Fax: 81-29-847-7614; E-mail: ; and Yasuhiro Funahashi,
| | | | | | | | | | | | | | | | | | | | | | | | | | - Yasuhiro Funahashi
- Corresponding Authors: Yusuke Adachi, Tsukuba Research Laboratories, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba, Ibaraki 3002635, Japan. Phone: 81-29-847-7098; Fax: 81-29-847-7614; E-mail: ; and Yasuhiro Funahashi,
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16
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Liang J, Wang S, Zhang G, He B, Bie Q, Zhang B. A New Antitumor Direction: Tumor-Specific Endothelial Cells. Front Oncol 2021; 11:756334. [PMID: 34988011 PMCID: PMC8721012 DOI: 10.3389/fonc.2021.756334] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2021] [Accepted: 11/25/2021] [Indexed: 12/19/2022] Open
Abstract
Targeting tumor blood vessels is an important strategy for tumor therapies. At present, antiangiogenic drugs are known to have significant clinical effects, but severe drug resistance and side effects also occur. Therefore, new specific targets for tumor and new treatment methods must be developed. Tumor-specific endothelial cells (TECs) are the main targets of antiangiogenic therapy. This review summarizes the differences between TECs and normal endothelial cells, assesses the heterogeneity of TECs, compares tumorigenesis and development between TECs and normal endothelial cells, and explains the interaction between TECs and the tumor microenvironment. A full and in-depth understanding of TECs may provide new insights for specific antitumor angiogenesis therapies.
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Affiliation(s)
- Jing Liang
- Department of Laboratory Medicine, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, China
| | - Shouqi Wang
- Department of Gastrointestinal Surgery, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, China
| | - Guowei Zhang
- Department of Gastrointestinal Surgery, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, China
| | - Baoyu He
- Department of Laboratory Medicine, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, China
| | - Qingli Bie
- Department of Laboratory Medicine, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, China
- Institute of Forensic Medicine and Laboratory Medicine, Jining Medical University, Jining, China
| | - Bin Zhang
- Department of Laboratory Medicine, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, China
- Institute of Forensic Medicine and Laboratory Medicine, Jining Medical University, Jining, China
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17
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Rimassa L, Kelley RK, Meyer T, Ryoo BY, Merle P, Park JW, Blanc JF, Lim HY, Tran A, Chan YW, McAdam P, Wang E, Cheng AL, El-Khoueiry AB, Abou-Alfa GK. Outcomes Based on Plasma Biomarkers for the Phase 3 CELESTIAL Trial of Cabozantinib versus Placebo in Advanced Hepatocellular Carcinoma. Liver Cancer 2021; 11:38-47. [PMID: 35222506 PMCID: PMC8820164 DOI: 10.1159/000519867] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Accepted: 09/24/2021] [Indexed: 02/04/2023] Open
Abstract
INTRODUCTION Cabozantinib, an inhibitor of MET, AXL, and VEGF receptors, significantly improved overall survival (OS) and progression-free survival (PFS) versus placebo in patients with previously treated advanced hepatocellular carcinoma (HCC). In this exploratory analysis, outcomes were evaluated according to plasma biomarker levels. METHODS Baseline plasma levels were evaluated for MET, AXL, VEGFR2, HGF, GAS6, VEGF-A, PlGF, IL-8, EPO, ANG2, IGF-1, VEGF-C, and c-KIT for 674/707 randomized patients; and Week 4 levels were evaluated for MET, AXL, VEGFR2, HGF, GAS6, VEGF-A, PlGF, IL-8, and EPO for 614 patients. OS and PFS were analyzed by baseline levels as dichotomized or continuous variables and by on-treatment changes at Week 4 as continuous variables; biomarkers were considered potentially prognostic if p < 0.05 and predictive if p < 0.05 for the interaction between treatment and the biomarker. Multivariable analyses adjusting for clinical covariates were also performed. RESULTS In the placebo group, high levels of MET, HGF, GAS6, IL-8, and ANG2 and low levels of IGF-1 were associated with shorter OS in univariate and multivariable analyses; these associations were also observed for MET, IL-8, and ANG2 in the cabozantinib group. Hazard ratios for OS and PFS favored cabozantinib over the placebo at low and high baseline levels for all biomarkers. No baseline biomarkers were predictive of a treatment benefit. Cabozantinib promoted pharmacodynamic changes in several biomarkers, including increases in VEGF-A, PlGF, AXL, and GAS6 levels and decreases in VEGFR2 and HGF levels; these changes were not associated with OS or PFS. CONCLUSION Cabozantinib improved OS and PFS versus placebo at high and low baseline concentrations for all biomarkers analyzed. Low baseline levels of MET, HGF, GAS6, IL-8, and ANG2 and high levels of IGF-1 were identified as potential favorable prognostic biomarkers for survival in previously treated advanced HCC. Although cabozantinib promoted pharmacodynamic changes in several biomarkers, these changes were not associated with survival.
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Affiliation(s)
- Lorenza Rimassa
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele (Milan), Italy,Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Rozzano (Milan), Italy,*Lorenza Rimassa,
| | - Robin Kate Kelley
- UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, California, USA
| | - Tim Meyer
- Royal Free Hospital and UCL Cancer Institute, London, United Kingdom
| | - Baek-Yeol Ryoo
- Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | | | | | | | - Ho Yeong Lim
- Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Albert Tran
- Université Côte d'Azur, Nice, France,CHU de Nice, Digestive Center, Nice, France,INSERM, U1065, C3M, Team 8, Nice, France
| | - Yi-Wah Chan
- Fios Genomics Ltd, Edinburgh, United Kingdom
| | - Paul McAdam
- Fios Genomics Ltd, Edinburgh, United Kingdom
| | | | - Ann-Lii Cheng
- National Taiwan University College of Medicine, Taipei, Taiwan
| | | | - Ghassan K. Abou-Alfa
- Memorial Sloan Kettering Cancer Center, New York, New York, USA,Weill Medical College at Cornell University, New York, New York, USA
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18
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Hou S, Niu G, Liu X, Bourbon PM, Zhang D, Cui P, Zhao K, Zhao D, Zeng H. A novel transcriptional complex on the VE-cadherin promoter regulated the downregulation of VE-cadherin in the Down Syndrome Candidate Region 1 isoform 1L-mediated angiogenesis. Microvasc Res 2021; 138:104209. [PMID: 34146582 PMCID: PMC9295908 DOI: 10.1016/j.mvr.2021.104209] [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: 03/06/2021] [Revised: 05/18/2021] [Accepted: 06/10/2021] [Indexed: 11/26/2022]
Abstract
Angiogenesis is critical for many diseases. Previously, we reported that Down Syndrome Candidate Region 1 isoform 1L (DSCR1-1L) was one of the most up-regulated genes in endothelial cells induced by VEGF and histamine, and regulated endothelial cell proliferation and Matrigel angiogenesis in mice. However, it was not known whether DSCR1-1L regulated angiogenesis in vivo and what was the molecular mechanism underlying it. In this study, gene knockdown and overexpression models were established to study the role of DSCR1-1L in angiogenesis in vivo. Further, the downstream regulatory target of DSCR1-1L was explored with molecular biological methods in vascular endothelial cells. We found that DSCR1-1L shRNAs significantly inhibited angiogenesis induced by VEGF in mice (p < 0.0001). In the gain-of-function assay, overexpression of DSCR1-1L cDNA in mouse endothelium of EC-FH-DSCR1-1L transgenic mice was sufficient to induce angiogenesis significantly (p < 0.01). DSCR1-1L regulated angiogenesis in the early stage by down-regulation of the VE-cadherin expression through targeting its transcription, but not mRNA stability. Three DSCR1-1L-targeted DNA elements in the VE-cadherin promoter were identified by promoter reporter assays, among which, a novel specific transcriptional complex was found. The DNA sequence (CTTCTG) in the VE-cadherin promoter was identified to directly interact with proteins by Electrophoresis Mobility Shift Assays and DNase I footprint assay. Hence, DSCR1-1L is an excellent therapeutic target for angiogenic diseases through down-regulating the formation of a novel transcriptional complex on the VE-cadherin promoter. DSCR1-1L shRNAs and cDNA have the potential to be developed for clinical application. Our results also contribute significantly to the field of mechanistic studies.
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MESH Headings
- Animals
- Antigens, CD/genetics
- Antigens, CD/metabolism
- Cadherins/genetics
- Cadherins/metabolism
- Cell Line, Tumor
- Cell Movement
- Cell Proliferation
- Down-Regulation
- Female
- Human Umbilical Vein Endothelial Cells/metabolism
- Humans
- Intracellular Signaling Peptides and Proteins/genetics
- Intracellular Signaling Peptides and Proteins/metabolism
- Male
- Melanoma, Experimental/blood supply
- Melanoma, Experimental/genetics
- Melanoma, Experimental/metabolism
- Mice, Nude
- Mice, Transgenic
- Muscle Proteins/genetics
- Muscle Proteins/metabolism
- Neovascularization, Pathologic
- Neovascularization, Physiologic
- Promoter Regions, Genetic
- Signal Transduction
- Mice
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Affiliation(s)
- Shiqiang Hou
- Center for Vascular Biology Research and Division of Gastroenterology, Departments of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai 200032, PR China
| | - Gengming Niu
- Center for Vascular Biology Research and Division of Gastroenterology, Departments of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Department of General Surgery, Huashan Hospital, Fudan University, Shanghai 200040, PR China
| | - Xin Liu
- Center for Vascular Biology Research and Division of Gastroenterology, Departments of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
| | - Pierre M Bourbon
- Center for Vascular Biology Research and Division of Gastroenterology, Departments of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
| | - Dongmei Zhang
- Center for Vascular Biology Research and Division of Gastroenterology, Departments of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Key Laboratory of Chinese Internal Medicine, Ministry of Education, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing 100700, PR China
| | - Pengfei Cui
- Center for Vascular Biology Research and Division of Gastroenterology, Departments of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Pancreatic Disease Institute, Department of General Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, China
| | - Kevin Zhao
- Center for Vascular Biology Research and Division of Gastroenterology, Departments of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
| | - Dezheng Zhao
- Center for Vascular Biology Research and Division of Gastroenterology, Departments of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
| | - Huiyan Zeng
- Center for Vascular Biology Research and Division of Gastroenterology, Departments of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
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19
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Deshmukh A, Rao KN, Arora RD, Nagarkar NM, Singh A, Shetty OS. Molecular Insights into Oral Malignancy. Indian J Surg Oncol 2021; 13:267-280. [DOI: 10.1007/s13193-021-01431-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Accepted: 08/25/2021] [Indexed: 11/29/2022] Open
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20
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Azad AK, Zhabyeyev P, Vanhaesebroeck B, Eitzen G, Oudit GY, Moore RB, Murray AG. Inactivation of endothelial cell phosphoinositide 3-kinase β inhibits tumor angiogenesis and tumor growth. Oncogene 2020; 39:6480-6492. [PMID: 32879446 DOI: 10.1038/s41388-020-01444-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2020] [Revised: 08/10/2020] [Accepted: 08/21/2020] [Indexed: 12/31/2022]
Abstract
Angiogenesis inhibitors, such as the receptor tyrosine kinase (RTK) inhibitor sunitinib, target vascular endothelial growth factor (VEGF) signaling in cancers. However, only a fraction of patients respond, and most ultimately develop resistance to current angiogenesis inhibitor therapies. Activity of alternative pro-angiogenic growth factors, acting via RTK or G-protein coupled receptors (GPCR), may mediate VEGF inhibitor resistance. The phosphoinositide 3-kinase (PI3K)β isoform is uniquely coupled to both RTK and GPCRs. We investigated the role of endothelial cell (EC) PI3Kβ in tumor angiogenesis. Pro-angiogenic GPCR ligands were expressed by patient-derived renal cell carcinomas (PD-RCC), and selective inactivation of PI3Kβ reduced PD-RCC-stimulated EC spheroid sprouting. EC-specific PI3Kβ knockout (ΕC-βKO) in mice potentiated the sunitinib-induced reduction in subcutaneous growth of LLC1 and B16F10, and lung metastasis of B16F10 tumors. Compared to single-agent sunitinib treatment, tumors in sunitinib-treated ΕC-βKO mice showed a marked decrease in microvessel density, and reduced new vessel formation. The fraction of perfused mature tumor microvessels was increased in ΕC-βKO mice suggesting immature microvessels were most sensitive to combined sunitinib and PI3Kβ inactivation. Taken together, EC PI3Kβ inactivation with sunitinib inhibition reduces microvessel turnover and decreases heterogeneity of the tumor microenvironment, hence PI3Kβ inhibition may be a useful adjuvant antiangiogenesis therapy with sunitinib.
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MESH Headings
- Angiogenesis Inhibitors/pharmacology
- Angiogenesis Inhibitors/therapeutic use
- Animals
- Antineoplastic Combined Chemotherapy Protocols/antagonists & inhibitors
- Antineoplastic Combined Chemotherapy Protocols/pharmacology
- Antineoplastic Combined Chemotherapy Protocols/therapeutic use
- Carcinoma, Renal Cell/blood supply
- Carcinoma, Renal Cell/drug therapy
- Carcinoma, Renal Cell/pathology
- Cell Line, Tumor
- Cell Proliferation/drug effects
- Class I Phosphatidylinositol 3-Kinases/antagonists & inhibitors
- Class I Phosphatidylinositol 3-Kinases/genetics
- Class I Phosphatidylinositol 3-Kinases/metabolism
- Endothelium, Vascular/cytology
- Endothelium, Vascular/pathology
- Human Umbilical Vein Endothelial Cells
- Humans
- Kidney Neoplasms/blood supply
- Kidney Neoplasms/drug therapy
- Kidney Neoplasms/pathology
- Melanoma, Experimental/blood supply
- Melanoma, Experimental/drug therapy
- Melanoma, Experimental/pathology
- Mice, Knockout
- Microvessels/drug effects
- Microvessels/pathology
- Morpholines/pharmacology
- Morpholines/therapeutic use
- Neovascularization, Pathologic/drug therapy
- Neovascularization, Pathologic/pathology
- Protein Kinase Inhibitors/pharmacology
- Protein Kinase Inhibitors/therapeutic use
- Pyrimidinones/pharmacology
- Pyrimidinones/therapeutic use
- Sunitinib/pharmacology
- Sunitinib/therapeutic use
- Thiazoles/pharmacology
- Thiazoles/therapeutic use
- Tumor Microenvironment/drug effects
- Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors
- Vascular Endothelial Growth Factor Receptor-2/metabolism
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Affiliation(s)
- Abul K Azad
- Department of Medicine, University of Alberta, Edmonton, AB, Canada
| | - Pavel Zhabyeyev
- Department of Medicine, University of Alberta, Edmonton, AB, Canada
- Department of Physiology, University of Alberta, Edmonton, AB, Canada
| | | | - Gary Eitzen
- Department of Cell Biology, University of Alberta, Edmonton, AB, Canada
| | - Gavin Y Oudit
- Department of Medicine, University of Alberta, Edmonton, AB, Canada
- Department of Physiology, University of Alberta, Edmonton, AB, Canada
| | - Ronald B Moore
- Department of Oncology, University of Alberta, Edmonton, AB, Canada
| | - Allan G Murray
- Department of Medicine, University of Alberta, Edmonton, AB, Canada.
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21
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Sepe P, Martinetti A, Mennitto A, Verzoni E, Claps M, Raimondi A, Sottotetti E, Grassi P, Guadalupi V, Stellato M, Zattarin E, Di Maio M, Procopio G. Prospective Translational Study Investigating Molecular PrEdictors of Resistance to First-Line PazopanIb in Metastatic reNal CEll Carcinoma (PIPELINE Study). Am J Clin Oncol 2020; 43:621-627. [PMID: 32889831 DOI: 10.1097/coc.0000000000000719] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
OBJECTIVES Despite the initial clinical benefit, resistance to antiangiogenic therapies develops through the activation of alternative pathways. We measured plasma levels of circulating angiogenic factors to explore their predictive role in metastatic renal cell carcinoma (mRCC) patients treated with pazopanib. MATERIALS AND METHODS mRCC patients receiving first-line pazopanib were prospectively enrolled. The levels of circulating interleuchine (IL)-6, IL-8, stromal derived factor-1, vascular endothelial growth factor-A, hepatocyte growth factor (HGF), osteopontin, and E-selectin were quantified at baseline and every 4 weeks until disease progression (PD). Patients were dichotomized into "low" and "high" subgroups by a cutoff point defined by the respective median circulating angiogenic factor (CAF) value at baseline. Then, association with the objective response was determined. Changes in CAF levels between baseline and PD were also compared. RESULTS Among 25 patients included in the final data set, 6 patients were still on treatment. As best response, 12 patients presented a partial response (48%), 9 showed stable disease, and 4 showed PD. The median follow-up was 31.9 months. The median progression-free survival was 14.8 months. Low baseline levels of IL-6, IL-8, HGF, and osteopontin were found to be significantly associated with objective response. In addition, patients with low baseline levels of HGF showed longer progression-free survival and overall survival, whereas patients with low baseline levels of IL-8 showed longer overall survival. Among patients experiencing PD, the median plasma levels of stromal derived factor-1 and vascular endothelial growth factor-A were significantly higher compared with the baseline (P=0.01; P=0.011). Conversely, the median levels of E-selectin were significantly lower compared with the baseline (P=0.017). CONCLUSION Changes in levels of selected CAFs were associated with response/resistance to pazopanib in mRCC patients.
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Affiliation(s)
- Pierangela Sepe
- Department of Medical Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan
| | - Antonia Martinetti
- Department of Medical Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan
| | - Alessia Mennitto
- Department of Medical Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan
| | - Elena Verzoni
- Department of Medical Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan
| | - Melanie Claps
- Department of Medical Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan
| | - Alessandra Raimondi
- Department of Medical Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan
| | - Elisa Sottotetti
- Department of Medical Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan
| | - Paolo Grassi
- Department of Medical Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan
| | - Valentina Guadalupi
- Department of Medical Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan
| | - Marco Stellato
- Department of Medical Oncology, Campus Bio-Medico University of Rome, Rome
| | - Emma Zattarin
- Department of Medical Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan
| | - Massimo Di Maio
- Department of Oncology, Ordine Mauriziano Hospital, University of Turin, Turin, Italy
| | - Giuseppe Procopio
- Department of Medical Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan
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22
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Montemagno C, Pagès G. Resistance to Anti-angiogenic Therapies: A Mechanism Depending on the Time of Exposure to the Drugs. Front Cell Dev Biol 2020; 8:584. [PMID: 32775327 PMCID: PMC7381352 DOI: 10.3389/fcell.2020.00584] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2020] [Accepted: 06/16/2020] [Indexed: 12/12/2022] Open
Abstract
Angiogenesis, the formation of new blood vessels from preexisting one, represents a critical process for oxygen and nutrient supply to proliferating cells, therefore promoting tumor growth and metastasis. The Vascular Endothelial Growth Factor (VEGF) pathway is one of the key mediators of angiogenesis in cancer. Therefore, several therapies including monoclonal antibodies or tyrosine kinase inhibitors target this axis. Although preclinical studies demonstrated strong antitumor activity, clinical studies were disappointing. Antiangiogenic drugs, used to treat metastatic patients suffering of different types of cancers, prolonged survival to different extents but are not curative. In this review, we focused on different mechanisms involved in resistance to antiangiogenic therapies from early stage resistance involving mainly tumor cells to late stages related to the adaptation of the microenvironment.
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Affiliation(s)
- Christopher Montemagno
- Département de Biologie Médicale, Centre Scientifique de Monaco, Monaco, Monaco.,CNRS UMR 7284, Institute for Research on Cancer and Aging of Nice, Université Côte d'Azur, Nice, France.,INSERM U1081, Centre Antoine Lacassagne, Nice, France
| | - Gilles Pagès
- Département de Biologie Médicale, Centre Scientifique de Monaco, Monaco, Monaco.,CNRS UMR 7284, Institute for Research on Cancer and Aging of Nice, Université Côte d'Azur, Nice, France.,INSERM U1081, Centre Antoine Lacassagne, Nice, France
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23
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A Transient Pseudosenescent Secretome Promotes Tumor Growth after Antiangiogenic Therapy Withdrawal. Cell Rep 2019; 25:3706-3720.e8. [PMID: 30590043 DOI: 10.1016/j.celrep.2018.12.017] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2017] [Revised: 10/21/2018] [Accepted: 12/05/2018] [Indexed: 01/07/2023] Open
Abstract
VEGF receptor tyrosine kinase inhibitors (VEGFR TKIs) approved to treat multiple cancer types can promote metastatic disease in certain limited preclinical settings. Here, we show that stopping VEGFR TKI treatment after resistance can lead to rebound tumor growth that is driven by cellular changes resembling senescence-associated secretory phenotypes (SASPs) known to promote cancer progression. A SASP-mimicking antiangiogenic therapy-induced secretome (ATIS) was found to persist during short withdrawal periods, and blockade of known SASP regulators, including mTOR and IL-6, could blunt rebound effects. Critically, senescence hallmarks ultimately reversed after long drug withdrawal periods, suggesting that the transition to a permanent growth-arrested senescent state was incomplete and the hijacking of SASP machinery ultimately transient. These findings may account for the highly diverse and reversible cytokine changes observed in VEGF inhibitor-treated patients, and suggest senescence-targeted therapies ("senotherapeutics")-particularly those that block SASP regulation-may improve outcomes in patients after VEGFR TKI failure.
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24
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Abstract
Resistance to cancer therapy remains a major challenge in clinical oncology. Although the initial treatment phase is often successful, eventual resistance, characterized by tumour relapse or spread, is discouraging. The majority of studies devoted to investigating the basis of resistance have focused on tumour-related changes that contribute to therapy resistance and tumour aggressiveness. However, over the last decade, the diverse roles of various host cells in promoting therapy resistance have become more appreciated. A growing body of evidence demonstrates that cancer therapy can induce host-mediated local and systemic responses, many of which shift the delicate balance within the tumour microenvironment, ultimately facilitating or supporting tumour progression. In this Review, recent advances in understanding how the host response to different cancer therapies may promote therapy resistance are discussed, with a focus on therapy-induced immunological, angiogenic and metastatic effects. Also summarized is the potential of evaluating the host response to cancer therapy in an era of precision medicine in oncology.
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Affiliation(s)
- Yuval Shaked
- Department of Cell Biology and Cancer Science, Technion Integrated Cancer Center, Technion - Israel Institute of Technology, Haifa, Israel.
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25
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Arai H, Battaglin F, Wang J, Lo JH, Soni S, Zhang W, Lenz HJ. Molecular insight of regorafenib treatment for colorectal cancer. Cancer Treat Rev 2019; 81:101912. [PMID: 31715423 PMCID: PMC7491975 DOI: 10.1016/j.ctrv.2019.101912] [Citation(s) in RCA: 122] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2019] [Revised: 10/22/2019] [Accepted: 10/23/2019] [Indexed: 12/22/2022]
Abstract
Regorafenib is a multi-targeting kinase inhibitor approved for the treatment of metastatic colorectal cancer patients in refractory to standard chemotherapy. Similarly to sorafenib, this agent was originally developed as a RAF1 inhibitor. However, the kinase inhibitory profile is distinct from sorafenib. A broad-spectrum of kinase inhibition induces wide-range drug sensitivity, irrespective of mutation status of major oncogenes. This agent's main therapeutic effects are anti-angiogenesis and the remodeling of tumor microenvironment through several mechanisms of action. The dual blockade of VEGF receptors and TIE2 can lead to both additive anti-angiogenesis effects and the suggestive unique regulation of vessel stability. Additionally, it inhibits molecular escape pathways to VEGF inhibition (e.g., FGF, PIGF, and PDGF signaling), enabling its continuous antiangiogenic effect even in tumors resistant to VEGF inhibitors. Furthermore, regorafenib has the important effect of enhancing anti-tumor immunity via macrophage modulation. Based on this concept, clinical trials have been recently launched for the development of a combination strategy with immune checkpoint inhibitors. Contrary to regorafenib induced clinical benefits and advances in the novel strategy, currently no predictive biomarkers have been identified. In the present review, we revisit and summarize regorafenib's unique mechanisms of action. The review could highlight molecular insights and provide some perspective for the search of predictive biomarkers used in metastatic colorectal cancer patients treated with regorafenib.
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Affiliation(s)
- Hiroyuki Arai
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, 1441 Eastlate Avenue, Los Angeles, CA 90033, United States
| | - Francesca Battaglin
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, 1441 Eastlate Avenue, Los Angeles, CA 90033, United States.
| | - Jingyuan Wang
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, 1441 Eastlate Avenue, Los Angeles, CA 90033, United States.
| | - Jae Ho Lo
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, 1441 Eastlate Avenue, Los Angeles, CA 90033, United States.
| | - Shivani Soni
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, 1441 Eastlate Avenue, Los Angeles, CA 90033, United States
| | - Wu Zhang
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, 1441 Eastlate Avenue, Los Angeles, CA 90033, United States.
| | - Heinz-Josef Lenz
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, 1441 Eastlate Avenue, Los Angeles, CA 90033, United States.
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26
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Cui P, Liu X, Zhao K, Hou S, Chen C, Zhao D, Zeng H. The novel axis of YAP1, transcription enhancer factor 3 and Down Syndrome Candidate Region 1 isoform 1L is a common signaling pathway downstream of several angiogenic factors. Microvasc Res 2019; 129:103955. [PMID: 31733305 DOI: 10.1016/j.mvr.2019.103955] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2019] [Revised: 06/06/2019] [Accepted: 11/11/2019] [Indexed: 01/06/2023]
Abstract
Angiogenesis is a hallmark of many diseases. Previously, we found that Down Syndrome Candidate Region 1 Isoform 1L (DSCR1-1L) was expressed in human tumor vessels, but was not detectable in normal tissues, and played important roles in angiogenesis induced by vascular endothelial growth factor (VEGF-A165). The expressions of DSCR1-1L mRNA and protein induced by VEGF-A165 were regulated via the direct interaction of transcription enhancer factor 3 (TEF3) with DSCR1-1L promoter. However, the function and the regulation of DSCR1-1L in angiogenesis had not been completely understood. In this study, we found that the expressions of DSCR1-1L mRNA and proteins were upregulated by other angiogenic factors, including VEGF-A121, VEGF-E, histamine, PAF, the endothelial cell (EC) growth medium, and the conditional medium obtained from cancer cells, but not by PlGF, bFGF, PDGF, and serotonin. The EC proliferation, migration and elongation induced by histamine and EC growth medium were inhibited by knocking down the mRNA and protein expressions of DSCR1-1L and TEF3. The TEF3 activation was regulated by its interaction with YAP1, and translocation from cytosol to nuclei, but not by increase of protein expression, after the stimulation of VEGF, histamine and EC growth medium. YAP1 regulated the protein expression of DSCR1-1L, the proliferation, migration and elongation of ECs induced by VEGF, histamine and EC growth medium. Taken together, this study identified a novel axis of YAP1, TEF3 and DSCR1-1L that was a common signaling pathway downstream of several angiogenic factors to regulate angiogenesis, suggesting that this pathway is an excellent therapeutic target for angiogenic diseases and cancers. Our results contribute significantly to the field of mechanistic studies.
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Affiliation(s)
- Pengfei Cui
- Center for Vascular Biology Research and Division of Gastroenterology, Departments of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA; Pancreatic Disease Institute, Department of General Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, China
| | - Xin Liu
- Center for Vascular Biology Research and Division of Gastroenterology, Departments of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA
| | - Kevin Zhao
- Center for Vascular Biology Research and Division of Gastroenterology, Departments of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA
| | - Shiqiang Hou
- Center for Vascular Biology Research and Division of Gastroenterology, Departments of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA; Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Chen Chen
- Center for Vascular Biology Research and Division of Gastroenterology, Departments of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA; Department of Surgery of Breast and Thyroid, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, China
| | - Dezheng Zhao
- Center for Vascular Biology Research and Division of Gastroenterology, Departments of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA
| | - Huiyan Zeng
- Center for Vascular Biology Research and Division of Gastroenterology, Departments of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.
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27
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Synergy Between Low Dose Metronomic Chemotherapy and the pH-centered Approach Against Cancer. Int J Mol Sci 2019; 20:ijms20215438. [PMID: 31683667 PMCID: PMC6862380 DOI: 10.3390/ijms20215438] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2019] [Revised: 10/25/2019] [Accepted: 10/29/2019] [Indexed: 12/12/2022] Open
Abstract
Low dose metronomic chemotherapy (MC) is becoming a mainstream treatment for cancer in veterinary medicine. Its mechanism of action is anti-angiogenesis by lowering vascular endothelial growth factor (VEGF) and increasing trombospondin-1 (TSP1). It has also been adopted as a compassionate treatment in very advanced human cancer. However, one of the main limitations of this therapy is its short-term effectiveness: 6 to 12 months, after which resistance develops. pH-centered cancer treatment (pHT) has been proposed as a complementary therapy in cancer, but it has not been adopted or tested as a mainstream protocol, in spite of existing evidence of its advantages and benefits. Many of the factors directly or indirectly involved in MC and anti-angiogenic treatment resistance are appropriately antagonized by pHT. This led to the testing of an association between these two treatments. Preliminary evidence indicates that the association of MC and pHT has the ability to reduce anti-angiogenic treatment limitations and develop synergistic anti-cancer effects. This review will describe each of these treatments and will analyze the fundamentals of their synergy.
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28
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Xu W, Puligandla M, Manola J, Bullock AJ, Tamasauskas D, McDermott DF, Atkins MB, Haas NB, Flaherty K, Uzzo RG, Dutcher JP, DiPaola RS, Bhatt RS. Angiogenic Factor and Cytokine Analysis among Patients Treated with Adjuvant VEGFR TKIs in Resected Renal Cell Carcinoma. Clin Cancer Res 2019; 25:6098-6106. [PMID: 31471309 DOI: 10.1158/1078-0432.ccr-19-0818] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2019] [Revised: 06/06/2019] [Accepted: 07/09/2019] [Indexed: 12/30/2022]
Abstract
PURPOSE The use of VEGFR TKIs for the adjuvant treatment of renal cell carcinoma (RCC) remains controversial. We investigated the effects of adjuvant VEGFR TKIs on circulating cytokines in the ECOG-ACRIN 2805 (ASSURE) trial. EXPERIMENTAL DESIGN Patients with resected high-risk RCC were randomized to sunitinib, sorafenib, or placebo. Plasma from 413 patients was analyzed from post-nephrectomy baseline, 4 weeks, and 6 weeks after treatment initiation. Mixed effects and Cox proportional hazards models were used to test for changes in circulating cytokines and associations between disease-free survival (DFS) and cytokine levels. RESULTS VEGF and PlGF increased after 4 weeks on sunitinib or sorafenib (P < 0.0001 for both) and returned to baseline at 6 weeks on sunitinib (corresponding to the break in the sunitinib schedule) but not sorafenib (which was administered continuously). sFLT-1 decreased after 4 weeks on sunitinib and 6 weeks on sorafenib (P < 0.0001). sVEGFR-2 decreased after both 4 and 6 weeks of treatment on sunitinib or sorafenib (P < 0.0001). Patients receiving placebo had no significant changes in cytokine levels. CXCL10 was elevated at 4 and 6 weeks on sunitinib and sorafenib but not on placebo. Higher baseline CXCL10 was associated with worse DFS (HR 1.41 per log increase in CXCL10, Bonferroni-adjusted P = 0.003). This remained significant after adjustment for T-stage, Fuhrman grade, and ECOG performance status. CONCLUSIONS Among patients treated with adjuvant VEGFR TKIs for RCC, drug-host interactions mediate changes in circulating cytokines. Elevated baseline CXCL10 was associated with worse DFS. Studies to understand functional consequences of these changes are under way.
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Affiliation(s)
- Wenxin Xu
- Beth Israel Deaconess Medical Center, Boston, Massachusetts
| | - Maneka Puligandla
- Dana-Farber Cancer Institute, ECOG-ACRIN Biostatistics Center, Boston, Massachusetts
| | - Judith Manola
- Dana-Farber Cancer Institute, ECOG-ACRIN Biostatistics Center, Boston, Massachusetts
| | | | | | | | - Michael B Atkins
- MedStar Georgetown University Hospital, Washington, District of Columbia
| | - Naomi B Haas
- Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania
| | | | | | | | | | - Rupal S Bhatt
- Beth Israel Deaconess Medical Center, Boston, Massachusetts.
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Hu J, Wang W, Liu C, Li M, Nice E, Xu H. Receptor tyrosine kinase inhibitor Sunitinib and integrin antagonist peptide HM-3 show similar lipid raft dependent biphasic regulation of tumor angiogenesis and metastasis. J Exp Clin Cancer Res 2019; 38:381. [PMID: 31462260 PMCID: PMC6714448 DOI: 10.1186/s13046-019-1324-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2019] [Accepted: 07/14/2019] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND Anti-angiogenesis remains an attractive strategy for cancer therapy. Some anti-angiogenic reagents have bell-shape dose-response curves with higher than the effective doses yielding lower anti-angiogenic effects. In this study, two different types of anti-angiogenic reagents, a receptor tyrosine kinase inhibitor Sunitinib and an integrin antagonist peptide HM-3, were selected and their effects on tumor angiogenesis and metastasis were compared. The involved molecular mechanisms were investigated. METHODS The effect of high dose Sunitinib and HM-3 on tumor angiogenesis and metastasis was investigated with two animal models: metastasis of B16F10 cells in syngeneic mice and metastasis of human MDA-MB-231 cells in nude mice. Furthermore, mechanistic studies were performed with cell migration and invasion assays and with biochemical pull-down assays of intracellular RhoGTPases. Distribution of integrin αvβ3, α5β1, VEGFR2 and the complex of integrin αvβ3 and VEGFR2 inside or outside of lipid rafts was detected with lipid raft isolation and Western-blot analysis. RESULTS Both Sunitinib and HM-3 showed a bell-shape dose-response curve on tumor angiogenesis and metastasis in both animal models. The effects of Sunitinib and HM-3 on endothelial cell and tumor cell proliferation and migration were characterized. Activation of intracellular RhoGTPases and actin stress fiber formation in endothelial and cancer cells following Sunitinib and HM-3 treatment correlated with cell migration analysis. Mechanistic studies confirmed that HM-3 and Sunitinib regulated distribution of integrin αvβ3, α5β1, VEGFR2 and αvβ3-VEGFR2 complexes, both inside and outside of the lipid raft regions to regulate endothelial cell migration and intracellular RhoGTPase activities. CONCLUSIONS These data confirmed that a general non-linear dose-effect relationship for these anti-angiogenic drugs exists and their mechanisms are correlative. It also suggests that the effective dose of an anti-angiogenic drug may have to be strictly defined to achieve its optimal clinical effects.
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Affiliation(s)
- Jialiang Hu
- State Key Laboratory of Natural Medicines, Ministry of Education, China Pharmaceutical University, Nanjing, 210009 People’s Republic of China
- The Engineering Research Center of Synthetic Polypeptide Drug Discovery and Evaluation of Jiangsu Province, Nanjing, 211198 People’s Republic of China
| | - Wenjing Wang
- State Key Laboratory of Natural Medicines, Ministry of Education, China Pharmaceutical University, Nanjing, 210009 People’s Republic of China
| | - Chen Liu
- State Key Laboratory of Natural Medicines, Ministry of Education, China Pharmaceutical University, Nanjing, 210009 People’s Republic of China
- The Engineering Research Center of Synthetic Polypeptide Drug Discovery and Evaluation of Jiangsu Province, Nanjing, 211198 People’s Republic of China
| | - Mengwei Li
- State Key Laboratory of Natural Medicines, Ministry of Education, China Pharmaceutical University, Nanjing, 210009 People’s Republic of China
- The Engineering Research Center of Synthetic Polypeptide Drug Discovery and Evaluation of Jiangsu Province, Nanjing, 211198 People’s Republic of China
| | - Edouard Nice
- Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC 3800 Australia
| | - Hanmei Xu
- State Key Laboratory of Natural Medicines, Ministry of Education, China Pharmaceutical University, Nanjing, 210009 People’s Republic of China
- The Engineering Research Center of Synthetic Polypeptide Drug Discovery and Evaluation of Jiangsu Province, Nanjing, 211198 People’s Republic of China
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Reguera-Nuñez E, Man S, Xu P, Hilberg F, Kerbel RS. Variable impact of three different antiangiogenic drugs alone or in combination with chemotherapy on multiple bone marrow-derived cell populations involved in angiogenesis and immunity. Angiogenesis 2019; 22:535-546. [DOI: 10.1007/s10456-019-09677-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2019] [Revised: 08/07/2019] [Accepted: 08/09/2019] [Indexed: 12/18/2022]
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Volk-Draper L, Patel R, Bhattarai N, Yang J, Wilber A, DeNardo D, Ran S. Myeloid-Derived Lymphatic Endothelial Cell Progenitors Significantly Contribute to Lymphatic Metastasis in Clinical Breast Cancer. THE AMERICAN JOURNAL OF PATHOLOGY 2019; 189:2269-2292. [PMID: 31421071 DOI: 10.1016/j.ajpath.2019.07.006] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/05/2018] [Revised: 06/20/2019] [Accepted: 07/09/2019] [Indexed: 12/24/2022]
Abstract
Lymphatic metastasis is a high-impact prognostic factor for mortality of breast cancer (BC) patients, and it directly depends on tumor-associated lymphatic vessels. We previously reported that lipopolysaccharide-induced inflammatory lymphangiogenesis is strongly promoted by myeloid-derived lymphatic endothelial cell progenitors (M-LECPs) derived from the bone marrow (BM). As BC recruits massive numbers of provascular myeloid cells, we hypothesized that M-LECPs, within this recruited population, are specifically programmed to promote tumor lymphatics that increase lymph node metastasis. In support of this hypothesis, high levels of M-LECPs were found in peripheral blood and tumor tissues of BC patients. Moreover, the density of M-LECPs and lymphatic vessels positive for myeloid marker proteins strongly correlated with patient node status. It was also established that tumor M-LECPs coexpress lymphatic-specific, stem/progenitor and M2-type macrophage markers that indicate their BM hematopoietic-myeloid origin and distinguish them from mature lymphatic endothelial cells, tumor-infiltrating lymphoid cells, and tissue-resident macrophages. Using four orthotopic BC models, we show that mouse M-LECPs are similarly recruited to tumors and integrate into preexisting lymphatics. Finally, we demonstrate that adoptive transfer of in vitro differentiated M-LECPs, but not naïve or nondifferentiated BM cells, significantly increased metastatic burden in ipsilateral lymph nodes. These data support a causative role of BC-induced lymphatic progenitors in tumor lymphangiogenesis and suggest molecular targets for their inhibition.
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Affiliation(s)
- Lisa Volk-Draper
- Department of Medical Microbiology, Immunology, and Cell Biology, Southern Illinois University School of Medicine, Springfield, Illinois
| | - Radhika Patel
- Department of Medical Microbiology, Immunology, and Cell Biology, Southern Illinois University School of Medicine, Springfield, Illinois
| | - Nihit Bhattarai
- Department of Medical Microbiology, Immunology, and Cell Biology, Southern Illinois University School of Medicine, Springfield, Illinois
| | - Jie Yang
- Department of Medical Microbiology, Immunology, and Cell Biology, Southern Illinois University School of Medicine, Springfield, Illinois
| | - Andrew Wilber
- Department of Medical Microbiology, Immunology, and Cell Biology, Southern Illinois University School of Medicine, Springfield, Illinois; Simmons Cancer Institute, Southern Illinois University School of Medicine, Springfield, Illinois
| | - David DeNardo
- Department of Oncology, Washington University, St. Louis, Missouri
| | - Sophia Ran
- Department of Medical Microbiology, Immunology, and Cell Biology, Southern Illinois University School of Medicine, Springfield, Illinois; Simmons Cancer Institute, Southern Illinois University School of Medicine, Springfield, Illinois.
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Vascular Endothelial Growth Factor Receptor (VEGFR-2)/KDR Inhibitors: Medicinal Chemistry Perspective. MEDICINE IN DRUG DISCOVERY 2019. [DOI: 10.1016/j.medidd.2019.100009] [Citation(s) in RCA: 74] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
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Ribatti D, Annese T, Ruggieri S, Tamma R, Crivellato E. Limitations of Anti-Angiogenic Treatment of Tumors. Transl Oncol 2019; 12:981-986. [PMID: 31121490 PMCID: PMC6529826 DOI: 10.1016/j.tranon.2019.04.022] [Citation(s) in RCA: 88] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2019] [Accepted: 04/11/2019] [Indexed: 01/26/2023] Open
Abstract
Clinical trials using anti-vascular endothelial growth factor /(VEGF) molecules induce a modest improvement in overall survival, measurable in weeks to just a few months, and tumors respond differently to these agents. In this review article, we have exposed some tumor characteristics and processes that may impair the effectiveness of anti-angiogenic approaches, including genotypic changes on endothelial cells, the vascular normalization phenomenon, and the vasculogenic mimicry. The usage of anti-angiogenic molecules leads to hypoxic tumor microenvironment which enhances tumor invasiveness. The role of tumor-infiltrating cells, including tumor associated macrophages and fibroblasts (TAMs and TAFs) in the therapeutic response to anti-angiogenic settings was also highlighted. Finally, among the new therapeutic approaches to target tumor vasculature, anti-PD-1 or anti-PD-L1 therapy sensitizing and prolonging the efficacy of anti-angiogenic therapy, have been discussed.
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Affiliation(s)
- Domenico Ribatti
- Department of Basic Medical Sciences, Neurosciences and Sensory Organs, University of Bari Medical School, Bari, Italy.
| | - Tiziana Annese
- Department of Basic Medical Sciences, Neurosciences and Sensory Organs, University of Bari Medical School, Bari, Italy
| | - Simona Ruggieri
- Department of Basic Medical Sciences, Neurosciences and Sensory Organs, University of Bari Medical School, Bari, Italy
| | - Roberto Tamma
- Department of Basic Medical Sciences, Neurosciences and Sensory Organs, University of Bari Medical School, Bari, Italy
| | - Enrico Crivellato
- Department of Medicine, Section of Human Anatomy, University of Udine, Italy
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Adachi Y, Matsuki M, Watanabe H, Takase K, Kodama K, Matsui J, Funahashi Y, Nomoto K. Antitumor and Antiangiogenic Activities of Lenvatinib in Mouse Xenograft Models of Vascular Endothelial Growth Factor-Induced Hypervascular Human Hepatocellular Carcinoma. Cancer Invest 2019; 37:185-198. [PMID: 31006280 DOI: 10.1080/07357907.2019.1601209] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
High expression of vascular endothelial growth factor (VEGF) in patients with hepatocellular carcinoma (HCC) is associated with poor prognosis. Here, we investigated the antitumor activity of lenvatinib, a multiple receptor tyrosine kinase inhibitor, in VEGF-overexpressing HCC models. In human umbilical vein endothelial cells, lenvatinib showed potent inhibitory activities against VEGF-induced proliferation and VEGF/basic fibroblast growth factor-induced tube formation. In VEGF-overexpressing HCC xenograft models, characterized by aggressive tumor growth and hypervascularity, lenvatinib had significant antitumor and antiangiogenic activities. These results suggest that potent activity of lenvatinib against VEGF signaling underlies its antitumor and antiangiogenic activities in the hypervascular HCC models.
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Affiliation(s)
- Yusuke Adachi
- a Tsukuba Research Laboratories , Eisai Co., Ltd , Ibaraki , Japan
| | - Masahiro Matsuki
- a Tsukuba Research Laboratories , Eisai Co., Ltd , Ibaraki , Japan
| | - Hideki Watanabe
- a Tsukuba Research Laboratories , Eisai Co., Ltd , Ibaraki , Japan
| | - Kazuma Takase
- a Tsukuba Research Laboratories , Eisai Co., Ltd , Ibaraki , Japan
| | - Kotaro Kodama
- a Tsukuba Research Laboratories , Eisai Co., Ltd , Ibaraki , Japan
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Peng J, Zhao S, Li Y, Niu G, Chen C, Ye T, Zhao D, Zeng H. DLL4 and Jagged1 are angiogenic targets of orphan nuclear receptor TR3/Nur77. Microvasc Res 2019; 124:67-75. [PMID: 30930165 DOI: 10.1016/j.mvr.2019.03.006] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2018] [Revised: 03/22/2019] [Accepted: 03/27/2019] [Indexed: 12/12/2022]
Abstract
Pathological angiogenesis is a hallmark of many diseases. Previously, we reported that orphan nuclear receptor TR3/Nur77 was a critical mediator of angiogenesis to regulate tumor growth and skin wound healing via regulating the expression of the junctional proteins and integrins. However, the molecular mechanism, by which TR3/Nur77 regulates angiogenesis is not completely understood. Here, we were the first to find that TR3/Nur77, via its various amino acid fragments, regulated the expression of DLL4 and Jagged 1 in cultured endothelial cells. DLL4 and Jagged1 mediated TR3/Nur77-induced angiogenic responses and signaling molecules, but not the expression of integrins. Instead, integrins regulated the expressions of DLL4 and Jagged1 induced by TR3/Nur77. Further, DLL4, Jagged1 and integrins α1, α2, β3 and β5 were regulated by TR3/Nur77 in animal sepsis models of lipopolysaccharide (LPS)-induced endotoxemia, and cecal ligation and puncture (CLP), in which, TR3/Nur77 expression was significantly and tranciently increased. Mouse survival rates were greatly increased in Nur77 knockout mice bearing both CLP and LPS models. The results elucidated a novel axis of VEGF/histamine ➔ TR3/Nur77 ➔ integrins ➔ DLL4/Jagged1 in angiogenesis, and demonstrated that TR3/Nur77 was an excellent target for sepsis. These studies supported our previous findings that TR3/Nur77 was an excellent therapeutic target, and further our understanding of the molecular mechanism, by which TR3/Nur77 regulated angiogenesis.
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Affiliation(s)
- Jin Peng
- Center for Vascular Biology Research and Division of Gastroenterology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA; Radiotherapy and Medical Oncology Department, Zhongnan Hospital, Wuhan University, Wuhan, PR China
| | - Shengqiang Zhao
- Center for Vascular Biology Research and Division of Gastroenterology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA; Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250021, PR China
| | - Yan Li
- Center for Vascular Biology Research and Division of Gastroenterology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA; Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250021, PR China
| | - Gengming Niu
- Center for Vascular Biology Research and Division of Gastroenterology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA; Department of General Surgery, Huashan Hospital, Fudan University, Shanghai 200040, PR China
| | - Chen Chen
- Center for Vascular Biology Research and Division of Gastroenterology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA; Department of Surgery of Breast and Thyroid, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, China
| | - Taiyang Ye
- Center for Vascular Biology Research and Division of Gastroenterology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA; Department of Obstetrics & Gynecology, Renji Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai, 200127, PR China
| | - Dezheng Zhao
- Center for Vascular Biology Research and Division of Gastroenterology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA
| | - Huiyan Zeng
- Center for Vascular Biology Research and Division of Gastroenterology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.
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Deyell RJ, Wu B, Rassekh SR, Tu D, Samson Y, Fleming A, Bouffet E, Sun X, Powers J, Seymour L, Baruchel S, Morgenstern DA. Phase I study of vinblastine and temsirolimus in pediatric patients with recurrent or refractory solid tumors: Canadian Cancer Trials Group Study IND.218. Pediatr Blood Cancer 2019; 66:e27540. [PMID: 30393943 DOI: 10.1002/pbc.27540] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2018] [Revised: 09/11/2018] [Accepted: 10/10/2018] [Indexed: 12/26/2022]
Abstract
UNLABELLED Combining mammalian target of rapamycin (mTOR) inhibitors and vinca alkaloids has shown therapeutic synergy in xenograft models of pediatric cancers. This phase I study assessed safety and toxicity of temsirolimus in combination with vinblastine in children. PROCEDURE Patients ≥ 1 and ≤ 18 years with recurrent/refractory solid or CNS tumors were eligible. Vinblastine (4 mg/m2 ) and temsirolimus (15 mg/m2 ) were administered i.v. weekly, with planned dose escalation of vinblastine using a rolling six phase I design. Pharmacokinetic and pharmacodynamic data were collected. RESULTS Seven patients with median age 12 years (range, 8-18 years) were enrolled; all were evaluable for toxicity and six for response. At dose level 1, four of six patients developed grade 3 mucositis, of which one met duration criteria for dose-limiting toxicity (DLT). Four patients required dose omissions for grade 3 or 4 hematologic toxicity, including one prolonged neutropenia DLT. A subsequent patient was enrolled on dose level -2 (temsirolimus 10 mg/m2 , vinblastine 4 mg/m2 ) with no protocol-related toxicity > grade 1, except grade 2 neutropenia. Two serious adverse events (SAE) occurred-an allergic reaction to temsirolimus (grade 2) and an intracranial hemorrhage in a CNS tumor patient (grade 3)-unlikely related to study therapy. Soluble VEGFR2 was reduced at cycle 1, day 36 in keeping with inhibition of angiogenesis. Four patients achieved prolonged stable disease for a median of 5.0 months (range, 3.1-8.3 months). CONCLUSION The combination of weekly temsirolimus (15 mg/m2 ) and vinblastine (4 mg/m2 ) exceeds the maximum tolerated dose in children, with frequent oral mucositis and hematologic toxicity.
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Affiliation(s)
- Rebecca J Deyell
- Division of Pediatric Hematology/Oncology/BMT, University of British Columbia, British Columbia Children's Hospital and Research Institute, Vancouver, British Columbia, Canada
| | - Bing Wu
- Department of Pediatrics, University of Toronto and New Agent and Innovative Therapy Program, The Hospital for Sick Children, Toronto, Ontario, Canada
| | - S Rod Rassekh
- Division of Pediatric Hematology/Oncology/BMT, University of British Columbia, British Columbia Children's Hospital and Research Institute, Vancouver, British Columbia, Canada
| | - Dongsheng Tu
- Canadian Cancer Trials Group and Queen's University, Kingston, Ontario, Canada
| | - Yvan Samson
- Centre Hospitalier Universitaire Sainte-Justine, Montreal, Quebec, Canada
| | - Adam Fleming
- McMaster Children's Hospital at Hamilton Health Sciences, Hamilton, Ontario, Canada
| | - Eric Bouffet
- Department of Pediatrics, University of Toronto and New Agent and Innovative Therapy Program, The Hospital for Sick Children, Toronto, Ontario, Canada
| | - Xiaoqun Sun
- Canadian Cancer Trials Group and Queen's University, Kingston, Ontario, Canada
| | - Jean Powers
- Canadian Cancer Trials Group and Queen's University, Kingston, Ontario, Canada
| | - Lesley Seymour
- Canadian Cancer Trials Group and Queen's University, Kingston, Ontario, Canada
| | - Sylvain Baruchel
- Department of Pediatrics, University of Toronto and New Agent and Innovative Therapy Program, The Hospital for Sick Children, Toronto, Ontario, Canada
| | - Daniel A Morgenstern
- Department of Pediatrics, University of Toronto and New Agent and Innovative Therapy Program, The Hospital for Sick Children, Toronto, Ontario, Canada
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Ye T, Peng J, Liu X, Hou S, Niu G, Li Y, Zeng H, Zhao D. Orphan nuclear receptor TR3/Nur77 differentially regulates the expression of integrins in angiogenesis. Microvasc Res 2018; 122:22-33. [PMID: 30391133 DOI: 10.1016/j.mvr.2018.10.011] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2018] [Revised: 10/12/2018] [Accepted: 10/25/2018] [Indexed: 12/13/2022]
Abstract
Pathological angiogenesis is a hallmark of many diseases. Previously, we reported that orphan nuclear receptor TR3/Nur77 (human homolog, Nur77, mouse homolog) is a critical mediator of angiogenesis to regulate tumor growth and skin wound healing via down-regulating the expression of the junctional proteins and integrin β4. However, the molecular mechanism, by which TR3/Nur77 regulated angiogenesis, was still not completely understood. In this report by analyzing the integrin expression profile in endothelial cells, we found that the TR3/Nur77 expression highly increased the expression of integrins α1 and β5, decreased the expression of integrins α2 and β3, but had some or no effect on the expression of integrins αv, α3, α4, α5, α6, β1 and β7. In the angiogenic responses mediated by TR3/Nur77, integrin α1 regulated endothelial cell proliferation and adhesion, but not migration. Integrin β5 shRNA inhibited cell migration, but increased proliferation and adhesion. Integrin α2 regulated all of the endothelial cell proliferation, migration and adhesion. However, integrin β3 did not play any role in endothelial cell proliferation, migration and adhesion. TR3/Nur77 regulated the transcription of integrins α1, α2, β3 and β5, via various amino acid fragments within its transactivation domain and DNA binding domain. Furthermore, TR3/Nur77 regulated the integrin α1 promoter activity by directly interacting with a novel DNA element within the integrin α1 promoter. These studies furthered our understanding of the molecular mechanism by which TR3/Nur77 regulated angiogenesis, and supported our previous finding that TR3/Nur77 was an excellent therapeutic target for pathological angiogenesis. Therefore, targeting TR3/Nur77 inhibits several signaling pathways that are activated by various angiogenic factors.
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Affiliation(s)
- Taiyang Ye
- Center for Vascular Biology Research and Division of Gastroenterology, Departments of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Department of Obstetrics & Gynecology, Renji Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai 200127, PR China
| | - Jin Peng
- Center for Vascular Biology Research and Division of Gastroenterology, Departments of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Radiotherapy and Medical Oncology Department, Zhongnan Hospital, Wuhan University, Wuhan, PR China
| | - Xin Liu
- Center for Vascular Biology Research and Division of Gastroenterology, Departments of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Beijing Traditional Chinese Medicine Hospital, Capital Medical University, Beijing, PR China
| | - Shiqiang Hou
- Center for Vascular Biology Research and Division of Gastroenterology, Departments of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai 200032, PR China
| | - Gengming Niu
- Center for Vascular Biology Research and Division of Gastroenterology, Departments of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Department of General Surgery, Huashan Hospital, Fudan University, Shanghai 200040, PR China
| | - Yan Li
- Center for Vascular Biology Research and Division of Gastroenterology, Departments of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250021, PR China
| | - Huiyan Zeng
- Center for Vascular Biology Research and Division of Gastroenterology, Departments of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
| | - Dezheng Zhao
- Center for Vascular Biology Research and Division of Gastroenterology, Departments of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
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Park I, Yang H, Park JS, Koh GY, Choi EK. VEGF-Grab Enhances the Efficacy of Radiation Therapy by Blocking VEGF-A and Treatment-Induced PlGF. Int J Radiat Oncol Biol Phys 2018; 102:609-618. [DOI: 10.1016/j.ijrobp.2018.06.401] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2017] [Revised: 06/28/2018] [Accepted: 06/29/2018] [Indexed: 12/14/2022]
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Mastri M, Lee CR, Tracz A, Kerbel RS, Dolan M, Shi Y, Ebos JML. Tumor-Independent Host Secretomes Induced By Angiogenesis and Immune-Checkpoint Inhibitors. Mol Cancer Ther 2018; 17:1602-1612. [PMID: 29695634 DOI: 10.1158/1535-7163.mct-17-1066] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2017] [Revised: 01/16/2018] [Accepted: 04/16/2018] [Indexed: 12/26/2022]
Abstract
The levels of various circulating blood proteins can change in response to cancer therapy. Monitoring therapy-induced secretomes (TIS) may have use as biomarkers for establishing optimal biological effect (such as dosing) or identifying sources of toxicity and drug resistance. Although TIS can derive from tumor cells directly, nontumor "host" treatment responses can also impact systemic secretory programs. For targeted inhibitors of the tumor microenvironment, including antiangiogenic and immune-checkpoint therapies, host TIS could explain unexpected collateral "side effects" of treatment. Here, we describe a comparative transcriptomic and proteomic analysis of host TIS in tissues and plasma from cancer-free mice treated with antibody and receptor tyrosine kinase inhibitors (RTKI) of the VEGF, cMet/ALK, and PD-1 pathways. We found that all cancer therapies elicit TIS independent of tumor growth, with systemic secretory gene change intensity higher in RTKIs compared with antibodies. Our results show that host TIS signatures differ between drug target, drug class, and dose. Notably, protein and gene host TIS signatures were not always predictive for each other, suggesting limitations to transcriptomic-only approaches to clinical biomarker development for circulating proteins. Together, these are the first studies to assess and compare "off-target" host secretory effects of VEGF and PD-1 pathway inhibition that occur independent of tumor stage or tumor response to therapy. Testing treatment impact on normal tissues to establish host-mediated TIS signatures (or "therasomes") may be important for identifying disease agnostic biomarkers to predict benefits (or limitations) of drug combinatory approaches. Mol Cancer Ther; 17(7); 1602-12. ©2018 AACR.
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Affiliation(s)
- Michalis Mastri
- Department of Cancer Genetics and Genomics, Roswell Park Comprehensive Cancer Center, Buffalo, New York
| | - Christina R Lee
- Biological Sciences Platform, Sunnybrook Research Institute, Toronto, Ontario, Canada
| | - Amanda Tracz
- Department of Cancer Genetics and Genomics, Roswell Park Comprehensive Cancer Center, Buffalo, New York
| | - Robert S Kerbel
- Biological Sciences Platform, Sunnybrook Research Institute, Toronto, Ontario, Canada
| | - Melissa Dolan
- Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, New York
| | - Yuhao Shi
- Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, New York
| | - John M L Ebos
- Department of Cancer Genetics and Genomics, Roswell Park Comprehensive Cancer Center, Buffalo, New York. .,Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, New York.,Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, New York
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Subbiah V, Gainor JF, Rahal R, Brubaker JD, Kim JL, Maynard M, Hu W, Cao Q, Sheets MP, Wilson D, Wilson KJ, DiPietro L, Fleming P, Palmer M, Hu MI, Wirth L, Brose MS, Ou SHI, Taylor M, Garralda E, Miller S, Wolf B, Lengauer C, Guzi T, Evans EK. Precision Targeted Therapy with BLU-667 for RET-Driven Cancers. Cancer Discov 2018; 8:836-849. [DOI: 10.1158/2159-8290.cd-18-0338] [Citation(s) in RCA: 229] [Impact Index Per Article: 32.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2018] [Revised: 04/09/2018] [Accepted: 04/11/2018] [Indexed: 11/16/2022]
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Kay NE, Strati P, LaPlant BR, Leis JF, Nikcevich D, Call TG, Pettinger AM, Lesnick CE, Hanson CA, Shanafelt TD. A randomized phase II trial comparing chemoimmunotherapy with or without bevacizumab in previously untreated patients with chronic lymphocytic leukemia. Oncotarget 2018; 7:78269-78280. [PMID: 27861157 PMCID: PMC5346637 DOI: 10.18632/oncotarget.13412] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2016] [Accepted: 11/09/2016] [Indexed: 11/25/2022] Open
Abstract
Bevacizumab is a monoclonal antibody targeting vascular endothelial growth factor (VEGF) with in vitro pro-apoptotic and antiangiogenic effects on chronic lymphocytic leukemia (CLL) cells. As monotherapy in patients with CLL, it has no clinical activity. Here we report the results of an open-label, randomized phase II trial comparing the combination of pentostatin, cyclophosphamide and rituximab (PCR) either without or with bevacizumab (PCR-B) in previously untreated CLL patients. A total of 65 evaluable patients were enrolled, 32 receiving PCR and 33 PCR-B. A higher rate of grade 3-4 cardiovascular toxicity was observed with PCR-B (33% vs. 3%, p < 0.003). Patients treated with PCR-B had a trend for a higher complete remission (CR) rate (54.5% vs 31.3%; p = 0.08), longer progression-free survival (PFS)(p = 0.06) and treatment-free survival (TFS)(p = 0.09). No differences in PFS and TFS by IGHV mutational status were observed with the addition of bevacizumab. A significant post-treatment increase in VEGF levels was observed in the PCR-B arm (29.77 to 57.05 pg/mL); in the PCR-B arm, lower baseline CCL-3 levels were significantly associated with achievement of CR (p = 0.01). In conclusion, the addition of bevacizumab to chemoimmunotherapy in CLL is generally well-tolerated and appears to prolong PFS and TFS.
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Affiliation(s)
- Neil E Kay
- Mayo Clinic College of Medicine, Rochester, MN, USA
| | - Paolo Strati
- Mayo Clinic College of Medicine, Rochester, MN, USA
| | | | - Jose F Leis
- Mayo Clinic College of Medicine, Scottsdale, AZ, USA
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Abstract
Vascular endothelial growth factor (VEGF) has been identified as the most potent cytokine involved in tumor angiogenesis and metastasis formation. Clinical results of anti-angiogenic therapies targeting VEGF and its receptors are very modest, resulting in a moderate improvement of overall survival. The clinical outcome is associated with the development of resistance and the increased risk of invasion and metastasis. In this article, I have analyzed the principal mechanisms of resistance to VEGF pathway inhibitors, including normalization of tumor blood vessels, hypoxia, recruitment of inflammatory cells and immature myeloid cells, alternative mechanisms of tumor vessel formation, genomic instability of tumor endothelial cells. In this context, the concept and strategies of anti-angiogenic therapies should be extensively re-considered and re-evaluated. In particular, rational combinations of anti-angiogenic agents based on pharmacokinetic and pharmacodynamics data are needed to overcome resistance and it is extremely important to determine the optimal duration and scheduling of anti-VEGF agents.
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Affiliation(s)
- Domenico Ribatti
- Department of Basic Medical Sciences, Neurosciences and Sensory Organs, University of Bari Medical School, Bari, Italy.,National Cancer Institute "Giovanni Paolo II", Bari, Italy
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Pisarsky L, Ghajar CM. Anti-angiogenic Therapy-Mediated Endothelial Damage: A Driver of Breast Cancer Recurrence? ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2018; 1100:19-45. [DOI: 10.1007/978-3-319-97746-1_2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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44
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Chang CJ, Yang YH, Chiu CJ, Lu LC, Liao CC, Liang CW, Hsu CH, Cheng AL. Targeting tumor-infiltrating Ly6G + myeloid cells improves sorafenib efficacy in mouse orthotopic hepatocellular carcinoma. Int J Cancer 2017; 142:1878-1889. [PMID: 29266245 DOI: 10.1002/ijc.31216] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2017] [Revised: 10/22/2017] [Accepted: 11/24/2017] [Indexed: 12/19/2022]
Abstract
Sorafenib, a multikinase inhibitor with antiangiogenic activity, is an approved therapy for hepatocellular carcinoma (HCC). It is unclear whether the proinflammatory and immunosuppressive mechanisms may limit the therapeutic efficacy of sorafenib in HCC. We used a syngeneic mouse liver cancer cell line to establish orthotopic liver or subcutaneous tumors to study how proinflammatory and immunosuppressive mechanisms impact on the efficacy of sorafenib. We found sorafenib exhibited a potent therapeutic effect in subcutaneous tumors, but a less potent effect in orthotopic liver tumors. The protein levels of interleukin-6 (IL-6) and vascular endothelial growth factor A (VEGF-A) were persistently elevated in orthotopic liver tumors, but not in subcutaneous tumors, treated with sorafenib. Likewise, the tumor-infiltrating Ly6G+ myeloid-derived suppressor cells (MDSCs) and immune suppressors were increased in orthotopic liver tumors, not in subcutaneous tumors, treated with sorafenib. The tumor-infiltrating Ly6G+ MDSCs of sorafenib-treated orthotopic liver tumors significantly induced IL-10 and TGF-β expressing CD4+ T cells, and downregulated the cytotoxic activity of CD8+ T cells. IL-6, but not VEGF-A, protected Ly6G+ MDSCs from sorafenib-induced cell death in vitro. The combination of anti-Ly6G antibody or anti-IL-6 antibody with sorafenib significantly reduced the cell proportion of Ly6G+ MDSCs in orthotopic liver tumors, enhanced the T cells proliferation and improved the therapeutic effect of sorafenib synergistically. Modulating tumor microenvironment through targeting tumor-infiltrating Ly6G+ MDSCs represents a potential strategy to improve the anti-HCC efficacy of sorafenib.
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Affiliation(s)
- Chun-Jung Chang
- Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Yao-Hsu Yang
- Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan
| | - Chiao-Juno Chiu
- Graduate Institute of Immunology, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Li-Chun Lu
- Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan.,Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan
| | - Chien-Chia Liao
- Graduate Institute of Immunology, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Cher-Wei Liang
- Graduate Institute of Pathology, National Taiwan University College of Medicine, Taipei, Taiwan.,Division of Pathology, Fu Jen Catholic University Hospital, New Taipei City, Taiwan
| | - Chih-Hung Hsu
- Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan.,Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan
| | - Ann-Lii Cheng
- Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan.,Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan.,Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.,National Taiwan University Cancer Center, National Taiwan University College of Medicine, Taipei, Taiwan
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45
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Herzog J, Ehrlich SM, Pfitzer L, Liebl J, Fröhlich T, Arnold GJ, Mikulits W, Haider C, Vollmar AM, Zahler S. Cyclin-dependent kinase 5 stabilizes hypoxia-inducible factor-1α: a novel approach for inhibiting angiogenesis in hepatocellular carcinoma. Oncotarget 2017; 7:27108-21. [PMID: 27027353 PMCID: PMC5053636 DOI: 10.18632/oncotarget.8342] [Citation(s) in RCA: 43] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2015] [Accepted: 03/16/2016] [Indexed: 01/25/2023] Open
Abstract
We recently introduced CDK5 as target in HCC, regulating DNA damage response. Based on this and on our previous knowledge about vascular effects of CDK5, we investigated the role of CDK5 in angiogenesis in HCC, one of the most vascularized tumors. We put a special focus on the transcription factor HIF-1α, a master regulator of tumor angiogenesis. The interaction of CDK5 with HIF-1α was tested by Western blot, PCR, reporter gene assay, immunohistochemistry, kinase assay, co-immunoprecipitation, mass spectrometry, and mutation studies. In vivo, different murine HCC models, were either induced by diethylnitrosamine or subcutaneous injection of HUH7 or HepG2 cells. The correlation of vascular density and CDK5 was assessed by immunostaining of a microarray of liver tissues from HCC patients. Inhibition of CDK5 in endothelial or HCC cells reduced HIF-1α levels in vitro and in vivo, and transcription of HIF-1α target genes (VEGFA, VEGFR1, EphrinA1). Mass spectrometry and site directed mutagenesis revealed a stabilizing phosphorylation of HIF-1α at Ser687 by CDK5. Vascular density was decreased in murine HCC models by CDK5 inhibition. In conclusion, inhibiting CDK5 is a multi-modal systemic approach to treat HCC, hitting angiogenesis, as well as the tumor cells themselves.
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Affiliation(s)
- Julia Herzog
- Department of Pharmacy, Pharmaceutical Biology, University of Munich, Munich, Germany
| | - Sandra M Ehrlich
- Department of Pharmacy, Pharmaceutical Biology, University of Munich, Munich, Germany
| | - Lisa Pfitzer
- Department of Pharmacy, Pharmaceutical Biology, University of Munich, Munich, Germany
| | - Johanna Liebl
- Department of Pharmacy, Pharmaceutical Biology, University of Munich, Munich, Germany
| | - Thomas Fröhlich
- Laboratory for Functional Genome Analysis (LAFUGA), Gene Center Munich, University of Munich, Munich, Germany
| | - Georg J Arnold
- Laboratory for Functional Genome Analysis (LAFUGA), Gene Center Munich, University of Munich, Munich, Germany
| | - Wolfgang Mikulits
- Department of Medicine I, Institute of Cancer Research, Comprehensive Cancer Center Vienna, Medical University of Vienna, Vienna, Austria
| | - Christine Haider
- Department of Medicine I, Institute of Cancer Research, Comprehensive Cancer Center Vienna, Medical University of Vienna, Vienna, Austria
| | - Angelika M Vollmar
- Department of Pharmacy, Pharmaceutical Biology, University of Munich, Munich, Germany
| | - Stefan Zahler
- Department of Pharmacy, Pharmaceutical Biology, University of Munich, Munich, Germany
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A novel self-nanoemulsifying formulation for sunitinib: Evaluation of anticancer efficacy. Colloids Surf B Biointerfaces 2017; 160:65-72. [DOI: 10.1016/j.colsurfb.2017.09.008] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2017] [Revised: 08/29/2017] [Accepted: 09/04/2017] [Indexed: 12/13/2022]
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Abstract
OBJECTIVE To test the effects of enhanced intracellular oxygen contents on the metastatic potential of colon cancer. BACKGROUND Colorectal cancer is the commonest gastrointestinal carcinoma. Distant metastases occur in half of patients and are responsible for most cancer-related deaths. Tumor hypoxia is central to the pathogenesis of metastases. Myo-Inositoltrispyrophosphate (ITPP), a nontoxic, antihypoxic compound, has recently shown significant benefits in experimental cancer, particularly when combined with standard chemotherapy. Whether ITPP protects from distant metastases in primary colon cancer is unknown. METHODS ITPP alone or combined with FOLFOX was tested in a mouse model with cecal implantation of green fluorescent protein-labeled syngeneic colorectal cancer cells. Tumor development was monitored through longitudinal magnetic resonance imaging-based morphometric analysis and survival. Established serum markers of tumor spread were measured serially and circulating tumor cells were detected via fluorescence measurements. RESULTS ITPP significantly reduced the occurrence of metastases as well as other indicators of tumor aggressiveness. Less circulating tumor cells along with reduction in malignant serum markers (osteopontin, Cxcl12) were noted. The ITPP benefits also affected the primary cancer site. Importantly, animals treated with ITPP had a significant survival benefit compared with respective controls, while a combination of FOLFOX with ITPP conferred the maximum benefits, including dramatic improvements in survival (mean 86 vs 188 d). CONCLUSIONS Restoring oxygen in metastatic colon cancer through ITPP inhibits tumor spread and markedly improves animal survival; an effect that is enhanced through the application of subsequent chemotherapy. These promising novel findings call for a clinical trial on ITPP in patients with colorectal cancer, which is under way.
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Gu L, Li H, Chen L, Li X, Wang B, Huang Q, Zhang F, Fan Y, Gao Y, Peng C, Ma X, Zhang X. Postoperative Adjuvant Sorafenib or Sunitinib for Nonmetastatic Renal Cell Carcinoma with Venous Tumor Thrombus: a Prospective Cohort Study. Transl Oncol 2017; 10:949-955. [PMID: 29035731 PMCID: PMC5645483 DOI: 10.1016/j.tranon.2017.09.009] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2017] [Revised: 09/22/2017] [Accepted: 09/22/2017] [Indexed: 01/22/2023] Open
Abstract
PURPOSE: To evaluate the efficacy and safety of antiangiogenic agents (sorafenib and sunitinib) as postoperative adjuvant therapy in patients with nonmetastatic renal cell carcinoma (RCC) and venous tumor thrombus (VTT). MATERIAL AND METHODS: From March 2006 to January 2016, 147 patients who met the inclusion criteria were enrolled; 27 patients received sorafenib, and 17 patients received sunitinib. After radical nephrectomy and thrombectomy, the duration of maintenance targeted medication treatment was approximately 1 year. The primary objective was to compare disease-free survival (DFS) between each experimental group and control. Secondary end points included overall survival (OS) and toxic effects. RESULTS: The three groups were well balanced in terms of age, body mass index, gender, performance status, medical history, American Society of Anesthesiologists score, surgical approach, and tumor side and size. However, more patients receiving adjuvant therapy had inferior vena cava tumor thrombus. DFS and OS did not differ significantly between groups (P = .459 and .871, respectively). After adjusting for potential confounding factors, results of multivariate analysis proved that postoperative adjuvant therapy was not an independent factor for predicting DFS and OS (P > .05 for both). The subgroup analyses for inferior vena cava tumor thrombus found similar results. The common adverse events were hand-foot syndrome, diarrhea, fatigue, and neutropenia. The adverse effects were mild in both groups, and the incidence was not significantly different between sorafenib and sunitinib. CONCLUSIONS: Adjuvant treatment postoperatively with sorafenib or sunitinib showed no survival benefit relative to control for patients with nonmetastatic RCC and VTT in a prospective cohort study.
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Affiliation(s)
- Liangyou Gu
- Department of Urology/State Key Laboratory of Kidney Diseases, Chinese PLA General Hospital/PLA Medical School, Beijing, China
| | - Hongzhao Li
- Department of Urology/State Key Laboratory of Kidney Diseases, Chinese PLA General Hospital/PLA Medical School, Beijing, China
| | - Luyao Chen
- Department of Urology, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Xintao Li
- Department of Urology/State Key Laboratory of Kidney Diseases, Chinese PLA General Hospital/PLA Medical School, Beijing, China
| | - Baojun Wang
- Department of Urology/State Key Laboratory of Kidney Diseases, Chinese PLA General Hospital/PLA Medical School, Beijing, China
| | - Qingbo Huang
- Department of Urology/State Key Laboratory of Kidney Diseases, Chinese PLA General Hospital/PLA Medical School, Beijing, China
| | - Fan Zhang
- Department of Urology/State Key Laboratory of Kidney Diseases, Chinese PLA General Hospital/PLA Medical School, Beijing, China
| | - Yang Fan
- Department of Urology/State Key Laboratory of Kidney Diseases, Chinese PLA General Hospital/PLA Medical School, Beijing, China
| | - Yu Gao
- Department of Urology/State Key Laboratory of Kidney Diseases, Chinese PLA General Hospital/PLA Medical School, Beijing, China
| | - Cheng Peng
- Department of Urology/State Key Laboratory of Kidney Diseases, Chinese PLA General Hospital/PLA Medical School, Beijing, China
| | - Xin Ma
- Department of Urology/State Key Laboratory of Kidney Diseases, Chinese PLA General Hospital/PLA Medical School, Beijing, China.
| | - Xu Zhang
- Department of Urology/State Key Laboratory of Kidney Diseases, Chinese PLA General Hospital/PLA Medical School, Beijing, China
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Sakamoto S, Takahashi H, Tan X, Inoue Y, Nomura Y, Arai Y, Fujino Y, Kawashima H, Yanagi Y. Changes in multiple cytokine concentrations in the aqueous humour of neovascular age-related macular degeneration after 2 months of ranibizumab therapy. Br J Ophthalmol 2017; 102:448-454. [PMID: 28765149 PMCID: PMC5890644 DOI: 10.1136/bjophthalmol-2017-310284] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2017] [Revised: 07/06/2017] [Accepted: 07/11/2017] [Indexed: 12/12/2022]
Abstract
Purpose To determine changes in multiple cytokine concentrations in the anterior chamber during the induction phase of ranibizumab treatment in patients with neovascular age-related macular degeneration (AMD). Methods This prospective study included 48 treatment-naïve neovascular AMD eyes of 48 patients who received three consecutive monthly injections of ranibizumab at the Japan Community Health Care Organization Tokyo Shinjuku Medical Center between November 2010 and August 2012. We collected ~0.2 mL aqueous humour before the first and third (2 months later) injections. Controls were 80 eyes with cataracts without retinal disease. The cytokines C-X-C motif chemokine ligand 1 (CXCL1), interferon-γ-induced protein 10 (IP-10), C-X-C motif chemokine ligand 12 (CXCL12), C-X-C motif chemokine ligand 13 (CXCL13), monocyte chemoattractant protein 1 (MCP-1), CCL11, C-C motif chemokine ligand 11 (CCL11), interleukin-6 (IL-6), interleukin-10 (IL-10) and matrix metalloproteinase 9 (MMP-9) were analysed using multiplex cytokine assays. Results Mean ages of the patients with AMD and controls were 73 and 75 years, respectively, and 31 (65%) and 37 (46%) subjects were men, respectively. Polypoidal choroidal vasculopathy was found in 27 eyes (56%). Mean concentrations of cytokines in aqueous humour in patients with neovascular AMD before the first and third ranibizumab injections were as follows (in pg/mL): CXCL1, 8.4 and 3.3; IP-10, 110 and 55; CXCL12, 480 and 240; CXCL13, 9.2 and 2.6; MCP-1, 620 and 220; CCL11, 7.1 and 2.8; IL-6, 5.9 and 1.6; IL-10, 0.15 and 0.015 (all p<0.0001), and MMP-9, 0.92 and 1.5 (p=0.0216), respectively. Concentrations of all cytokines decreased significantly after two consecutive ranibizumab injections, except for MMP-9, which increased significantly. Conclusions After two monthly consecutive antivascular endothelial growth factor injections, inflammatory cytokine levels in the aqueous humour of the eyes with AMD were strongly suppressed, while MMP-9 levels increased.
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Affiliation(s)
- Shinichi Sakamoto
- Department of Ophthalmology, Jichi Medical University, Shimotsuke, Tochigi, Japan
| | - Hidenori Takahashi
- Department of Ophthalmology, Jichi Medical University, Shimotsuke, Tochigi, Japan.,Department of Ophthalmology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan.,Department of Ophthalmology, Japan Community Health Care Organization Tokyo Shinjuku Medical Center, Tokyo, Japan
| | - Xue Tan
- Department of Ophthalmology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan
| | - Yuji Inoue
- Department of Ophthalmology, Jichi Medical University, Shimotsuke, Tochigi, Japan.,Department of Ophthalmology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan
| | - Yoko Nomura
- Department of Ophthalmology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan
| | - Yusuke Arai
- Department of Ophthalmology, Jichi Medical University, Shimotsuke, Tochigi, Japan
| | - Yujiro Fujino
- Department of Ophthalmology, Japan Community Health Care Organization Tokyo Shinjuku Medical Center, Tokyo, Japan
| | - Hidetoshi Kawashima
- Department of Ophthalmology, Jichi Medical University, Shimotsuke, Tochigi, Japan
| | - Yasuo Yanagi
- Department of Medical Retina, Singapore National Eye Centre, Singapore, Singapore.,Department of Medical Retina, Singapore Eye Research Institute, Singapore, Singapore.,Department of Ophthalmology and Visual Sciences Academic Clinical Program, Duke-NUS, Medical School, National University of Singapore, Singapore, Singapore
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50
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Xie L, Ji T, Guo W. Anti-angiogenesis target therapy for advanced osteosarcoma (Review). Oncol Rep 2017; 38:625-636. [PMID: 28656259 PMCID: PMC5562076 DOI: 10.3892/or.2017.5735] [Citation(s) in RCA: 82] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2017] [Accepted: 06/12/2017] [Indexed: 12/11/2022] Open
Abstract
Osteosarcomas (OS), especially those with metastatic or unresectable disease, have limited treatment options. The greatest advancement in treatments occurred in the 1980s when multi-agent chemotherapy, including doxorubicin, cisplatin, high-dose methotrexate, and, in some regimens, ifosfamide, was demonstrated to improve overall survival compared with surgery alone. However, standard chemotherapeutic options have been limited by poor response rates in patients with relapsed or advanced cases. It has been reported that VEGFR expression correlates with the outcome of patients with osteosarcoma and circulating VEGF level has been associated with the development of lung metastasis. At present, it seems to us that progress has not been made since Grignani reported a phase II cohort trial of sorafenib and sorafenib combined with everolimus for advanced osteosarcoma, which, in a sense, have become a milestone as a second-line therapy for osteosarcoma. Although the recognization of muramyltripepetide phosphatidyl-ethanolamine has made some progress based on its combination with standard chemotherapy, its effect on refractory cases is controversial. Personalized comprehensive molecular profiling of high-risk osteosarcoma up to now has not changed the therapeutic prospect of advanced osteosarcoma significantly. Thus, how far have we moved forward and what therapeutic strategy should we prefer for anti-angiogenesis therapy? This review provides an overview of the most updated anti-angiogenesis therapy in OS and discusses some clinical options in order to maintain or even improve progression-free survival.
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Affiliation(s)
- Lu Xie
- Musculoskeletal Tumor Center, Peking University People's Hospital, Beijing 100044, P.R. China
| | - Tao Ji
- Musculoskeletal Tumor Center, Peking University People's Hospital, Beijing 100044, P.R. China
| | - Wei Guo
- Musculoskeletal Tumor Center, Peking University People's Hospital, Beijing 100044, P.R. China
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