1
|
Wang X, Chen X, Zhu J, Li S. Quantifying the impact of metronomic chemotherapy chemo-switch regimen and the sequencing of chemotherapy and radiotherapy on pancreatic ductal adenocarcinoma treatment. J Theor Biol 2025; 599:112033. [PMID: 39725272 DOI: 10.1016/j.jtbi.2024.112033] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2024] [Revised: 12/14/2024] [Accepted: 12/16/2024] [Indexed: 12/28/2024]
Abstract
Metronomic chemotherapy (MCT) is a novel chemotherapy approach characterized by a high-frequency, low-dose administration strategy. The "chemo-switch" regimen involves the sequential use of two dosing strategies: maximum tolerated dose (MTD) chemotherapy and MCT. For patients with pancreatic ductal adenocarcinoma (PDAC), selecting novel chemotherapy regimens appropriately according to their physical conditions may help address the challenges associated with MTD chemotherapy, such as excessive toxicity, prolonged tumor recovery, and suboptimal efficacy. There is currently limited research on mathematical models related to novel chemotherapy regimens and PDAC, as well as on the impact of different drug administration strategies and the sequence of chemoradiotherapy in combined treatment. To address these gaps, we propose a two-dimensional multiscale mathematical model. Initially, we model the individual effects of MTD chemotherapy, antiangiogenic therapy, and radiotherapy. Subsequently, we analyze the anti-tumor effects of various chemotherapy regimens and their underlying mechanisms. Furthermore, we assess how different drug administration regimens and the sequencing of chemotherapy and radiotherapy affect treatment outcomes. Simulation results indicate that, compared to standard MTD chemotherapy, using the MCT regimen or introducing MCT during MTD chemotherapy (chemo-switch regimen) demonstrates better anti-tumor efficacy and sustained tumor perfusion, enhancing drug accumulation within tumor regions. Combined therapy exhibits superior efficacy compared to monotherapy. Placing radiotherapy after anti-angiogenic therapy and chemotherapy suggests more effective in suppressing tumor growth and sustaining tumor perfusion. It is noteworthy that while this study focuses on PDAC treatment, its findings can be extrapolated to other fibrotic tumors, thereby facilitating similar analyses across different tumor types.
Collapse
Affiliation(s)
- Xu Wang
- College of Information Engineering, Zhejiang University of Technology, Hangzhou, China
| | - Xi Chen
- Department of General Surgery, Second Affiliated Hospital Zhejiang University School of Medicine, Hangzhou, China
| | - Jinhui Zhu
- Department of General Surgery, Second Affiliated Hospital Zhejiang University School of Medicine, Hangzhou, China
| | - Sheng Li
- College of Information Engineering, Zhejiang University of Technology, Hangzhou, China.
| |
Collapse
|
2
|
Xing L, Wang Z, Feng Y, Luo H, Dai G, Sang L, Zhang C, Qian J. The biological roles of CD47 in ovarian cancer progression. Cancer Immunol Immunother 2024; 73:145. [PMID: 38832992 PMCID: PMC11150368 DOI: 10.1007/s00262-024-03708-3] [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: 03/18/2024] [Accepted: 04/19/2024] [Indexed: 06/06/2024]
Abstract
Ovarian cancer is one of the most lethal malignant tumors, characterized by high incidence and poor prognosis. Patients relapse occurred in 65-80% after initial treatment. To date, no effective treatment has been established for these patients. Recently, CD47 has been considered as a promising immunotherapy target. In this paper, we reviewed the biological roles of CD47 in ovarian cancer and summarized the related mechanisms. For most types of cancers, the CD47/Sirpα immune checkpoint has attracted the most attention in immunotherapy. Notably, CD47 monoclonal antibodies and related molecules are promising in the immunotherapy of ovarian cancer, and further research is needed. In the future, new immunotherapy regimens targeting CD47 can be applied to the clinical treatment of ovarian cancer patients.
Collapse
Affiliation(s)
- Linan Xing
- Department of Gynecology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, People's Republic of China
| | - Zhao Wang
- Department of Gynecological Oncology, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, 310022, People's Republic of China
| | - Yue Feng
- Department of Gynecological Oncology, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, 310022, People's Republic of China
| | - Haixia Luo
- Department of Gynecology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, People's Republic of China
| | - Guijiang Dai
- Department of Comprehensive Office, The Second Affiliated Hospital of MuDanjiang Medical University, Mudanjiang, 157009, People's Republic of China
| | - Lin Sang
- Department of Obstetrics and Gynecology, People's Hospital of Anji, Huzhou, 310022, People's Republic of China
| | - Chunlong Zhang
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, 150081, People's Republic of China.
| | - Jianhua Qian
- Department of Gynecology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, People's Republic of China.
| |
Collapse
|
3
|
Basar OY, Mohammed S, Qoronfleh MW, Acar A. Optimizing cancer therapy: a review of the multifaceted effects of metronomic chemotherapy. Front Cell Dev Biol 2024; 12:1369597. [PMID: 38813084 PMCID: PMC11133583 DOI: 10.3389/fcell.2024.1369597] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2024] [Accepted: 04/29/2024] [Indexed: 05/31/2024] Open
Abstract
Metronomic chemotherapy (MCT), characterized by the continuous administration of chemotherapeutics at a lower dose without prolonged drug-free periods, has garnered significant attention over the last 2 decades. Extensive evidence from both pre-clinical and clinical settings indicates that MCT induces distinct biological effects than the standard Maximum Tolerated Dose (MTD) chemotherapy. The low toxicity profile, reduced likelihood of inducing acquired therapeutic resistance, and low cost of MCT render it an attractive chemotherapeutic regimen option. One of the most prominent aspects of MCT is its anti-angiogenesis effects. It has been shown to stimulate the expression of anti-angiogenic molecules, thereby inhibiting angiogenesis. In addition, MCT has been shown to decrease the regulatory T-cell population and promote anti-tumor immune response through inducing dendritic cell maturation and increasing the number of cytotoxic T-cells. Combination therapies utilizing MCT along with oncolytic virotherapy, radiotherapy or other chemotherapeutic regimens have been studied extensively. This review provides an overview of the current status of MCT research and the established mechanisms of action of MCT treatment and also offers insights into potential avenues of development for MCT in the future.
Collapse
Affiliation(s)
- Oyku Yagmur Basar
- Department of Biological Sciences, Middle East Technical University, Ankara, Türkiye
| | - Sawsan Mohammed
- Qatar University, QU Health, College of Medicine, Doha, Qatar
| | - M. Walid Qoronfleh
- Q3 Research Institute (QRI), Research and Policy Division, Ypsilanti, MI, United States
| | - Ahmet Acar
- Department of Biological Sciences, Middle East Technical University, Ankara, Türkiye
| |
Collapse
|
4
|
Garg V, Kumar L. Metronomic chemotherapy in ovarian cancer. Cancer Lett 2023; 579:216469. [PMID: 37923056 DOI: 10.1016/j.canlet.2023.216469] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2023] [Revised: 10/15/2023] [Accepted: 10/27/2023] [Indexed: 11/07/2023]
Abstract
Translational research and the development of targeted therapies have transformed the therapeutic landscape in epithelial ovarian cancer over the last decade. However, recurrent ovarian cancer continues to pose formidable challenges to therapeutic interventions, necessitating innovative strategies to optimize treatment outcomes. Current research focuses on the development of pharmaceuticals that target potential resistance pathways to DNA repair pathways. However, the cost and toxicity of some of these therapies are prohibitive and majority of patients lack access to clinical trials. Metronomic chemotherapy, characterized by the continuous administration of low doses of chemotherapeutic agents without long treatment breaks, has emerged as a promising approach with potential implications beyond recurrent setting. It acts primarily by inhibition of angiogenesis and activation of host immune system. We here review the mechanism of action of metronomic chemotherapy, as well as its current role, limitations, and avenues for further research in the management of epithelial ovarian cancer.
Collapse
Affiliation(s)
- Vikas Garg
- Clinical Research Fellow, Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, 700 University Avenue, 7th Floor, Station 7W386, M5G 1Z5, Toronto, ON, Canada.
| | - Lalit Kumar
- Oncology and BMT, Department of Medical Oncology, Artemis Hospital, Gurugram, India.
| |
Collapse
|
5
|
Wang L, Du C, Jiang B, Chen L, Wang Z. Adjusting the dose of traditional drugs combined with immunotherapy: reshaping the immune microenvironment in lung cancer. Front Immunol 2023; 14:1256740. [PMID: 37901223 PMCID: PMC10600379 DOI: 10.3389/fimmu.2023.1256740] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2023] [Accepted: 09/05/2023] [Indexed: 10/31/2023] Open
Abstract
Immunotherapy is currently the most promising clinical treatment for lung cancer, not only revolutionizing second-line therapy but now also approved for first-line treatment. However, its clinical efficiency is not high and not all patients benefit from it. Thus, finding the best combination strategy to expand anti-PD-1/PD-L1-based immunotherapy is now a hot research topic. The conventional use of chemotherapeutic drugs and targeted drugs inevitably leads to resistance, toxic side effects and other problems. Recent research, however, suggests that by adjusting the dosage of drugs and blocking the activation of mutational mechanisms that depend on acquired resistance, it is possible to reduce toxic side effects, activate immune cells, and reshape the immune microenvironment of lung cancer. Here, we discuss the effects of different chemotherapeutic drugs and targeted drugs on the immune microenvironment. We explore the effects of adjusting the dosing sequence and timing, and the mechanisms of such responses, and show how the effectiveness and reliability of combined immunotherapy provide improved treatment outcomes.
Collapse
Affiliation(s)
- Linlin Wang
- Department of Immunotherapy, Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, Henan, China
- Gansu University of Traditional Chinese Medicine, Lanzhou, Gansu, China
| | - Changqi Du
- Gansu University of Traditional Chinese Medicine, Lanzhou, Gansu, China
| | - Bing Jiang
- Gansu University of Traditional Chinese Medicine, Lanzhou, Gansu, China
| | - Lin Chen
- Guangzhou Medical University-Guangzhou Institute of Biomedicine and Health (GMU-GIBH) Joint School of Life Sciences, Guangdong-Hong Kong-Macau Joint Laboratory for Cell Fate Regulation and Diseases, Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Zibing Wang
- Department of Immunotherapy, Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, Henan, China
| |
Collapse
|
6
|
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.
Collapse
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
| |
Collapse
|
7
|
Mustafa A, Elkhamisy F, Arghiani N, Pranjol MZI. Potential crosstalk between pericytes and cathepsins in the tumour microenvironment. Biomed Pharmacother 2023; 164:114932. [PMID: 37236029 DOI: 10.1016/j.biopha.2023.114932] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2023] [Revised: 05/17/2023] [Accepted: 05/22/2023] [Indexed: 05/28/2023] Open
Abstract
Cancer remains a formidable global health challenge, and as such, investigators are constantly exploring underlying mechanisms that drive its progression. One area of interest is the role of lysosomal enzymes, such as cathepsins, in regulating cancer growth and development in the tumour microenvironment (TME). Pericytes, a key component of vasculature, play a key role in regulating blood vessel formation in the TME, have been shown to be influenced by cathepsins and their activity. Although cathepsins such as cathepsins D and L have been shown to induce angiogenesis, currently no direct link is known between pericytes and cathepsins interaction. This review aims to shed light on the potential interplay between pericytes and cathepsins in the TME, highlighting the possible implications for cancer therapy and future research directions.
Collapse
Affiliation(s)
- A Mustafa
- School of Life Sciences, University of Sussex, Falmer, Brighton BN1 9QG, UK
| | - F Elkhamisy
- School of Life Sciences, University of Sussex, Falmer, Brighton BN1 9QG, UK
| | - N Arghiani
- School of Life Sciences, University of Sussex, Falmer, Brighton BN1 9QG, UK; Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.
| | - M Z I Pranjol
- School of Life Sciences, University of Sussex, Falmer, Brighton BN1 9QG, UK.
| |
Collapse
|
8
|
Bevere M, Gkountakos A, Martelli FM, Scarpa A, Luchini C, Simbolo M. An Insight on Functioning Pancreatic Neuroendocrine Neoplasms. Biomedicines 2023; 11:303. [PMID: 36830839 PMCID: PMC9953748 DOI: 10.3390/biomedicines11020303] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2022] [Revised: 01/16/2023] [Accepted: 01/18/2023] [Indexed: 01/24/2023] Open
Abstract
Pancreatic neuroendocrine neoplasms (PanNENs) are rare neoplasms arising from islets of the Langerhans in the pancreas. They can be divided into two groups, based on peptide hormone secretion, functioning and nonfunctioning PanNENs. The first group is characterized by different secreted peptides causing specific syndromes and is further classified into subgroups: insulinoma, gastrinoma, glucagonoma, somatostatinoma, VIPoma and tumors producing serotonin and adrenocorticotrophic hormone. Conversely, the second group does not release peptides and is usually associated with a worse prognosis. Today, although the efforts to improve the therapeutic approaches, surgery remains the only curative treatment for patients with PanNENs. The development of high-throughput techniques has increased the molecular knowledge of PanNENs, thereby allowing us to understand better the molecular biology and potential therapeutic vulnerabilities of PanNENs. Although enormous advancements in therapeutic and molecular aspects of PanNENs have been achieved, there is poor knowledge about each subgroup of functioning PanNENs.Therefore, we believe that combining high-throughput platforms with new diagnostic tools will allow for the efficient characterization of the main differences among the subgroups of functioning PanNENs. In this narrative review, we summarize the current landscape regarding diagnosis, molecular profiling and treatment, and we discuss the future perspectives of functioning PanNENs.
Collapse
Affiliation(s)
- Michele Bevere
- Department of Diagnostics and Public Health, Section of Anatomical Pathology, University and Hospital Trust of Verona, 37134 Verona, Italy
- ARC-Net Applied Research on Cancer Centre, University and Hospital Trust of Verona, 37134 Verona, Italy
| | - Anastasios Gkountakos
- Department of Diagnostics and Public Health, Section of Anatomical Pathology, University and Hospital Trust of Verona, 37134 Verona, Italy
- ARC-Net Applied Research on Cancer Centre, University and Hospital Trust of Verona, 37134 Verona, Italy
| | - Filippo Maria Martelli
- Department of Diagnostics and Public Health, Section of Anatomical Pathology, University and Hospital Trust of Verona, 37134 Verona, Italy
| | - Aldo Scarpa
- Department of Diagnostics and Public Health, Section of Anatomical Pathology, University and Hospital Trust of Verona, 37134 Verona, Italy
- ARC-Net Applied Research on Cancer Centre, University and Hospital Trust of Verona, 37134 Verona, Italy
| | - Claudio Luchini
- Department of Diagnostics and Public Health, Section of Anatomical Pathology, University and Hospital Trust of Verona, 37134 Verona, Italy
| | - Michele Simbolo
- Department of Diagnostics and Public Health, Section of Anatomical Pathology, University and Hospital Trust of Verona, 37134 Verona, Italy
| |
Collapse
|
9
|
Shet D, Gatty RC. Impressive response to oral metronomic chemotherapy in ovarian cancer. CURRENT PROBLEMS IN CANCER: CASE REPORTS 2022. [DOI: 10.1016/j.cpccr.2022.100197] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
|
10
|
Kweon S, Jeong YS, Chung SW, Lee H, Lee HK, Park SJ, Choi JU, Park J, Chung SJ, Byun Y. Metronomic dose-finding approach in oral chemotherapy by experimentally-driven integrative mathematical modeling. Biomaterials 2022; 286:121584. [DOI: 10.1016/j.biomaterials.2022.121584] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2022] [Revised: 05/11/2022] [Accepted: 05/15/2022] [Indexed: 11/02/2022]
|
11
|
Symonds LK, Jenkins I, Linden HM, Kurland B, Gralow JR, Gadi VK, Ellis GK, Wu Q, Rodler E, Chalasani P, Chai X, Riedel J, SCCA Network Investigators, Stopeck A, Brown-Glaberman U, Specht JM. A Phase II Study Evaluating the Safety and Efficacy of Sunitinib Malate in Combination With Weekly Paclitaxel Followed by Doxorubicin and Daily Oral Cyclophosphamide Plus G-CSF as Neoadjuvant Chemotherapy for Locally Advanced or Inflammatory Breast Cancer. Clin Breast Cancer 2022; 22:32-42. [PMID: 34158245 PMCID: PMC8611115 DOI: 10.1016/j.clbc.2021.05.009] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Revised: 05/01/2021] [Accepted: 05/17/2021] [Indexed: 01/03/2023]
Abstract
INTRODUCTION Neoadjuvant chemotherapy is standard treatment for locally advanced breast cancer (LABC) or inflammatory breast cancer (IBC). We hypothesized that adding sunitinib, a tyrosine kinase inhibitor with antitumor and antiangiogenic activity, to an anthracycline and taxane regimen would improve pathologic complete response (pCR) rates to a prespecified endpoint of 45% in patients with HER2-negative LABC or IBC. METHODS We conducted a multicenter, phase II trial of neoadjuvant sunitinib with paclitaxel (S+T) followed by doxorubicin and cyclophosphamide plus G-CSF for patients with HER2-negative LABC or IBC. Patients received sunitinib 25 mg PO daily with paclitaxel 80 mg/m2 IV weekly ×12 followed by doxorubicin 24 mg/m2 IV weekly + cyclophosphamide 60 mg/m2 PO daily with G-CSF support. Response was evaluated using pCR in the breast and the CPS + EG score (clinical-pathologic scoring + estrogen receptor [ER] and grade). RESULTS Seventy patients enrolled, and 66 were evaluable for efficacy. Eighteen patients (27%) had pCR in the breast (10 had ER+ disease and 8 had triple-negative disease). When defining response as pCR and/or CPS + EG score ≤2, 31 (47%) were responders. In pateints with ER positive disease, 23 (64%) were responders. The most common toxicities were cytopenias and fatigue. CONCLUSIONS Neoadjuvant S+T followed by AC+G-CSF was safe and tolerable in LABC and IBC. The study did not meet the prespecified endpoint for pCR; however, 47% were responders using pCR and/or CPS + EG score ≤2. ER positive patients had the highest response rate (64%). The addition of sunitinib to neoadjuvant chemotherapy may provide promising incremental benefit for patients with ER positive LABC.
Collapse
Affiliation(s)
- LK Symonds
- Medical Oncology, University of Washington, Seattle, WA
| | - I Jenkins
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA
| | - HM Linden
- Medical Oncology, University of Washington, Seattle, WA,Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA
| | - B Kurland
- eResearch Technologies, Inc. (ERT), Pittsburgh, PA
| | - JR Gralow
- Medical Oncology, University of Washington, Seattle, WA,Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA
| | - VK Gadi
- Medical Oncology, University of Illinois Cancer Center, Chicago, IL
| | - GK Ellis
- Medical Oncology, University of Washington, Seattle, WA
| | - Q Wu
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA
| | - E Rodler
- Hematology and Oncology, UC Davis, Sacramento, CA
| | - P Chalasani
- Hematology and Oncology, University of Arizona Cancer Center, Tucson, AZ
| | | | - J Riedel
- Clinical Cancer Genetics, Duke Cancer Institute, Durham, NC
| | | | - A Stopeck
- Hematology and Oncology, Stony Brook University, Stonybrook, NY
| | | | - JM Specht
- Medical Oncology, University of Washington, Seattle, WA,Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA
| |
Collapse
|
12
|
Cdk5 drives formation of heterogeneous pancreatic neuroendocrine tumors. Oncogenesis 2021; 10:83. [PMID: 34862365 PMCID: PMC8642406 DOI: 10.1038/s41389-021-00372-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Revised: 11/02/2021] [Accepted: 11/11/2021] [Indexed: 01/07/2023] Open
Abstract
Pancreatic neuroendocrine tumors (PanNETs) are a heterogeneous population of neoplasms that arise from hormone-secreting islet cells of the pancreas and have increased markedly in incidence over the past four decades. Non-functional PanNETs, which occur more frequently than hormone-secreting tumors, are often not diagnosed until later stages of tumor development and have poorer prognoses. Development of successful therapeutics for PanNETs has been slow, partially due to a lack of diverse animal models for pre-clinical testing. Here, we report development of an inducible, conditional mouse model of PanNETs by using a bi-transgenic system for regulated expression of the aberrant activator of Cdk5, p25, specifically in β-islet cells. This model produces a heterogeneous population of PanNETs that includes a subgroup of well-differentiated, non-functional tumors. Production of these tumors demonstrates the causative potential of aberrantly active Cdk5 for generation of PanNETs. Further, we show that human PanNETs express Cdk5 pathway components, are dependent on Cdk5 for growth, and share genetic and transcriptional overlap with the INS-p25OE model. The utility of this model is enhanced by the ability to form tumor-derived allografts. This new model of PanNETs will facilitate molecular delineation of Cdk5-dependent PanNETs and the development of new targeted therapeutics.
Collapse
|
13
|
Muñoz R, Girotti A, Hileeto D, Arias FJ. Metronomic Anti-Cancer Therapy: A Multimodal Therapy Governed by the Tumor Microenvironment. Cancers (Basel) 2021; 13:cancers13215414. [PMID: 34771577 PMCID: PMC8582362 DOI: 10.3390/cancers13215414] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Revised: 10/19/2021] [Accepted: 10/25/2021] [Indexed: 02/06/2023] Open
Abstract
Simple Summary Metronomic chemotherapy with different mechanisms of action against cancer cells and their microenvironment represents an exceptional holistic cancer treatment. Each type of tumor has its own characteristics, including each individual tumor in each patient. Understanding the complexity of the dynamic interactions that take place between tumor and stromal cells and the microenvironment in tumor progression and metastases, as well as the response of the host and the tumor itself to anticancer therapy, will allow therapeutic actions with long-lasting effects to be implemented using metronomic regimens. This study aims to highlight the complexity of cellular interactions in the tumor microenvironment and summarize some of the preclinical and clinical results that explain the multimodality of metronomic therapy, which, together with its low toxicity, supports an inhibitory effect on the primary tumor and metastases. We also highlight the possible use of nano-therapeutic agents as good partners for metronomic chemotherapy. Abstract The concept of cancer as a systemic disease, and the therapeutic implications of this, has gained special relevance. This concept encompasses the interactions between tumor and stromal cells and their microenvironment in the complex setting of primary tumors and metastases. These factors determine cellular co-evolution in time and space, contribute to tumor progression, and could counteract therapeutic effects. Additionally, cancer therapies can induce cellular and molecular responses in the tumor and host that allow them to escape therapy and promote tumor progression. In this study, we describe the vascular network, tumor-infiltrated immune cells, and cancer-associated fibroblasts as sources of heterogeneity and plasticity in the tumor microenvironment, and their influence on cancer progression. We also discuss tumor and host responses to the chemotherapy regimen, at the maximum tolerated dose, mainly targeting cancer cells, and a multimodal metronomic chemotherapy approach targeting both cancer cells and their microenvironment. In a combination therapy context, metronomic chemotherapy exhibits antimetastatic efficacy with low toxicity but is not exempt from resistance mechanisms. As such, a better understanding of the interactions between the components of the tumor microenvironment could improve the selection of drug combinations and schedules, as well as the use of nano-therapeutic agents against certain malignancies.
Collapse
Affiliation(s)
- Raquel Muñoz
- Department of Biochemistry, Physiology and Molecular Biology, University of Valladolid, Paseo de Belén, 47011 Valladolid, Spain
- Smart Biodevices for NanoMed Group, University of Valladolid, LUCIA Building, Paseo de Belén, 47011 Valladolid, Spain;
- Correspondence:
| | - Alessandra Girotti
- BIOFORGE (Group for Advanced Materials and Nanobiotechnology), University of Valladolid, CIBER-BBN, LUCIA Building, Paseo de Belén, 47011 Valladolid, Spain;
| | - Denise Hileeto
- School of Optometry and Vision Science, University of Waterloo, Waterloo, ON N2L 361, Canada;
| | - Francisco Javier Arias
- Smart Biodevices for NanoMed Group, University of Valladolid, LUCIA Building, Paseo de Belén, 47011 Valladolid, Spain;
| |
Collapse
|
14
|
Maharjan CK, Ear PH, Tran CG, Howe JR, Chandrasekharan C, Quelle DE. Pancreatic Neuroendocrine Tumors: Molecular Mechanisms and Therapeutic Targets. Cancers (Basel) 2021; 13:5117. [PMID: 34680266 PMCID: PMC8533967 DOI: 10.3390/cancers13205117] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2021] [Revised: 10/08/2021] [Accepted: 10/09/2021] [Indexed: 12/16/2022] Open
Abstract
Pancreatic neuroendocrine tumors (pNETs) are unique, slow-growing malignancies whose molecular pathogenesis is incompletely understood. With rising incidence of pNETs over the last four decades, larger and more comprehensive 'omic' analyses of patient tumors have led to a clearer picture of the pNET genomic landscape and transcriptional profiles for both primary and metastatic lesions. In pNET patients with advanced disease, those insights have guided the use of targeted therapies that inhibit activated mTOR and receptor tyrosine kinase (RTK) pathways or stimulate somatostatin receptor signaling. Such treatments have significantly benefited patients, but intrinsic or acquired drug resistance in the tumors remains a major problem that leaves few to no effective treatment options for advanced cases. This demands a better understanding of essential molecular and biological events underlying pNET growth, metastasis, and drug resistance. This review examines the known molecular alterations associated with pNET pathogenesis, identifying which changes may be drivers of the disease and, as such, relevant therapeutic targets. We also highlight areas that warrant further investigation at the biological level and discuss available model systems for pNET research. The paucity of pNET models has hampered research efforts over the years, although recently developed cell line, animal, patient-derived xenograft, and patient-derived organoid models have significantly expanded the available platforms for pNET investigations. Advancements in pNET research and understanding are expected to guide improved patient treatments.
Collapse
Affiliation(s)
- Chandra K. Maharjan
- Department of Neuroscience and Pharmacology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA;
| | - Po Hien Ear
- Department of Surgery, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA; (P.H.E.); (C.G.T.); (J.R.H.)
| | - Catherine G. Tran
- Department of Surgery, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA; (P.H.E.); (C.G.T.); (J.R.H.)
| | - James R. Howe
- Department of Surgery, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA; (P.H.E.); (C.G.T.); (J.R.H.)
| | - Chandrikha Chandrasekharan
- Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA;
| | - Dawn E. Quelle
- Department of Neuroscience and Pharmacology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA;
- Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
- Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA 52242, USA
| |
Collapse
|
15
|
Pericytes augment glioblastoma cell resistance to temozolomide through CCL5-CCR5 paracrine signaling. Cell Res 2021; 31:1072-1087. [PMID: 34239070 PMCID: PMC8486800 DOI: 10.1038/s41422-021-00528-3] [Citation(s) in RCA: 93] [Impact Index Per Article: 23.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2020] [Accepted: 06/04/2021] [Indexed: 02/07/2023] Open
Abstract
Glioblastoma (GBM) is a prevalent and highly lethal form of glioma, with rapid tumor progression and frequent recurrence. Excessive outgrowth of pericytes in GBM governs the ecology of the perivascular niche, but their function in mediating chemoresistance has not been fully explored. Herein, we uncovered that pericytes potentiate DNA damage repair (DDR) in GBM cells residing in the perivascular niche, which induces temozolomide (TMZ) chemoresistance. We found that increased pericyte proportion correlates with accelerated tumor recurrence and worse prognosis. Genetic depletion of pericytes in GBM xenografts enhances TMZ-induced cytotoxicity and prolongs survival of tumor-bearing mice. Mechanistically, C-C motif chemokine ligand 5 (CCL5) secreted by pericytes activates C-C motif chemokine receptor 5 (CCR5) on GBM cells to enable DNA-dependent protein kinase catalytic subunit (DNA-PKcs)-mediated DDR upon TMZ treatment. Disrupting CCL5-CCR5 paracrine signaling through the brain-penetrable CCR5 antagonist maraviroc (MVC) potently inhibits pericyte-promoted DDR and effectively improves the chemotherapeutic efficacy of TMZ. GBM patient-derived xenografts with high CCL5 expression benefit from combined treatment with TMZ and MVC. Our study reveals the role of pericytes as an extrinsic stimulator potentiating DDR signaling in GBM cells and suggests that targeting CCL5-CCR5 signaling could be an effective therapeutic strategy to improve chemotherapeutic efficacy against GBM.
Collapse
|
16
|
Lin A, Feng J, Chen X, Wang D, Wong M, Zhang G, Na J, Zhang T, Chen Z, Chen YT, Nancy Du YC. High levels of truncated RHAMM cooperate with dysfunctional p53 to accelerate the progression of pancreatic cancer. Cancer Lett 2021; 514:79-89. [PMID: 34044069 PMCID: PMC8235875 DOI: 10.1016/j.canlet.2021.05.011] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Revised: 04/19/2021] [Accepted: 05/06/2021] [Indexed: 12/13/2022]
Abstract
Pancreatic cancer has the lowest survival rate out of all types of cancer. Pancreatic cancer patients are often diagnosed at advanced stages, hence an urgent need for a better therapeutic development of this devastating disease. Receptor for hyaluronan-mediated motility (RHAMM), not expressed in adult normal pancreas, has been suggested as a prognostic factor and a potential therapeutic target for pancreatic ductal adenocarcinoma (PDAC) and pancreatic neuroendocrine tumor (PNET). In this study, we initially sought to determine whether genetic deletion of RHAMM would slow down pancreatic cancer progression using Rhamm-/- mice. However, we found that Rhamm-/- mice expressed a truncated HMMRΔexon8-16 protein at higher abundance levels than wild-type RHAMM. While HMMRΔexon8-16 did not enable malignant progression of pancreatic intraepithelial neoplasia in p48-Cre; LSL-KRASG12D mice, it accelerated the formation of invasive PDAC and shortened the survival of p48-Cre; LSL-KRASG12D mice with heterozygous p53 knockout. KrasG12D PDAC mice with homozygous p53 knockout mice died around 10 weeks, and the effect of HMMRΔexon8-16 was not apparent in these short lifespan mice. In addition, HMMRΔexon8-16 shortened the survival of PNET-bearing RIP-Tag mice, which had inactivated p53. In our analysis of TCGA dataset, pancreatic cancer patients with mutant TP53 or loss of one copy of TP53 had higher RHAMM expression, which, combined, predicted worse outcomes. Taken together, by collaborating with dysfunctional p53, high levels of HMMRΔexon8-16 , which lacks the centrosome targeting domain and degrons for interaction with the Anaphase-Promoting Complex (APC), accelerated pancreatic cancer progression.
Collapse
Affiliation(s)
- Anthony Lin
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, 10065, USA
| | - Jennifer Feng
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, 10065, USA
| | - Xiang Chen
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, 10065, USA
| | - Dunrui Wang
- Laboratory of Cellular Oncology, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Megan Wong
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, 10065, USA
| | - George Zhang
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, 10065, USA
| | - Joseph Na
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, 10065, USA
| | - Tiantian Zhang
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, 10065, USA
| | - Zhengming Chen
- Division of Biostatistics and Epidemiology, Department of Population Health Sciences, Weill Cornell Medicine, New York, NY, 10065, USA
| | - Yao-Tseng Chen
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, 10065, USA
| | - Yi-Chieh Nancy Du
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, 10065, USA.
| |
Collapse
|
17
|
Antineoplastic agents aggravate the damages caused by nicotine on the peri-implant bone: an in vivo histomorphometric and immunohistochemical study in rats. Clin Oral Investig 2021; 26:1477-1489. [PMID: 34386857 DOI: 10.1007/s00784-021-04121-1] [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: 06/14/2021] [Accepted: 08/01/2021] [Indexed: 10/20/2022]
Abstract
OBJECTIVE To assess the interaction between chemotherapy and normal tissues is critical to assure quality of life during and after the treatment of cancer. This study evaluated the influence of cisplatin (CIS) and 5-fluorouracil (5-FU) over the peri-implant tissues around osseointegrated titanium implants in animals previously exposed to nicotine. Materials and methods One hundred twenty male rats were divided into two groups, receiving via subcutaneous injection, either physiological saline solution (PSS) (n = 30) or nicotine hemissulfate (NIC) (n = 90) for 30 days prior to implants' placement. One titanium implant (4.0 × 2.2 mm) was installed in each tibia of all animals. PSS and NIC were continued for 30 days after surgery. Five days after cessation, rats were subdivided into three subgroups in accordance with systemic treatments with either PSS, CIS, or 5-FU. Euthanasia was performed at 50, 65, and 95 days post-surgery. Histometric, histopathological, and immunohistochemical analyses were performed. RESULTS NIC-CIS and NIC-5FU presented lower BIC (50, 65, and 95 days) and bone area fraction occupancy (BAFO) (65 and 95 days) than group NIC. Intense inflammatory infiltration, severe tissue breakdown, reduced expression of bone formation biomarkers, and upregulation of TRAP were observed in NIC-CIS and NIC-5FU when compared with group NIC. TRAP expression was significantly higher in NIC-5FU as compared with NIC-CIS at 50 and 95 days. Groups NIC, NIC-CIS, and NIC-5FU presented statistically significant negative impact in all outcome parameters than group PSS. CONCLUSION CIS and 5-FU severely disrupted the peri-implant tissues around osseointegrated implants in animals previously exposed to nicotine. CLINICAL RELEVANCE Assessing the interaction between chemotherapy and normal tissues is critical to assure quality of life during and after the cancer treatment.
Collapse
|
18
|
Anjum S, Ishaque S, Fatima H, Farooq W, Hano C, Abbasi BH, Anjum I. Emerging Applications of Nanotechnology in Healthcare Systems: Grand Challenges and Perspectives. Pharmaceuticals (Basel) 2021; 14:ph14080707. [PMID: 34451803 PMCID: PMC8401281 DOI: 10.3390/ph14080707] [Citation(s) in RCA: 57] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Revised: 07/15/2021] [Accepted: 07/17/2021] [Indexed: 02/07/2023] Open
Abstract
Healthcare, as a basic human right, has often become the focus of the development of innovative technologies. Technological progress has significantly contributed to the provision of high-quality, on-time, acceptable, and affordable healthcare. Advancements in nanoscience have led to the emergence of a new generation of nanostructures. Each of them has a unique set of properties that account for their astonishing applications. Since its inception, nanotechnology has continuously affected healthcare and has exerted a tremendous influence on its transformation, contributing to better outcomes. In the last two decades, the world has seen nanotechnology taking steps towards its omnipresence and the process has been accelerated by extensive research in various healthcare sectors. The inclusion of nanotechnology and its allied nanocarriers/nanosystems in medicine is known as nanomedicine, a field that has brought about numerous benefits in disease prevention, diagnosis, and treatment. Various nanosystems have been found to be better candidates for theranostic purposes, in contrast to conventional ones. This review paper will shed light on medically significant nanosystems, as well as their applications and limitations in areas such as gene therapy, targeted drug delivery, and in the treatment of cancer and various genetic diseases. Although nanotechnology holds immense potential, it is yet to be exploited. More efforts need to be directed to overcome these limitations and make full use of its potential in order to revolutionize the healthcare sector in near future.
Collapse
Affiliation(s)
- Sumaira Anjum
- Department of Biotechnology, Kinnaird College for Women, Lahore 54000, Pakistan; (S.I.); (H.F.); (W.F.); (I.A.)
- Correspondence: ; Tel.: +92-300-6957038
| | - Sara Ishaque
- Department of Biotechnology, Kinnaird College for Women, Lahore 54000, Pakistan; (S.I.); (H.F.); (W.F.); (I.A.)
| | - Hijab Fatima
- Department of Biotechnology, Kinnaird College for Women, Lahore 54000, Pakistan; (S.I.); (H.F.); (W.F.); (I.A.)
| | - Wajiha Farooq
- Department of Biotechnology, Kinnaird College for Women, Lahore 54000, Pakistan; (S.I.); (H.F.); (W.F.); (I.A.)
| | - Christophe Hano
- Laboratoire de Biologie des Ligneux et des Grandes Cultures (LBLGC), INRAe USC1328, Université d’Orléans, 28000 Chartres, France;
| | - Bilal Haider Abbasi
- Department of Biotechnology, Quaid-i-Azam University, Islamabad 54000, Pakistan;
| | - Iram Anjum
- Department of Biotechnology, Kinnaird College for Women, Lahore 54000, Pakistan; (S.I.); (H.F.); (W.F.); (I.A.)
| |
Collapse
|
19
|
Sun R, Kong X, Qiu X, Huang C, Wong PP. The Emerging Roles of Pericytes in Modulating Tumor Microenvironment. Front Cell Dev Biol 2021; 9:676342. [PMID: 34179005 PMCID: PMC8232225 DOI: 10.3389/fcell.2021.676342] [Citation(s) in RCA: 47] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Accepted: 04/06/2021] [Indexed: 12/17/2022] Open
Abstract
Pericytes (PCs), known as mural cells, play an important blood vessel (BV) supporting role in regulating vascular stabilization, permeability and blood flow in microcirculation as well as blood brain barrier. In carcinogenesis, defective interaction between PCs and endothelial cells (ECs) contributes to the formation of leaky, chaotic and dysfunctional vasculature in tumors. However, recent works from other laboratories and our own demonstrate that the direct interaction between PCs and other stromal cells/cancer cells can modulate tumor microenvironment (TME) to favor cancer growth and progression, independent of its BV supporting role. Furthermore, accumulating evidence suggests that PCs have an immunomodulatory role. In the current review, we focus on recent advancement in understanding PC's regulatory role in the TME by communicating with ECs, immune cells, and tumor cells, and discuss how we can target PC's functions to re-model TME for an improved cancer treatment strategy.
Collapse
Affiliation(s)
- Ruipu Sun
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.,Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Xiangzhan Kong
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.,Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Xiaoyi Qiu
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.,Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Cheng Huang
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.,Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Ping-Pui Wong
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.,Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| |
Collapse
|
20
|
Dou Y, Jiang D. [Research Progress of Small Molecule Anti-angiogenic Drugs
in Non-small Cell Lung Cancer]. ZHONGGUO FEI AI ZA ZHI = CHINESE JOURNAL OF LUNG CANCER 2021; 24:56-62. [PMID: 33478192 PMCID: PMC7849040 DOI: 10.3779/j.issn.1009-3419.2021.102.02] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 12/02/2022]
Abstract
肺癌是世界上发病率最高的癌症之一,且尚无二线进展后的标准治疗方案,而肿瘤血管生成目前已被确定为恶性肿瘤的重要治疗靶点,小分子多靶点血管激酶抑制剂可通过抑制血管生成相关信号通路,抑制肿瘤血管的生成。目前已开展多项小分子抗血管生成药物治疗非小细胞肺癌的临床试验,且已有部分血管内皮生长因子受体酪氨酸激酶抑制剂(vascular endothelial growth factor receptor-tyrosine kinase inhibitors, VEGFR-TKIs)获批治疗晚期非小细胞肺癌,本文基于国内外多项小分子抗血管生成药物治疗非小细胞肺癌的发展现状,归纳了多个VEGFR-TKIs及成纤维细胞生长因子受体(fibroblast growth factor receptor, FGFR)-TKI单药或联合[包括分别与化疗、表皮生长因子受体(epidermal growth factor receptor, EGFR)-TKIs、免疫治疗、放疗等联合)]治疗非小细胞肺癌的疗效与安全性研究,同时探讨了VEGFR-TKIs可能存在的耐药机制及疗效预测指标等,并对未来抗血管治疗非小细胞肺癌的发展趋势以及存在的潜在问题进行展望,同时为肺癌后续的精准治疗及个体化治疗提供新的思路。
Collapse
Affiliation(s)
- Yan Dou
- Department of Oncology, The Fourth Hospital of Hebei Medical University, Shijiazhuang 050011, China
| | - Da Jiang
- Department of Oncology, The Fourth Hospital of Hebei Medical University, Shijiazhuang 050011, China
| |
Collapse
|
21
|
Zhuang X, Maione F, Robinson J, Bentley M, Kaul B, Whitworth K, Jumbu N, Jinks E, Bystrom J, Gabriele P, Garibaldi E, Delmastro E, Nagy Z, Gilham D, Giraudo E, Bicknell R, Lee SP. CAR T cells targeting tumor endothelial marker CLEC14A inhibit tumor growth. JCI Insight 2020; 5:138808. [PMID: 33004686 PMCID: PMC7566713 DOI: 10.1172/jci.insight.138808] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2020] [Accepted: 08/20/2020] [Indexed: 01/11/2023] Open
Abstract
Engineering T cells to express chimeric antigen receptors (CARs) specific for antigens on hematological cancers has yielded remarkable clinical responses, but with solid tumors, benefit has been more limited. This may reflect lack of suitable target antigens, immune evasion mechanisms in malignant cells, and/or lack of T cell infiltration into tumors. An alternative approach, to circumvent these problems, is targeting the tumor vasculature rather than the malignant cells directly. CLEC14A is a glycoprotein selectively overexpressed on the vasculature of many solid human cancers and is, therefore, of considerable interest as a target antigen. Here, we generated CARs from 2 CLEC14A-specific antibodies and expressed them in T cells. In vitro studies demonstrated that, when exposed to their target antigen, these engineered T cells proliferate, release IFN-γ, and mediate cytotoxicity. Infusing CAR engineered T cells into healthy mice showed no signs of toxicity, yet these T cells targeted tumor tissue and significantly inhibited tumor growth in 3 mouse models of cancer (Rip-Tag2, mPDAC, and Lewis lung carcinoma). Reduced tumor burden also correlated with significant loss of CLEC14A expression and reduced vascular density within malignant tissues. These data suggest the tumor vasculature can be safely and effectively targeted with CLEC14A-specific CAR T cells, offering a potent and widely applicable therapy for cancer. T cells expressing a chimeric antigen receptor specific for the tumor vascular marker CLEC14A inhibited tumor growth in three mouse cancer models.
Collapse
Affiliation(s)
- Xiaodong Zhuang
- Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
| | - Federica Maione
- Laboratory of Transgenic Mouse Models, Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy, and Department of Science and Drug Technology, University of Torino, Torino, Italy
| | - Joseph Robinson
- Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
| | - Michael Bentley
- Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
| | - Baksho Kaul
- Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
| | - Katharine Whitworth
- Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
| | - Neeraj Jumbu
- Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
| | - Elizabeth Jinks
- Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
| | - Jonas Bystrom
- Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
| | - Pietro Gabriele
- Radiation Therapy Laboratory, Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy
| | - Elisabetta Garibaldi
- Radiation Therapy Laboratory, Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy
| | - Elena Delmastro
- Radiation Therapy Laboratory, Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy
| | - Zsuzsanna Nagy
- Institute of Inflammation and Ageing, University of Birmingham, Birmingham, United Kingdom
| | - David Gilham
- Clinical and Experimental Immunotherapy Group, University of Manchester, Manchester, United Kingdom
| | - Enrico Giraudo
- Laboratory of Transgenic Mouse Models, Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy, and Department of Science and Drug Technology, University of Torino, Torino, Italy
| | - Roy Bicknell
- Institute of Cardiovascular Science, University of Birmingham, Birmingham, United Kingdom
| | - Steven P Lee
- Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
| |
Collapse
|
22
|
Mainetti LE, Rico MJ, Kaufman CD, Grillo MC, Guercetti J, Baglioni MV, Del Giúdice A, Capitani MC, Fusini M, Rozados VR, Scharovsky OG. Losartan improves the therapeutic effect of metronomic cyclophosphamide in triple negative mammary cancer models. Oncotarget 2020; 11:3048-3060. [PMID: 32850009 PMCID: PMC7429183 DOI: 10.18632/oncotarget.27694] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2020] [Accepted: 05/25/2020] [Indexed: 12/24/2022] Open
Abstract
Metronomic chemotherapy refers to the minimum biologically effective doses of a chemotherapy agent given as a continuous regimen without extended rest periods. Drug repurposing is defined as the use of an already known drug for a new medical indication, different from the original one. In oncology the combination of these two therapeutic approaches is called "Metronomics". The aim of this work is to evaluate the therapeutic effect of cyclophosphamide in a metronomic schedule in combination with the repurposed drug losartan in two genetically different mice models of triple negative breast cancer. Our findings showed that adding losartan to metronomic cyclophosphamide significantly improved the therapeutic outcome. In both models the combined treatment increased the mice's survival without sings of toxicity. Moreover, we elucidated some of the mechanisms of action involved, which include a decrease of intratumor hypoxia, stimulation of the immune response and remodeling of the tumor microenvironment. The remarkable therapeutic effect, the lack of toxicity, the low cost of the drugs and its oral administration, strongly suggest its translation to the clinical setting in the near future.
Collapse
Affiliation(s)
- Leandro E. Mainetti
- Instituto de Genética Experimental, Facultad de Ciencias Médicas, Universidad Nacional de Rosario, Rosario, Argentina
- Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires, Argentina
- These authors contributed equally and are co-first authors
| | - María José Rico
- Instituto de Genética Experimental, Facultad de Ciencias Médicas, Universidad Nacional de Rosario, Rosario, Argentina
- Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires, Argentina
- These authors contributed equally and are co-first authors
| | - Cintia Daniela Kaufman
- Instituto de Genética Experimental, Facultad de Ciencias Médicas, Universidad Nacional de Rosario, Rosario, Argentina
- Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires, Argentina
| | - Monica Carolina Grillo
- Instituto de Genética Experimental, Facultad de Ciencias Médicas, Universidad Nacional de Rosario, Rosario, Argentina
| | - Julian Guercetti
- Instituto de Genética Experimental, Facultad de Ciencias Médicas, Universidad Nacional de Rosario, Rosario, Argentina
| | - María Virginia Baglioni
- Instituto de Genética Experimental, Facultad de Ciencias Médicas, Universidad Nacional de Rosario, Rosario, Argentina
- Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires, Argentina
| | - Antonela Del Giúdice
- Instituto de Genética Experimental, Facultad de Ciencias Médicas, Universidad Nacional de Rosario, Rosario, Argentina
- Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires, Argentina
| | - Maria Celeste Capitani
- Instituto de Genética Experimental, Facultad de Ciencias Médicas, Universidad Nacional de Rosario, Rosario, Argentina
| | - Matias Fusini
- Instituto de Genética Experimental, Facultad de Ciencias Médicas, Universidad Nacional de Rosario, Rosario, Argentina
| | - Viviana Rosa Rozados
- Instituto de Genética Experimental, Facultad de Ciencias Médicas, Universidad Nacional de Rosario, Rosario, Argentina
- Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires, Argentina
- These authors contributed equally and are co-senior authors
| | - O. Graciela Scharovsky
- Instituto de Genética Experimental, Facultad de Ciencias Médicas, Universidad Nacional de Rosario, Rosario, Argentina
- Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires, Argentina
- Metronomics Global Health Initiative, Marseille, France
- These authors contributed equally and are co-senior authors
| |
Collapse
|
23
|
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.
Collapse
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
| |
Collapse
|
24
|
Koumarianou A, Alexandraki KI, Wallin G, Kaltsas G, Daskalakis K. Pathogenesis and Clinical Management of Mesenteric Fibrosis in Small Intestinal Neuroendocine Neoplasms: A Systematic Review. J Clin Med 2020; 9:E1777. [PMID: 32521677 PMCID: PMC7357094 DOI: 10.3390/jcm9061777] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2020] [Revised: 06/04/2020] [Accepted: 06/04/2020] [Indexed: 02/07/2023] Open
Abstract
Mesenteric fibrosis (MF) constitutes an underrecognized sequela in patients with small intestinal neuroendocrine neoplasms (SI-NENs), often complicating the disease clinical course. The aim of the present systematic review, carried out by Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) methodology, is to provide an update in evolving aspects of MF pathogenesis and its clinical management in SI-NENs. Complex and dynamic interactions are present in the microenvironment of tumor deposits in the mesentery. Serotonin, as well as the signaling pathways of certain growth factors play a pivotal, yet not fully elucidated role in the pathogenesis of MF. Clinically, MF often results in significant morbidity by causing either acute complications, such as intestinal obstruction and/or acute ischemia or more chronic conditions involving abdominal pain, venous stasis, malabsorption and malnutrition. Surgical resection in patients with locoregional disease only or symptomatic distant stage disease, as well as palliative minimally invasive interventions in advanced inoperable cases seem clinically meaningful, whereas currently available systemic and/or targeted treatments do not unequivocally affect the development of MF in SI-NENs. Increased awareness and improved understanding of the molecular pathogenesis of MF in SI-NENs may provide better diagnostic and predictive tools for its timely recognition and intervention and also facilitates the development of agents targeting MF.
Collapse
Affiliation(s)
- Anna Koumarianou
- Hematology Oncology Unit, Fourth Department of Internal Medicine, Attikon University General Hospital, National and Kapodistrian University of Athens, 12462 Athens, Greece
| | - Krystallenia I. Alexandraki
- 1st Department of Propaedeutic Internal Medicine, Endocrine Unit, National and Kapodistrian, University of Athens, 11527 Athens, Greece; (K.I.A.); (G.K.); (K.D.)
| | - Göran Wallin
- Department of Surgery, Faculty of Medicine and Health, Örebro University, 701 85 Örebro, Sweden;
| | - Gregory Kaltsas
- 1st Department of Propaedeutic Internal Medicine, Endocrine Unit, National and Kapodistrian, University of Athens, 11527 Athens, Greece; (K.I.A.); (G.K.); (K.D.)
| | - Kosmas Daskalakis
- 1st Department of Propaedeutic Internal Medicine, Endocrine Unit, National and Kapodistrian, University of Athens, 11527 Athens, Greece; (K.I.A.); (G.K.); (K.D.)
- Department of Surgery, Faculty of Medicine and Health, Örebro University, 701 85 Örebro, Sweden;
| |
Collapse
|
25
|
Zhang Z, Zhang Y, Luo F, Ma Y, Fang W, Zhan J, Li S, Yang Y, Zhao Y, Hong S, Zhou T, Zhang Y, Zhao S, Huang Y, Zhao H, Zhang L. Dual blockade of EGFR and VEGFR pathways: Results from a pilot study evaluating apatinib plus gefitinib as a first-line treatment for advanced EGFR-mutant non-small cell lung cancer. Clin Transl Med 2020; 10:e33. [PMID: 32508029 PMCID: PMC7403827 DOI: 10.1002/ctm2.33] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Background Dual blockade of both EGFR and VEGFR pathways in EGFR‐mutant NSCLC have shown enhanced antitumor efficacy versus EGFR‐TKIs alone. Apatinib is an orally effective VEGFR‐2 tyrosine kinase inhibitor (TKI). This pilot study aims to evaluate the tolerability, pharmacokinetic profile, and antitumor activity of apatinib plus gefitinib as a therapy for EGFR‐mutant advanced NSCLC. Methods Advanced non‐squamous NSCLC participants harbored with the EGFR 19 deletion or the 21 L858R point mutation were included. There were two cohorts: Cohort A: apatinib 500 mg + gefitinib 250 mg. Cohort B: apatinib 250 mg + gefitinib 250 mg. The primary endpoint was safety profile. Other endpoints consisted of PK analysis, objective response rate (ORR), and progression‐free survival (PFS). Exploratory analysis was conducted using next‐generation sequencing of plasma circulating‐tumor DNA. Results Between July 2016 and April 2017, 13 of NSCLC patients were recruited. Six patients were pooled in Cohort A, while seven patients were in Cohort B. Adverse events (AEs) were tolerable (mostly grade 1–2) and the treatment‐related AEs were similar in both cohorts: rash (100% vs 71.4%), diarrhea (66.7% vs 71.4%), hypertension (66.7% vs 71.4%), proteinuria (66.7% vs 42.9%), and hand‐foot skin reaction (33.3% vs 28.6%). The area under plasma concentration‐time curve for the steady state of apatinib was 2864.73 ± 2605.54 ng mL–1 h–1 in Cohort A and 2445.09 ± 1550.89 ng mL–1 h–1 in Cohort B. Of the 11 patients evaluable for efficacy, Cohort A achieved an ORR of 80.0% and reached a median PFS of 19.2 months, while it was 83.3% and 13.4 months in Cohort B. Patients without a concomitant mutation at baseline had a prolonged PFS tendency (20.99 months v 13.21 months, P = .0624). The EGFR‐T790M mutation remained the dominant resistance mechanism. Conclusion Apatinib (500 mg) plus gefitinib (250 mg) showed a tolerable safety profile and encouraging antitumor activity for advanced EGFR‐mutant NSCLC in the first‐line setting. Phase III trials of apatinib (500 mg) plus gefitinib (250 mg) are warranted. Trial registration Clinicaltrials.gov, NCT02824458, date of registration June 23, 2016.
Collapse
Affiliation(s)
- Zhonghan Zhang
- Department of Medical Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, P. R. China
| | - Yang Zhang
- Department of Clinical Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, P. R. China
| | - Fan Luo
- Department of Medical Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, P. R. China
| | - Yuxiang Ma
- Department of Clinical Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, P. R. China
| | - Wenfeng Fang
- Department of Medical Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, P. R. China
| | - Jing Zhan
- Department of Clinical Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, P. R. China
| | - Su Li
- Department of Clinical Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, P. R. China
| | - Yunpeng Yang
- Department of Medical Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, P. R. China
| | - Yuanyuan Zhao
- Department of Medical Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, P. R. China
| | - Shaodong Hong
- Department of Medical Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, P. R. China
| | - Ting Zhou
- Department of Medical Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, P. R. China
| | - Yaxiong Zhang
- Department of Medical Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, P. R. China
| | - Shen Zhao
- Department of Medical Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, P. R. China
| | - Yan Huang
- Department of Medical Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, P. R. China
| | - Hongyun Zhao
- Department of Clinical Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, P. R. China
| | - Li Zhang
- Department of Medical Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, P. R. China
| |
Collapse
|
26
|
Rao M, Oh K, Moffitt R, Thompson P, Li J, Liu J, Sasson A, Georgakis G, Kim J, Choi M, Powers S. Comparative single-cell RNA sequencing (scRNA-seq) reveals liver metastasis-specific targets in a patient with small intestinal neuroendocrine cancer. Cold Spring Harb Mol Case Stud 2020; 6:mcs.a004978. [PMID: 32054662 PMCID: PMC7133744 DOI: 10.1101/mcs.a004978] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2019] [Accepted: 02/03/2020] [Indexed: 01/08/2023] Open
Abstract
Genomic analysis of a patient's tumor is the cornerstone of precision oncology, but it does not address whether metastases should be treated differently. Here we tested whether comparative single-cell RNA sequencing (scRNA-seq) of a primary small intestinal neuroendocrine tumor to a matched liver metastasis could guide the treatment of a patient's metastatic disease. Following surgery, the patient was put on maintenance treatment with a somatostatin analog. However, the scRNA-seq analysis revealed that the neuroendocrine epithelial cells in the liver metastasis were less differentiated and expressed relatively little SSTR2, the predominant somatostatin receptor. There were also differences in the tumor microenvironments. RNA expression of vascular endothelial growth factors was higher in the primary tumor cells, reflected by an increased number of endothelial cells. Interestingly, vascular expression of the major VEGF receptors was considerably higher in the liver metastasis, indicating that the metastatic vasculature may be primed for expansion and susceptible to treatment with angiogenesis inhibitors. The patient eventually progressed on Sandostatin, and although consideration was given to adding an angiogenesis inhibitor to her regimen, her disease progression involved non-liver metastases that had not been characterized. Although in this specific case comparative scRNA-seq did not alter treatment, its potential to help guide therapy of metastatic disease was clearly demonstrated.
Collapse
Affiliation(s)
- Manisha Rao
- Department of Pathology, Stony Brook University, Stony Brook, New York 11794, USA
| | - Ki Oh
- Department of Medicine, Stony Brook University, Stony Brook, New York 11794, USA
| | - Richard Moffitt
- Department of Pathology, Stony Brook University, Stony Brook, New York 11794, USA.,Department of Biomedical Informatics, Stony Brook University, Stony Brook, New York 11794, USA
| | - Patricia Thompson
- Department of Pathology, Stony Brook University, Stony Brook, New York 11794, USA
| | - Jinyu Li
- Department of Pathology, Stony Brook University, Stony Brook, New York 11794, USA
| | - Jingxuan Liu
- Department of Pathology, Stony Brook University, Stony Brook, New York 11794, USA
| | - Aaron Sasson
- Department of Medicine, Stony Brook University, Stony Brook, New York 11794, USA
| | - George Georgakis
- Department of Medicine, Stony Brook University, Stony Brook, New York 11794, USA
| | - Joseph Kim
- Department of Medicine, Stony Brook University, Stony Brook, New York 11794, USA
| | - Minsig Choi
- Department of Medicine, Stony Brook University, Stony Brook, New York 11794, USA
| | - Scott Powers
- Department of Pathology, Stony Brook University, Stony Brook, New York 11794, USA
| |
Collapse
|
27
|
Abstract
The increased incidence and prevalence of neuroendocrine tumors (NETs) over the past few decades has been accompanied by an improvement in overall survival. There are differences in the management of small bowel NETs versus pNETs. The management of all patients with NETs must be individualized based on patient characteristics as well tumor-related factors. This article reviews the role of somatostatin analogues, historical results with chemotherapy in gastroenteropancreatic NETs (GEPNETs), and more recent evidence for the use of cytotoxic chemotherapy in GEPNETs. The article also discusses molecular targeted therapies approved for use in GEPNETs and some ongoing clinical trials.
Collapse
Affiliation(s)
- Chandrikha Chandrasekharan
- Division of Medical Oncology, University of Iowa, 200 Hawkins Drive, C GH 32, Iowa City, Iowa 52242, USA.
| |
Collapse
|
28
|
Haibe Y, Kreidieh M, El Hajj H, Khalifeh I, Mukherji D, Temraz S, Shamseddine A. Resistance Mechanisms to Anti-angiogenic Therapies in Cancer. Front Oncol 2020; 10:221. [PMID: 32175278 PMCID: PMC7056882 DOI: 10.3389/fonc.2020.00221] [Citation(s) in RCA: 242] [Impact Index Per Article: 48.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2019] [Accepted: 02/10/2020] [Indexed: 12/12/2022] Open
Abstract
Tumor growth and metastasis rely on tumor vascular network for the adequate supply of oxygen and nutrients. Tumor angiogenesis relies on a highly complex program of growth factor signaling, endothelial cell (EC) proliferation, extracellular matrix (ECM) remodeling, and stromal cell interactions. Numerous pro-angiogenic drivers have been identified, the most important of which is the vascular endothelial growth factor (VEGF). The importance of pro-angiogenic inducers in tumor growth, invasion and extravasation make them an excellent therapeutic target in several types of cancers. Hence, the number of anti-angiogenic agents developed for cancer treatment has risen over the past decade, with at least eighty drugs being investigated in preclinical studies and phase I-III clinical trials. To date, the most common approaches to the inhibition of the VEGF axis include the blockade of VEGF receptors (VEGFRs) or ligands by neutralizing antibodies, as well as the inhibition of receptor tyrosine kinase (RTK) enzymes. Despite promising preclinical results, anti-angiogenic monotherapies led only to mild clinical benefits. The minimal benefits could be secondary to primary or acquired resistance, through the activation of alternative mechanisms that sustain tumor vascularization and growth. Mechanisms of resistance are categorized into VEGF-dependent alterations, non-VEGF pathways and stromal cell interactions. Thus, complementary approaches such as the combination of these inhibitors with agents targeting alternative mechanisms of blood vessel formation are urgently needed. This review provides an updated overview on the pathophysiology of angiogenesis during tumor growth. It also sheds light on the different pro-angiogenic and anti-angiogenic agents that have been developed to date. Finally, it highlights the preclinical evidence for mechanisms of angiogenic resistance and suggests novel therapeutic approaches that might be exploited with the ultimate aim of overcoming resistance and improving clinical outcomes for patients with cancer.
Collapse
Affiliation(s)
- Yolla Haibe
- Division of Hematology/Oncology, Department of Internal Medicine, American University of Beirut-Medical Center, Beirut, Lebanon
| | - Malek Kreidieh
- Division of Hematology/Oncology, Department of Internal Medicine, American University of Beirut-Medical Center, Beirut, Lebanon
| | - Hiba El Hajj
- Division of Hematology/Oncology, Department of Internal Medicine, American University of Beirut-Medical Center, Beirut, Lebanon
- Department of Experimental Pathology, Immunology and Microbiology, American University of Beirut-Medical Center, Beirut, Lebanon
| | - Ibrahim Khalifeh
- Department of Pathology and Laboratory Medicine, American University of Beirut Medical Center, Beirut, Lebanon
| | - Deborah Mukherji
- Division of Hematology/Oncology, Department of Internal Medicine, American University of Beirut-Medical Center, Beirut, Lebanon
| | - Sally Temraz
- Division of Hematology/Oncology, Department of Internal Medicine, American University of Beirut-Medical Center, Beirut, Lebanon
| | - Ali Shamseddine
- Division of Hematology/Oncology, Department of Internal Medicine, American University of Beirut-Medical Center, Beirut, Lebanon
| |
Collapse
|
29
|
Wong C, Tang LH, Davidson C, Vosburgh E, Chen W, Foran DJ, Notterman DA, Levine AJ, Xu EY. Two well-differentiated pancreatic neuroendocrine tumor mouse models. Cell Death Differ 2020; 27:269-283. [PMID: 31160716 PMCID: PMC7206057 DOI: 10.1038/s41418-019-0355-0] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2019] [Revised: 04/26/2019] [Accepted: 05/07/2019] [Indexed: 02/08/2023] Open
Abstract
Multiple endocrine neoplasia type 1 (MEN1) is a genetic syndrome in which patients develop neuroendocrine tumors (NETs), including pancreatic neuroendocrine tumors (PanNETs). The prolonged latency of tumor development in MEN1 patients suggests a likelihood that other mutations cooperate with Men1 to induce PanNETs. We propose that Pten loss combined with Men1 loss accelerates tumorigenesis. To test this, we developed two genetically engineered mouse models (GEMMs)-MPR (Men1flox/flox Ptenflox/flox RIP-Cre) and MPM (Men1flox/flox Ptenflox/flox MIP-Cre) using the Cre-LoxP system with insulin-specific biallelic inactivation of Men1 and Pten. Cre in the MPR mouse model was driven by the transgenic rat insulin 2 promoter while in the MPM mouse model was driven by the knock-in mouse insulin 1 promoter. Both mouse models developed well-differentiated (WD) G1/G2 PanNETs at a much shorter latency than Men1 or Pten single deletion alone and exhibited histopathology of human MEN1-like tumor. The MPR model, additionally, developed pituitary neuroendocrine tumors (PitNETs) in the same mouse at a much shorter latency than Men1 or Pten single deletion alone as well. Our data also demonstrate that Pten plays a role in NE tumorigenesis in pancreas and pituitary. Treatment with the mTOR inhibitor rapamycin delayed the growth of PanNETs in both MPR and MPM mice, as well as the growth of PitNETs, resulting in prolonged survival in MPR mice. Our MPR and MPM mouse models are the first to underscore the cooperative roles of Men1 and Pten in cancer, particularly neuroendocrine cancer. The early onset of WD PanNETs mimicking the human counterpart in MPR and MPM mice at 7 weeks provides an effective platform for evaluating therapeutic opportunities for NETs through targeting the MENIN-mediated and PI3K/AKT/mTOR signaling pathways.
Collapse
Affiliation(s)
- Chung Wong
- Raymond and Beverly Sackler Foundation Laboratory, New Brunswick, NJ, 08901, USA
- Regeneron Inc., Tarrytown, NY, 10591, USA
| | - Laura H Tang
- Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY, 10065, USA
| | - Christian Davidson
- Department of Pathology, University of Utah, Huntsman Cancer Institute, Salt Lake City, UT, 84112, USA
| | - Evan Vosburgh
- Raymond and Beverly Sackler Foundation Laboratory, New Brunswick, NJ, 08901, USA
- Rutgers Cancer Institute of New Jersey, Rutgers, the State University of New Jersey, New Brunswick, NJ, 08903, USA
- Department of Medicine, Robert Wood Johnson Medical School, Rutgers, the State University of New Jersey, New Brunswick, NJ, 08901, USA
- Department of Medicine, Yale University School of Medicine, New Haven, CT, 06510, USA
| | - Wenjin Chen
- Rutgers Cancer Institute of New Jersey, Rutgers, the State University of New Jersey, New Brunswick, NJ, 08903, USA
- Department of Pathology and Laboratory Medicine, Robert Wood Johnson Medical School, Rutgers, the State University of New Jersey, New Brunswick, NJ, 08901, USA
| | - David J Foran
- Rutgers Cancer Institute of New Jersey, Rutgers, the State University of New Jersey, New Brunswick, NJ, 08903, USA
- Department of Pathology and Laboratory Medicine, Robert Wood Johnson Medical School, Rutgers, the State University of New Jersey, New Brunswick, NJ, 08901, USA
| | - Daniel A Notterman
- Department of Molecular Biology, Princeton University, Princeton, NJ, 08544, USA
| | - Arnold J Levine
- School of Natural Sciences, Institute for Advanced Study, Princeton, NJ, 08540, USA
| | - Eugenia Y Xu
- Raymond and Beverly Sackler Foundation Laboratory, New Brunswick, NJ, 08901, USA.
- Rutgers Cancer Institute of New Jersey, Rutgers, the State University of New Jersey, New Brunswick, NJ, 08903, USA.
- Department of Pediatrics, Robert Wood Johnson Medical School, Rutgers, the State University of New Jersey, New Brunswick, NJ, 08901, USA.
- Department of Molecular Biology, Princeton University, Princeton, NJ, 08544, USA.
| |
Collapse
|
30
|
Tsioumpekou M, Cunha SI, Ma H, Åhgren A, Cedervall J, Olsson AK, Heldin CH, Lennartsson J. Specific targeting of PDGFRβ in the stroma inhibits growth and angiogenesis in tumors with high PDGF-BB expression. Am J Cancer Res 2020; 10:1122-1135. [PMID: 31938055 PMCID: PMC6956815 DOI: 10.7150/thno.37851] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2019] [Accepted: 10/01/2019] [Indexed: 01/12/2023] Open
Abstract
PDGF-BB/PDGFRβ signaling plays an important role during vascularization by mediating pericyte recruitment to the vasculature, promoting the integrity and function of vessels. Until now it has not been possible to assess the specific role of PDGFRβ signaling in tumor progression and angiogenesis due to lack of appropriate animal models and molecular tools. Methods: In the present study, we used a transgenic knock-in mouse strain carrying a silent mutation in the PDGFRβ ATP binding site that allows specific targeting of PDGFRβ using the compound 1-NaPP1. To evaluate the impact of selective PDGFRβ inhibition of stromal cells on tumor growth we investigated four tumor cell lines with no or low PDGFRβ expression, i.e. Lewis lung carcinoma (LLC), EO771 breast carcinoma, B16 melanoma and a version of B16 that had been engineered to overexpress PDGF-BB (B16/PDGF-BB). Results: We found that specific impairment of PDGFRβ kinase activity by 1-NaPP1 treatment efficiently suppressed growth in tumors with high expression of PDGF-BB, i.e. LLC and B16/PDGF-BB, while the clinically used PDGFRβ kinase inhibitor imatinib did not suppress tumor growth. Notably, tumors with low levels of PDGF-BB, i.e. EO771 and B16, neither responded to 1-NaPP1 nor to imatinib treatment. Inhibition of PDGFRβ by either drug impaired tumor vascularization and also affected pericyte coverage; however, specific targeting of PDGFRβ by 1-NaPP1 resulted in a more pronounced decrease in vessel function with increased vessel apoptosis in high PDGF-BB expressing tumors, compared to treatment with imatinib. In vitro analysis of PDGFRβ ASKA mouse embryo fibroblasts and the mesenchymal progenitor cell line 10T1/2 revealed that PDGF-BB induced NG2 expression, consistent with the in vivo data. Conclusion: Specific targeting of PDGFRβ signaling significantly inhibits tumor progression and angiogenesis depending on PDGF-BB expression. Our data suggest that targeting PDGFRβ in the tumor stroma could have therapeutic value in patients with high tumor PDGF-BB expression.
Collapse
|
31
|
Fazio N, Cella CA, Del Re M, Laffi A, Rubino M, Zagami P, Spada F. Pharmacodynamics, clinical findings and approval status of current and emerging tyrosine-kinase inhibitors for pancreatic neuroendocrine tumors. Expert Opin Drug Metab Toxicol 2019; 15:993-1004. [PMID: 31794273 DOI: 10.1080/17425255.2019.1700951] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Introduction: Pancreatic neuroendocrine tumors (panNETs) represent a rare group of malignancies. For decades, chemotherapy, somatostatin analogs and interferon represented the only systemic therapies; however, over the latest years, new options were registered, including Everolimus, Sunitinib (SUN), and Peptide Receptor Radionuclide Therapy.Areas covered: This review discusses the role of tyrosine kinase inhibitors (TKIs) in advanced panNETs.Expert opinion: TKIs showed an antiangiogenic and antiproliferative impact on advanced panNETs. Sunitinib is the only TKI currently available in clinical practice, having been approved on the basis of relevant results of a specific panNET phase III trial. New TKIs, such as Cabozantinib, Lenvatinib, Pazopanib, Surufatinib are still on investigation in panNETs. Although some phase II studies with the new TKIs yielded better PFS and RR compared with SUN, different study designs and tumor populations may have induced selection biases. However, it was reported that panNETs resistant to SUN could respond to a new TKI, indicating a possible further therapeutic line in this context. The global investigation plan of TKIs in panNETs is not homogeneous and it is difficult to understand what kind of development this can have in the near future for clinical practice.
Collapse
Affiliation(s)
- Nicola Fazio
- Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, IEO, IRCCS, Milan, Italy
| | - Chiara A Cella
- Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, IEO, IRCCS, Milan, Italy
| | - Marzia Del Re
- Unit of Clinical Pharmacology and Pharmacogenetics, Department of Clinical and Experimental Medicine, University Hospital of Pisa, Pisa, Italy
| | - Alice Laffi
- Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, IEO, IRCCS, Milan, Italy
| | - Manila Rubino
- Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, IEO, IRCCS, Milan, Italy
| | - Paola Zagami
- Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, IEO, IRCCS, Milan, Italy
| | - Francesca Spada
- Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, IEO, IRCCS, Milan, Italy
| |
Collapse
|
32
|
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.
Collapse
Affiliation(s)
- Yuval Shaked
- Department of Cell Biology and Cancer Science, Technion Integrated Cancer Center, Technion - Israel Institute of Technology, Haifa, Israel.
| |
Collapse
|
33
|
Athira VR, Saranya MK, Shivanandappa T, Yajurvedi HN. Multiple dose treatment reduces cyclophosphamide-induced ovarian follicular loss in mice. Birth Defects Res 2019; 112:71-80. [PMID: 31643145 DOI: 10.1002/bdr2.1603] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2019] [Revised: 08/18/2019] [Accepted: 09/21/2019] [Indexed: 12/16/2022]
Abstract
This study compares the effects of single dose and multiple dose treatment of cyclophosphamide (CP) on oxidative stress-mediated follicular damage in mouse ovary. In the first experiment, adult female mice were administered with a single dose of CP (100 mg/kg body weight/mouse) and autopsied 72 hr after treatment. In the second experiment, adult female mice were injected with multiple doses of CP (40 mg/kg body weight/day/mouse for 10 consecutive days) and sacrificed on Day 11. There was a 58, 48, 53, and 51% loss of primordial, primary, preantral, and antral follicles, respectively, following the administration of a single dose of CP, whereas, multiple dose of CP caused only 35% reduction in primordial follicles coupled with 28, 23, and 38%, loss of primary, preantral, and antral follicles, respectively. There was a decrease in activities of the ovarian antioxidant enzymes and increase in reactive oxygen species (ROS) and malondialdehyde (MDA) concentrations following single dose CP, whereas multiple dose treatment caused an increase in activities of these enzymes and decrease in ROS and MDA concentrations. The serum concentration of estradiol was significantly decreased following single or multiple dose treatment. The ovarian damage caused by a single high dose of CP administration is higher than that by multiple doses of smaller amount, though the total amount of CP administered was higher with multiple treatment. The results of the current study reveal the benefit of metronomic chemotherapy in cancer treatment, for its effectiveness in reducing ovarian toxicity, a major side effect in young female patients.
Collapse
|
34
|
Pozas J, San Román M, Alonso-Gordoa T, Pozas M, Caracuel L, Carrato A, Molina-Cerrillo J. Targeting Angiogenesis in Pancreatic Neuroendocrine Tumors: Resistance Mechanisms. Int J Mol Sci 2019; 20:E4949. [PMID: 31597249 PMCID: PMC6801829 DOI: 10.3390/ijms20194949] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2019] [Revised: 10/04/2019] [Accepted: 10/05/2019] [Indexed: 02/07/2023] Open
Abstract
Despite being infrequent tumors, the incidence and prevalence of pancreatic neuroendocrine tumors (P-NETs) has been rising over the past few decades. In recent years, rigorous phase III clinical trials have been conducted, allowing the approval of several drugs that have become the standard of care in these patients. Although various treatments are used in clinical practice, including somatostatin analogues (SSAs), biological therapies like sunitinib or everolimus, peptide receptor radionuclide therapy (PRRT) or even chemotherapy, a consensus regarding the optimal sequence of treatment has not yet been reached. Notwithstanding, sunitinib is largely used in these patients after the promising results shown in SUN111 phase III clinical trial. However, both prompt progression as well as tumor recurrence after initial response have been reported, suggesting the existence of primary and acquired resistances to this antiangiogenic drug. In this review, we aim to summarize the most relevant mechanisms of angiogenesis resistance that are key contributors of tumor progression and dissemination. Furthermore, several targeted molecules acting selectively against these pathways have shown promising results in preclinical models, and preliminary results from ongoing clinical trials are awaited.
Collapse
Affiliation(s)
- Javier Pozas
- Medical Oncology Department, University Hospital Ramon y Cajal, 28034 Madrid, Spain.
| | - María San Román
- Medical Oncology Department, University Hospital Ramon y Cajal, 28034 Madrid, Spain.
| | - Teresa Alonso-Gordoa
- Medical Oncology Department, University Hospital Ramon y Cajal, 28034 Madrid, Spain.
- The Ramón y Cajal Health Research Institute (IRYCIS), CIBERONC, 28034 Madrid, Spain.
- Alcalá University, 28805 Madrid, Spain.
| | - Miguel Pozas
- Medical Oncology Department, University Hospital Ramon y Cajal, 28034 Madrid, Spain.
| | - Laura Caracuel
- Medical Oncology Department, University Hospital Ramon y Cajal, 28034 Madrid, Spain.
| | - Alfredo Carrato
- Medical Oncology Department, University Hospital Ramon y Cajal, 28034 Madrid, Spain.
- The Ramón y Cajal Health Research Institute (IRYCIS), CIBERONC, 28034 Madrid, Spain.
- Alcalá University, 28805 Madrid, Spain.
| | - Javier Molina-Cerrillo
- Medical Oncology Department, University Hospital Ramon y Cajal, 28034 Madrid, Spain.
- The Ramón y Cajal Health Research Institute (IRYCIS), CIBERONC, 28034 Madrid, Spain.
- Alcalá University, 28805 Madrid, Spain.
| |
Collapse
|
35
|
Zhang Z, Zhao Y, Lu F, Hou X, Ma Y, Luo F, Zeng K, Zhao S, Zhang Y, Zhou T, Yang Y, Fang W, Huang Y, Zhang L, Zhao H. Multi-targeted tyrosine kinase inhibitors as third-line regimen in advanced non-small cell lung cancer: a network meta-analysis. ANNALS OF TRANSLATIONAL MEDICINE 2019; 7:452. [PMID: 31700888 DOI: 10.21037/atm.2019.08.51] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Background Four multi-targeted tyrosine kinase inhibitors (TKIs) including apatinib, anlotinib, fruquintinib and lenvatinib are currently available as third-line regimen for advanced non-small cell lung cancer (NSCLC) patients who failed at least two lines of systemic therapy. Limited evidence was provided to demonstrate the general efficacy and safety profile of these drugs as third-line treatment approach for NSCLC. Methods Eligible literature was searched from electronic database. Data of objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), treatment related adverse event (TRAE), treatment related adverse event grade 3-5 (TRAE3-5), hypertension, proteinuria, hand-foot skin reaction (HFSR), elevated ALT/AST, nausea and vomiting, diarrhea were synthetically extracted. Multiple-treatments comparisons (MTCs) based on a Bayesian consistency model integrated the efficacy and toxicity outcomes. Rank probabilities of each regimen were assessed and clustered by the surface under the cumulative ranking curve. Results Five phase II/III randomized trials involving 915 advanced NSCLC patients were enrolled. MTCs showed that four multi-targeted TKIs shared equivalent efficacy in terms of outcome measures, of which anlotinib stood out in ORR (OR =39.26; 95% CI: 2.36-2,748.06), DCR (OR =8.69; 95% CI: 1.70-50.18) and PFS (HR =0.27; 95% CI: 0.10-0.78) when compared with placebo plus BSC. No significantly differences were observed among these TKIs and placebo with respect to OS, TRAE and TRAE 3-5. Fruquintinib and lenvatinib may relate to high rate of HFSR while anlotinib may relate to hypertension. Conclusions Multi-targeted TKIs (apatinib, anlotinib, fruquintinib and lenvatinib) with acceptable efficacy and safety profile were options for advanced NSCLC in third-line setting.
Collapse
Affiliation(s)
- Zhonghan Zhang
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China
| | - Yuanyuan Zhao
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China
| | - Feiteng Lu
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China
| | - Xue Hou
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China
| | - Yuxiang Ma
- Department of Clinical Research, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China
| | - Fan Luo
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China
| | - Kangmei Zeng
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China
| | - Shen Zhao
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China
| | - Yaxiong Zhang
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China
| | - Ting Zhou
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China
| | - Yunpeng Yang
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China
| | - Wenfeng Fang
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China
| | - Yan Huang
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China
| | - Li Zhang
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China
| | - Hongyun Zhao
- Department of Clinical Research, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China
| |
Collapse
|
36
|
Newton JM, Hanoteau A, Liu HC, Gaspero A, Parikh F, Gartrell-Corrado RD, Hart TD, Laoui D, Van Ginderachter JA, Dharmaraj N, Spanos WC, Saenger Y, Young S, Sikora AG. Immune microenvironment modulation unmasks therapeutic benefit of radiotherapy and checkpoint inhibition. J Immunother Cancer 2019; 7:216. [PMID: 31409394 PMCID: PMC6693252 DOI: 10.1186/s40425-019-0698-6] [Citation(s) in RCA: 55] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2019] [Accepted: 07/31/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Immune checkpoint inhibitors (ICIs) for solid tumors, including those targeting programmed cell death 1 (PD-1) and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), have shown impressive clinical efficacy, however, most patients do not achieve durable responses. One major therapeutic obstacle is the immunosuppressive tumor immune microenvironment (TIME). Thus, we hypothesized that a strategy combining tumor-directed radiation with TIME immunomodulation could improve ICI response rates in established solid tumors. METHODS Using a syngeneic mouse model of human papillomavirus (HPV)-associated head and neck cancer, mEER, we developed a maximally effective regimen combining PD-1 and CTLA-4 inhibition, tumor-directed radiation, and two existing immunomodulatory drugs: cyclophosphamide (CTX) and a small-molecule inducible nitric oxide synthase (iNOS) inhibitor, L-n6-(1-iminoethyl)-lysine (L-NIL). We compared the effects of the various combinations of this regimen on tumor growth, overall survival, establishment of immunologic memory, and immunologic changes with flow cytometry and quantitative multiplex immunofluorescence. RESULTS We found PD-1 and CTLA-4 blockade, and radiotherapy alone or in combination, incapable of clearing established tumors or reversing the unfavorable balance of effector to suppressor cells in the TIME. However, modulation of the TIME with cyclophosphamide (CTX) and L-NIL in combination with dual checkpoint inhibition and radiation led to rejection of over 70% of established mEER tumors and doubled median survival in the B16 melanoma model. Anti-tumor activity was CD8+ T cell-dependent and led to development of immunologic memory against tumor-associated HPV antigens. Immune profiling revealed that CTX/L-NIL induced remodeling of myeloid cell populations in the TIME and tumor-draining lymph node and drove subsequent activation and intratumoral infiltration of CD8+ effector T cells. CONCLUSIONS Overall, this study demonstrates that modulation of the immunosuppressive TIME is required to unlock the benefits of ICIs and radiotherapy to induce immunologic rejection of treatment-refractory established solid tumors.
Collapse
Affiliation(s)
- Jared M. Newton
- Department of Otolaryngology-Head and Neck Surgery, Baylor College of Medicine, Houston, TX USA
- Interdepartmental Program in Translational Biology and Molecular Medicine, Houston, TX USA
| | - Aurelie Hanoteau
- Department of Otolaryngology-Head and Neck Surgery, Baylor College of Medicine, Houston, TX USA
| | - Hsuan-Chen Liu
- Department of Otolaryngology-Head and Neck Surgery, Baylor College of Medicine, Houston, TX USA
- Interdepartmental Program in Translational Biology and Molecular Medicine, Houston, TX USA
| | - Angelina Gaspero
- Department of Otolaryngology-Head and Neck Surgery, Baylor College of Medicine, Houston, TX USA
| | - Falguni Parikh
- Department of Otolaryngology-Head and Neck Surgery, Baylor College of Medicine, Houston, TX USA
| | - Robyn D. Gartrell-Corrado
- Department of Pediatrics, Division of Pediatric Hematology/Oncology, Columbia University Irving Medical Center/New York Presbyterian, New York, NY USA
| | - Thomas D. Hart
- Department of Medicine, Division of Hematology/Oncology, Columbia University Irving Medical Center/New York Presbyterian, New York, NY USA
| | - Damya Laoui
- Laboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel (VUB), Brussels, Belgium
- Laboratory of Myeloid Cell Immunology, VIB Center for Inflammation Research, Brussels, Belgium
| | - Jo A. Van Ginderachter
- Laboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel (VUB), Brussels, Belgium
- Laboratory of Myeloid Cell Immunology, VIB Center for Inflammation Research, Brussels, Belgium
| | - Neeraja Dharmaraj
- Department of Oral and Maxillofacial Surgery, School of Dentistry, The University of Texas Health Science Center at Houston, Houston, TX USA
| | - William C. Spanos
- Department of Surgery, University of South Dakota, Sanford School of Medicine, Vermillion, SD USA
| | - Yvonne Saenger
- Department of Medicine, Division of Hematology/Oncology, Columbia University Irving Medical Center/New York Presbyterian, New York, NY USA
| | - Simon Young
- Department of Oral and Maxillofacial Surgery, School of Dentistry, The University of Texas Health Science Center at Houston, Houston, TX USA
| | - Andrew G. Sikora
- Department of Otolaryngology-Head and Neck Surgery, Baylor College of Medicine, Houston, TX USA
- Department of Cell and Gene Therapy, Baylor College of Medicine, Houston, TX USA
| |
Collapse
|
37
|
Langkjer ST, Kenholm J, Jensen JD, Wedervang K, Brixen AT, Grunnet M, Stenbygaard L, Gilje B, Danø H, Glavicic V, Jacobsen EH, Brems-Eskildsen AS, Kruse HL, Dongsgaard T, Neimann J, Geisler J. The NAME trial: a direct comparison of classical oral Navelbine versus Metronomic Navelbine in metastatic breast cancer. Future Oncol 2019; 15:2561-2569. [DOI: 10.2217/fon-2019-0124] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023] Open
Abstract
Chemotherapy for metastatic breast cancer (MBC) is in general given in cycles of maximum tolerated doses to potentially maximize the therapeutic outcome. However, when compared with targeted therapies for MBC, conventional and dose intensified chemotherapy has caused only modest survival benefits during the recent decades, often compromising the quality of life considerably. Navelbine is an antineoplastic agent that has shown efficacy in the treatment of a variety of cancer types, including breast cancer. Early clinical trials involving both breast cancer and lung cancer patients suggest that metronomic dosing of Navelbine might be at least as effective as classical administration (once weekly, etc.). The NAME trial compares these two strategies of Navelbine administration in MBC patients.
Collapse
Affiliation(s)
- Sven Tyge Langkjer
- Department of Oncology, Aarhus University Hospital, 8200 Aarhus C, Denmark
| | - Julia Kenholm
- Department of Oncology, Regionshospitalet Herning, 7400 Herning, Denmark
| | | | - Kim Wedervang
- Department of Oncology, Sønderborg Sygehus, 6400 Sønderborg, Denmark
| | | | - Mie Grunnet
- Department of Oncology, Rigshospitalet, 2100 Copenhagen, Denmark
| | - Lars Stenbygaard
- Department of Oncology, Aalborg Sygehus Syd, 9100 Aalborg, Denmark
| | - Bjørnar Gilje
- Department of Hematology & Oncology, Stavanger University Hospital, 4011 Stavanger, Norway
| | - Hella Danø
- Department of Oncology, Hilleroed Hospital, 3400 Hilleroed, Denmark
| | - Vesna Glavicic
- Department of Oncology, Naestved, 4700 Naestved, Denmark
| | | | | | - Helle Lemvig Kruse
- Department of Oncology, Aarhus University Hospital, 8200 Aarhus C, Denmark
| | - Trine Dongsgaard
- Department of Oncology, Regionshospitalet Herning, 7400 Herning, Denmark
| | - Jeppe Neimann
- Department of Oncology, Aarhus University Hospital, 8200 Aarhus C, Denmark
| | - Jürgen Geisler
- Department of Oncology, Akershus University Hospital, 1478 Lørenskog, Norway
- Institute of Clinical Medicine, University of Oslo, 0372 Oslo, Norway
| |
Collapse
|
38
|
Bonanno L, Pavan A, Pasello G, Indraccolo S. Editorial on "The AvaALL Randomized Clinical Trial". J Thorac Dis 2019; 11:S1237-S1240. [PMID: 31245096 DOI: 10.21037/jtd.2019.02.62] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Affiliation(s)
- Laura Bonanno
- Medical Oncology 2, Istituto Oncologico Veneto IOV - IRCCS, Padova, Italy
| | - Alberto Pavan
- Medical Oncology 2, Istituto Oncologico Veneto IOV - IRCCS, Padova, Italy.,Department of Surgery, Oncology and Gastroenterology, Università degli Studi di Padova, Padova, Italy
| | - Giulia Pasello
- Medical Oncology 2, Istituto Oncologico Veneto IOV - IRCCS, Padova, Italy
| | - Stefano Indraccolo
- Immunology and Molecular Oncology Unit, Istituto Oncologico Veneto IOV - IRCCS, Padova, Italy
| |
Collapse
|
39
|
Krug S, Mordhorst JP, Moser F, Theuerkorn K, Ruffert C, Egidi M, Rinke A, Gress TM, Michl P. Interaction between somatostatin analogues and targeted therapies in neuroendocrine tumor cells. PLoS One 2019; 14:e0218953. [PMID: 31237925 PMCID: PMC6592550 DOI: 10.1371/journal.pone.0218953] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2018] [Accepted: 06/12/2019] [Indexed: 01/17/2023] Open
Abstract
Somatostatin analogues (SSA) represent the standard of care for symptom control in patients with functional gastro-entero-pancreatic neuroendocrine tumors (GEP-NET). In addition, SSA exert significant anti-proliferative effects in mid-gut and pancreatic NET (PanNET). In parallel, molecularly targeted therapies (MTT) have been shown to improve progression free survival (PFS) in patients with PanNET. However, due to either primary or acquired resistance to MTT, their impact on overall survival (OS) remains unclear. To date, various hypotheses exist to explain differences in patient responsiveness to SSA and MTT. However, data addressing one of the most pivotal questions, whether combining SSA with novel MTT will result in synergistic or additive efficacy compared to monotherapy, are lacking. The aim of this study is to characterize the interaction, optimal sequence and dosing of SSA-based and molecularly targeted therapies in PanNET. Somatostatin receptor subtypes 1–5 (SSTR) were evaluated in the neuroendocrine cell lines Bon1, QGP1 and Ins-1 via immunoblot and qRT-PCR. The impact of the SSA-analogue lanreotide alone or in combination with the MTT sunitinib, everolimus and regorafenib on intracellular signalling, hormone secretion and cell proliferation was determined in cell lysates and supernatants. In addition, synergistic effects of SSA and MTT in various sequential therapeutic approaches were investigated. SSTR were differently expressed in the examined neuroendocrine tumor cell lines. SSTR modulation via lanreotide moderately influenced proliferation, mainly via modulating AKT and ERK signalling, which was paralleled by decreased chromogranin A (CgA) expression and secretion. Interestingly, MTT treatment with regorafenib upregulated the expression of SSTR-2 and -5, while sunitinib and everolimus did not significantly alter SSTR expression. Cell viability was significantly reduced by all MTT, with regorafenib exerting the most significant effects. However, compared to the marked effects of MTT alone, synergistic effects of combined MTT and lanreotide treatment were only modest and time- and dose-dependent. SSTR are differentially expressed in various NEN cell lines. Their expression is influenced by MTT treatment. Various sequential or simultaneous combinations of lanreotide and MTT did not lead to significant synergistic effects.
Collapse
Affiliation(s)
- Sebastian Krug
- Department of Internal Medicine I, Martin Luther University Halle/Wittenberg, Halle (Saale), Germany
- Department of Gastroenterology and Endocrinology, Philipps-University, Marburg, Germany
| | - Jan-Philipp Mordhorst
- Department of Internal Medicine I, Martin Luther University Halle/Wittenberg, Halle (Saale), Germany
| | - Fabian Moser
- Department of Internal Medicine I, Martin Luther University Halle/Wittenberg, Halle (Saale), Germany
| | - Katharina Theuerkorn
- Department of Internal Medicine I, Martin Luther University Halle/Wittenberg, Halle (Saale), Germany
| | - Claudia Ruffert
- Department of Internal Medicine I, Martin Luther University Halle/Wittenberg, Halle (Saale), Germany
| | - Maren Egidi
- Department of Internal Medicine I, Martin Luther University Halle/Wittenberg, Halle (Saale), Germany
| | - Anja Rinke
- Department of Gastroenterology and Endocrinology, Philipps-University, Marburg, Germany
| | - Thomas M. Gress
- Department of Gastroenterology and Endocrinology, Philipps-University, Marburg, Germany
| | - Patrick Michl
- Department of Internal Medicine I, Martin Luther University Halle/Wittenberg, Halle (Saale), Germany
- * E-mail:
| |
Collapse
|
40
|
Buicko JL, Finnerty BM, Zhang T, Kim BJ, Fahey TJ, Nancy Du YC. Insights into the biology and treatment strategies of pancreatic neuroendocrine tumors. ACTA ACUST UNITED AC 2019; 2. [PMID: 31535089 DOI: 10.21037/apc.2019.06.02] [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: 12/11/2022]
Abstract
Pancreatic neuroendocrine tumors (PNETs) are the second most common primary pancreatic neoplasms after pancreatic ductal adenocarcinoma. PNETs present with widely various clinical manifestation and unfavorable survival rate. The recent advances in next generation sequencing have significantly increased our understanding of the molecular landscape of PNETs and help guide the development of targeted therapies. This review intends to outline a holistic picture of the tumors by discussing current understanding of clinical presentations, up-to-date treatment strategies, novel mouse models, and molecular biology of PNETs. Furthermore, we will provide insight into the future development of more effective targeted therapies that are necessary to manage PNETs.
Collapse
Affiliation(s)
- Jessica L Buicko
- Department of Surgery, Weill Cornell Medicine, New York, NY 10065, USA
| | | | - Tiantian Zhang
- Department of Pathology & Laboratory Medicine, Weill Cornell Medicine, New York, NY 10065, USA
| | - Bu Jung Kim
- Department of Pathology & Laboratory Medicine, Weill Cornell Medicine, New York, NY 10065, USA
| | - Thomas J Fahey
- Department of Surgery, Weill Cornell Medicine, New York, NY 10065, USA
| | - Yi-Chieh Nancy Du
- Department of Pathology & Laboratory Medicine, Weill Cornell Medicine, New York, NY 10065, USA
| |
Collapse
|
41
|
Yu DL, Stegelmeier AA, Chow N, Rghei AD, Matuszewska K, Lawler J, Bridle BW, Petrik JJ, Wootton SK. AAV-mediated expression of 3TSR inhibits tumor and metastatic lesion development and extends survival in a murine model of epithelial ovarian carcinoma. Cancer Gene Ther 2019; 27:356-367. [PMID: 31160686 DOI: 10.1038/s41417-019-0108-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2019] [Accepted: 05/19/2019] [Indexed: 02/07/2023]
Abstract
An integral step in the development of solid tumors is the recruitment of blood vessels to fuel tumor growth. Antiangiogenic therapies can inhibit this process and control solid tumor growth. Thrombospondin-1 is an antiangiogenic protein possessing three type I repeats (3TSR) near the center of the protein and a CD47-binding peptide (CD47) in its C-terminus. Previously, we showed that treatment with recombinant 3TSR induces tumor regression, normalizes tumor vasculature, and improves uptake of chemotherapy drugs in an orthotopic, syngeneic mouse model of advanced stage epithelial ovarian cancer (EOC). While effective, this intervention required daily intraperitoneal injections. To circumvent this, here we employ adeno-associated virus (AAV) gene therapy vectors to express 3TSR alone or in combination with the CD47-binding peptide of TSP-1 and evaluate the impact on tumor development and survival in a mouse model of EOC. A single intraperitoneal injection of 1 × 1011 vg of AAV expressing 3TSR, CD47-binding peptide, or 3TSR + CD47 effectively suppressed primary tumor growth; however, only AAV-3TSR was able to inhibit development of secondary lesions at 90-days post-tumor implantation and significantly improve survival. Taken together, AAV-mediated expression of 3TSR appears safe and effective at inhibiting tumor development and represents a novel, less invasive approach for treating ovarian carcinoma.
Collapse
Affiliation(s)
- Darrick L Yu
- Department of Pathobiology, University of Guelph, Guelph, ON, N1G 2W1, Canada
| | | | - Natalie Chow
- Department of Pathobiology, University of Guelph, Guelph, ON, N1G 2W1, Canada
| | - Amira D Rghei
- Department of Pathobiology, University of Guelph, Guelph, ON, N1G 2W1, Canada
| | - Kathy Matuszewska
- Department of Biomedical Sciences, University of Guelph, Guelph, ON, N1G 2W1, Canada
| | - Jack Lawler
- Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA
| | - Byram W Bridle
- Department of Pathobiology, University of Guelph, Guelph, ON, N1G 2W1, Canada.
| | - James J Petrik
- Department of Biomedical Sciences, University of Guelph, Guelph, ON, N1G 2W1, Canada.
| | - Sarah K Wootton
- Department of Pathobiology, University of Guelph, Guelph, ON, N1G 2W1, Canada.
| |
Collapse
|
42
|
Cohen S, Schwartz M, Dottino P, Beddoe AM. Use of a multi-drug regimen gemcitabine, 5-fluorouracil, irinotecan, cisplatin, bevacizumab, docetaxel, and cyclophosphamide (GFIP/BDC) for heavily pretreated relapsed epithelial ovarian, fallopian tube and primary peritoneal cancer. J Ovarian Res 2019; 12:36. [PMID: 31027500 PMCID: PMC6485135 DOI: 10.1186/s13048-019-0506-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2018] [Accepted: 03/29/2019] [Indexed: 11/24/2022] Open
Abstract
Background Epithelial ovarian cancer has the highest fatality rate of all gynecologic malignancies. Although the majority of patients achieve complete clinical response after initial cytoreductive surgery and platinum-based chemotherapy, most recur and almost all will eventually acquire platinum-resistance for which treatment options become limited. The objective of the study was to describe response and tolerability of metronomic chemotherapy regimen GFIP/BDC, a modification of the G-FLIP regimen, in patients with persistent or recurrent epithelial ovarian, fallopian tube, and primary peritoneal cancer. Methods A retrospective descriptive analysis of 20 patients from a single academic institution who received combination GFIP/BDC therapy from January 1, 2011 to August 31, 2016 for persistent or recurrent EOC/FT/PP. Treatment consisted of a 2-day combination of gemcitabine 300 mg, 5-fluorouracil 500 mg/m2, irinotecan 20-30 mg/m2, cisplatin 20 mg/m2, bevacizumab 4 mg/kg, docetaxel 20 mg/m2, and cyclophosphamide 200 mg/m2 administered every 14 days. Toxicities were retrospectively graded using CTCAE v4.0. Results Twenty patients were identified with a median age 57.5 years (range 32–71). A total of 85% of patients were non-Hispanic white, 90% had cancer of high-grade serous histology, and all had a GOG performance status of 0–1. Patients had received a median of 3 prior regimens and 95% were platinum-resistant. Median number of cycles of GFIP/BDC administered was 9 (range 3–48) and patients remained on treatment for a median of 5.1 months (range 1.5–24). Eleven patients (55%) experienced a partial clinical response with a median duration of 6 months (range 1.5–20). Six patients (30%) survived progression free for at least 6 months. Ten patients (50%) experienced at least one grade 3/4 adverse event. Grade 3 adverse events were hematologic (n = 5), constitutional (n = 3), gastrointestinal (n = 3), neurologic (n = 2), and vascular (n = 1). There was only one grade 4 adverse event which was severe neutropenia. Patients discontinued treatment due to disease progression 65% (n = 13), toxicity 20% (n = 4), patient preference 10% (n = 2), and 5% (n = 1) is currently on treatment. Conclusions Selected patients with epithelial ovarian, fallopian tube or primary peritoneal cancer who have failed multiple lines of conventional cytotoxic treatment may benefit from GFIP/BDC. Toxicity might be a limiting factor for administration.
Collapse
Affiliation(s)
- Samantha Cohen
- Department of Obstetrics, Gynecology and Reproductive Sciences, Division of Gynecologic Oncology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1170, New York, NY, 10029, USA
| | - Melissa Schwartz
- Department of Obstetrics, Gynecology and Reproductive Sciences, Division of Gynecologic Oncology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1170, New York, NY, 10029, USA.
| | - Peter Dottino
- Department of Obstetrics, Gynecology and Reproductive Sciences, Division of Gynecologic Oncology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1170, New York, NY, 10029, USA
| | - Ann Marie Beddoe
- Department of Obstetrics, Gynecology and Reproductive Sciences, Division of Gynecologic Oncology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1170, New York, NY, 10029, USA
| |
Collapse
|
43
|
Simsek C, Esin E, Yalcin S. Metronomic Chemotherapy: A Systematic Review of the Literature and Clinical Experience. JOURNAL OF ONCOLOGY 2019; 2019:5483791. [PMID: 31015835 PMCID: PMC6446118 DOI: 10.1155/2019/5483791] [Citation(s) in RCA: 86] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/27/2018] [Revised: 12/24/2018] [Accepted: 02/05/2019] [Indexed: 02/07/2023]
Abstract
Metronomic chemotherapy, continuous and dose-dense administration of chemotherapeutic drugs with lowered doses, is being evaluated for substituting, augmenting, or appending conventional maximum tolerated dose regimens, with preclinical and clinical studies for the past few decades. To date, the principle mechanisms of its action include impeding tumoral angiogenesis and modulation of hosts' immune system, affecting directly tumor cells, their progenitors, and neighboring stromal cells. Its better toxicity profile, lower cost, and easier use are main advantages over conventional therapies. The evidence of metronomic chemotherapy for personalized medicine is growing, starting with unfit elderly patients and also for palliative treatment. The literature reviewed in this article mainly demonstrates that metronomic chemotherapy is advantageous for selected patients and for certain types of malignancies, which make it a promising therapeutic approach for filling in the gaps. More clinical studies are needed to establish a solidified role for metronomic chemotherapy with other treatment models in modern cancer management.
Collapse
Affiliation(s)
- Cem Simsek
- Department of Internal Medicine, Hacettepe University, Ankara, Turkey
| | - Ece Esin
- Department of Medical Oncology, A.Y. Ankara Training Hospital, Ankara, Turkey
| | - Suayib Yalcin
- Department of Medical Oncology, Hacettepe University, Ankara, Turkey
| |
Collapse
|
44
|
Ward C, Meehan J, Gray M, Kunkler IH, Langdon SP, Murray A, Argyle D. Preclinical Organotypic Models for the Assessment of Novel Cancer Therapeutics and Treatment. Curr Top Microbiol Immunol 2019. [PMID: 30859401 DOI: 10.1007/82_2019_159] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
The immense costs in both financial terms and preclinical research effort that occur in the development of anticancer drugs are unfortunately not matched by a substantial increase in improved clinical therapies due to the high rate of failure during clinical trials. This may be due to issues with toxicity or lack of clinical effectiveness when the drug is evaluated in patients. Currently, much cancer research is driven by the need to develop therapies that can exploit cancer cell adaptations to conditions in the tumor microenvironment such as acidosis and hypoxia, the requirement for more-specific, targeted treatments, or the exploitation of 'precision medicine' that can target known genomic changes in patient DNA. The high attrition rate for novel anticancer therapies suggests that the preclinical methods used in screening anticancer drugs need improvement. This chapter considers the advantages and disadvantages of 3D organotypic models in both cancer research and cancer drug screening, particularly in the areas of targeted drugs and the exploitation of genomic changes that can be used for therapeutic advantage in precision medicine.
Collapse
Affiliation(s)
- Carol Ward
- The Royal (Dick) School of Veterinary Studies and Roslin Institute, University of Edinburgh, Easter Bush, Roslin, Midlothian, EH25 9RG, Edinburgh, UK.
- Cancer Research UK Edinburgh Centre and Division of Pathology Laboratories, Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road South, EH4 2XU, Edinburgh, UK.
| | - James Meehan
- Cancer Research UK Edinburgh Centre and Division of Pathology Laboratories, Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road South, EH4 2XU, Edinburgh, UK
- School of Engineering and Physical Sciences, Institute of Sensors, Signals and Systems, Heriot-Watt University, EH14 4AS, Edinburgh, UK
| | - Mark Gray
- The Royal (Dick) School of Veterinary Studies and Roslin Institute, University of Edinburgh, Easter Bush, Roslin, Midlothian, EH25 9RG, Edinburgh, UK
- Cancer Research UK Edinburgh Centre and Division of Pathology Laboratories, Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road South, EH4 2XU, Edinburgh, UK
| | - Ian H Kunkler
- Cancer Research UK Edinburgh Centre and Division of Pathology Laboratories, Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road South, EH4 2XU, Edinburgh, UK
| | - Simon P Langdon
- Cancer Research UK Edinburgh Centre and Division of Pathology Laboratories, Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road South, EH4 2XU, Edinburgh, UK
| | - Alan Murray
- School of Engineering, Faraday Building, The King's Buildings, Mayfield Road, EH9 3JL, Edinburgh, UK
| | - David Argyle
- The Royal (Dick) School of Veterinary Studies and Roslin Institute, University of Edinburgh, Easter Bush, Roslin, Midlothian, EH25 9RG, Edinburgh, UK
| |
Collapse
|
45
|
Abstract
Research over the last decades has provided strong evidence for the pivotal role of the tumor-associated blood and lymphatic vasculature in supporting immunoevasion and in subverting T cell-mediated immunosurveillance. Conversely, tumor blood and lymphatic vessel growth is in part regulated by the immune system, with infiltrating innate as well as adaptive immune cells providing both immunosuppressive and various angiogenic signals. Thus, tumor angiogenesis and escape of immunosurveillance are two cancer hallmarks that are tightly linked and interregulated by cell constituents from compartments secreting both chemokines and cytokines. In this review, we discuss the implication and regulation of innate and adaptive immune cells in regulating blood and lymphatic angiogenesis in tumor progression and metastases. Moreover, we also highlight novel therapeutic approaches that target the tumor vasculature as well as the immune compartment to sustain and improve therapeutic efficacy in cancer.
Collapse
Affiliation(s)
- Massimiliano Mazzone
- VIB-Center for Cancer Biology and Department of Oncology, KU Leuven, Leuven B-3000 Belgium;
| | - Gabriele Bergers
- VIB-Center for Cancer Biology and Department of Oncology, KU Leuven, Leuven B-3000 Belgium;
- Department of Neurological Surgery, UCSF Comprehensive Cancer Center, San Francisco, California 94158, USA;
| |
Collapse
|
46
|
Abstract
Pancreatic neuroendocrine tumors are rare tumors of the pancreas originating from the islets of the Langerhans. These tumors comprise 1% to 3% of all newly diagnosed pancreatic cancers every year and have a unique heterogeneity in clinical presentation. Whole-genome sequencing has led to an increased understanding of the molecular biology of these tumors. In this review, we will summarize the current knowledge of the signaling pathways involved in the tumorigenesis of pancreatic neuroendocrine tumors as well as the major studies targeting these pathways at preclinical and clinical levels.
Collapse
|
47
|
Cuny T, de Herder W, Barlier A, Hofland LJ. Role of the tumor microenvironment in digestive neuroendocrine tumors. Endocr Relat Cancer 2018; 25:R519-R544. [PMID: 30306777 DOI: 10.1530/erc-18-0025] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) represent a group of heterogeneous tumors whose incidence increased over the past few years. Around half of patients already present with metastatic disease at the initial diagnosis. Despite extensive efforts, cytotoxic and targeted therapies have provided only limited efficacy for patients with metastatic GEP-NETs, mainly due to the development of a certain state of resistance. One factor contributing to both the failure of systemic therapies and the emergence of an aggressive tumor phenotype may be the tumor microenvironment (TME), comprising dynamic and adaptative assortment of extracellular matrix components and non-neoplastic cells, which surround the tumor niche. Accumulating evidence shows that the TME can simultaneously support both tumor growth and metastasis and contribute to a certain state of resistance to treatment. In this review, we summarize the current knowledge of the TME of GEP-NETs and discuss the current therapeutic agents that target GEP-NETs and those that could be of interest in the (near) future.
Collapse
Affiliation(s)
- Thomas Cuny
- Division Endocrinology, Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands
- Aix-Marseille Université, Institut National de la Santé et de la Recherche Médicale (INSERM), U1251, Marseille Medical Genetics (MMG), Marseille, France
- Department of Endocrinology, Assistance Publique - Hôpitaux de Marseille (AP-HM), Hôpital de la Conception, Centre de Référence des Maladies Rares Hypophysaires HYPO, Marseille, France
| | - Wouter de Herder
- Division Endocrinology, Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands
| | - Anne Barlier
- Aix-Marseille Université, Institut National de la Santé et de la Recherche Médicale (INSERM), U1251, Marseille Medical Genetics (MMG), Marseille, France
- Department of Endocrinology, Assistance Publique - Hôpitaux de Marseille (AP-HM), Hôpital de la Conception, Centre de Référence des Maladies Rares Hypophysaires HYPO, Marseille, France
| | - Leo J Hofland
- Division Endocrinology, Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands
| |
Collapse
|
48
|
Gahete MD, Jimenez-Vacas JM, Alors-Perez E, Herrero-Aguayo V, Fuentes-Fayos AC, Pedraza-Arevalo S, Castaño JP, Luque RM. Mouse models in endocrine tumors. J Endocrinol 2018; 240:JOE-18-0571.R1. [PMID: 30475226 DOI: 10.1530/joe-18-0571] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2018] [Accepted: 11/26/2018] [Indexed: 12/14/2022]
Abstract
Endocrine and neuroendocrine tumors comprise a highly heterogeneous group of neoplasms that can arise from (neuro)endocrine cells, either from endocrine glands or from the widespread diffuse neuroendocrine system, and, consequently, are widely distributed throughout the body. Due to their diversity, heterogeneity and limited incidence, studying in detail the molecular and genetic alterations that underlie their development and progression is still a highly elusive task. This, in turn, hinders the discovery of novel therapeutic options for these tumors. To circumvent these limitations, numerous mouse models of endocrine and neuroendocrine tumors have been developed, characterized and used in pre-clinical, co-clinical (implemented in mouse models and patients simultaneously) and post-clinical studies, for they represent powerful and necessary tools in basic and translational tumor biology research. Indeed, different in vivo mouse models, including cell line-based xenografts (CDXs), patient-derived xenografts (PDXs) and genetically engineered mouse models (GEMs), have been used to delineate the development, progression and behavior of human tumors. Results gained with these in vivo models have facilitated the clinical application in patients of diverse breakthrough discoveries made in this field. Herein, we review the generation, characterization and translatability of the most prominent mouse models of endocrine and neuroendocrine tumors reported to date, as well as the most relevant clinical implications obtained for each endocrine and neuroendocrine tumor type.
Collapse
Affiliation(s)
- Manuel D Gahete
- M Gahete, Department of Cell Biology, Physiology and Immunology, University of Córdoba, Cordoba, 14011, Spain
| | - Juan M Jimenez-Vacas
- J Jimenez-Vacas, Department of Cell Biology, Physiology and Immunology, University of Córdoba, Cordoba, Spain
| | - Emilia Alors-Perez
- E Alors-Perez, Department of Cell Biology, Physiology and Inmunology, Maimonides Institute for Biomedical Research of Cordoba (IMIBIC) / University of Cordoba, Cordoba, Spain
| | - Vicente Herrero-Aguayo
- V Herrero-Aguayo, Department of Cell Biology, Physiology and Immunology, University of Córdoba, Cordoba, Spain
| | - Antonio C Fuentes-Fayos
- A Fuentes-Fayos, Department of Cell Biology, Physiology and Immunology, University of Córdoba, Cordoba, Spain
| | - Sergio Pedraza-Arevalo
- S Pedraza-Arevalo, Department of Cell Biology, Physiology and Immunology, University of Córdoba, Cordoba, Spain
| | - Justo P Castaño
- J Castaño, Dpt. of Cell Biology-University of Córdoba, IMIBIC-Maimonides Biomedical Research Institute of Cordoba, Cordoba, E-14004, Spain
| | - Raul M Luque
- R Luque, Dept of Cell Biology, Phisiology and Inmunology, Section of Cell Biology, University of Cordoba, Cordoba, Spain, Cordoba, 14014, Spain
| |
Collapse
|
49
|
Microvascular Mural Cells in Cancer. Trends Cancer 2018; 4:838-848. [PMID: 30470305 DOI: 10.1016/j.trecan.2018.10.004] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2018] [Revised: 10/04/2018] [Accepted: 10/05/2018] [Indexed: 02/08/2023]
Abstract
Microvascular mural cells (MMCs) are important regulators of tumor vessel properties, such as endothelial cell differentiation and vessel permeability, and are recognized as modulators of tumor angiogenesis and growth. Emerging experimental studies suggest impact of MMCs on additional aspects of tumor biology, exerted by functionally distinct subsets. These have been shown to control metastasis both in primary tumors and in the premetastatic niche. Other studies link marker-defined MMCs to tumor immune surveillance and drug sensitivity. In parallel, recent efforts to profile MMCs in clinical samples are confirming the existence of clinically relevant marker-defined MMC subsets which show marker- and tumor-type- specific associations with prognosis and response to treatment. Collectively, findings encourage to continued analyses of MMC subsets as candidate biomarkers and drug targets.
Collapse
|
50
|
Qin RS, Zhang ZH, Zhu NP, Chen F, Guo Q, Hu HW, Fu SZ, Liu SS, Chen Y, Fan J, Han YW. Enhanced antitumor and anti-angiogenic effects of metronomic Vinorelbine combined with Endostar on Lewis lung carcinoma. BMC Cancer 2018; 18:967. [PMID: 30305062 PMCID: PMC6180630 DOI: 10.1186/s12885-018-4738-2] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2018] [Accepted: 08/09/2018] [Indexed: 12/13/2022] Open
Abstract
Background Conventional chemotherapy is commonly used to treat non-small cell lung cancer (NSCLC) however it increases therapeutic resistance. In contrast, metronomic chemotherapy (MET) is based on frequent drug administration at lower doses, resulting in inhibition of neovascularization and induction of tumor dormancy. This study aims to evaluate the inhibitory effects, adverse events, and potential mechanisms of MET Vinorelbine (NVB) combined with an angiogenesis inhibitor (Endostar). Methods Circulating endothelial progenitor cells (CEPs), apoptosis rate, expression of CD31, vascular endothelial growth factor (VEGF), hypoxia inducible factor-1 (HIF-1α) were determined using flow cytometry, western blot analysis, immunofluorescence staining and Enzyme-linked immunosorbent assay (ELISA) analysis. And some animals were also observed using micro fluorine-18-deoxyglucose PET/computed tomography (18F-FDG PET/CT) to identify changes by comparing SUVmax values. In addition, white blood cell (WBC) counts and H&E-stained sections of liver, lungs, kidney, and heart were performed in order to monitor toxicity assessments. Results We found that treatment with MET NVB + Endo was most effective in inhibiting tumor growth, decreasing expression of CD31, VEGF, HIF-1α, and CEPs, and reducing side effects, inducing apoptosis, such as expression of Bcl-2, Bax and caspase-3. Administration with a maximum tolerated dose of NVB combined with Endostar (MTD NVB + Endo) demonstrated similar anti-tumor effects, including changes in glucose metabolism with micro fluorine-18-deoxyglucose PET/computed tomography (18F-FDG PET/CT) imaging, however angiogenesis was not inhibited. Compared with either agent alone, the combination of drugs resulted in better anti-tumor effects. Conclusion These results indicated that MET NVB combined with Endo significantly enhanced anti-tumor and anti-angiogenic responses without overt toxicity in a xenograft model of human lung cancer.
Collapse
Affiliation(s)
- Rong-Sheng Qin
- Suining first people's hospital, Sichuan Province, Suining, 629000, China
| | - Zhen-Hua Zhang
- Department of Oncology, the Affiliated Hospital of Southwest Medical University, Sichuan Province, Luzhou, 646000, China
| | - Neng-Ping Zhu
- Department of Oncology, the Affiliated Hospital of Southwest Medical University, Sichuan Province, Luzhou, 646000, China
| | - Fei Chen
- Suining first people's hospital, Sichuan Province, Suining, 629000, China
| | - Qian Guo
- Suining first people's hospital, Sichuan Province, Suining, 629000, China
| | - Hao-Wen Hu
- Suining first people's hospital, Sichuan Province, Suining, 629000, China
| | - Shao-Zhi Fu
- Department of Oncology, the Affiliated Hospital of Southwest Medical University, Sichuan Province, Luzhou, 646000, China
| | - Shan-Shan Liu
- Department of Oncology, the Affiliated Hospital of Southwest Medical University, Sichuan Province, Luzhou, 646000, China
| | - Yue Chen
- Department of Nuclear Medicine, the Affiliated Hospital of Southwest Medical University, Sichuan Province, Luzhou, 646000, China
| | - Juan Fan
- Department of Oncology, the Affiliated Hospital of Southwest Medical University, Sichuan Province, Luzhou, 646000, China.
| | - Yun-Wei Han
- Department of Oncology, the Affiliated Hospital of Southwest Medical University, Sichuan Province, Luzhou, 646000, China.
| |
Collapse
|