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For:
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Rini BI, Michaelson MD, Rosenberg JE, Bukowski RM, Sosman JA, Stadler WM, Hutson TE, Margolin K, Harmon CS, DePrimo SE, Kim ST, Chen I, George DJ. Antitumor activity and biomarker analysis of sunitinib in patients with bevacizumab-refractory metastatic renal cell carcinoma. J Clin Oncol 2008;26:3743-8. [PMID: 18669461 DOI: 10.1200/jco.2007.15.5416] [Citation(s) in RCA: 329] [Impact Index Per Article: 19.4] [Reference Citation Analysis] [What about the content of this article? (0)] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open |
Supplementary Information
The online version contains supplementary material available at 10.1186/s12964-021-00734-x.
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Affiliation(s)
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Cited by Other Article(s) |
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1
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Rîmbu MC, Popescu L, Mihăilă M, Sandulovici RC, Cord D, Mihăilescu CM, Gălățanu ML, Panțuroiu M, Manea CE, Boldeiu A, Brîncoveanu O, Savin M, Grigoroiu A, Ungureanu FD, Amzoiu E, Popescu M, Truță E. Synergistic Effects of Green Nanoparticles on Antitumor Drug Efficacy in Hepatocellular Cancer. Biomedicines 2025; 13:641. [PMID: 40149616 PMCID: PMC11940350 DOI: 10.3390/biomedicines13030641] [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: 01/23/2025] [Revised: 02/19/2025] [Accepted: 02/27/2025] [Indexed: 03/29/2025] Open
Abstract
Background/Objectives: Cancer remains one of the leading causes of mortality worldwide. Despite significant advancements in treatment strategies and drug development, survival rates remain low and the adverse effects of conventional therapies severely impact patients' quality of life. This study evaluates the therapeutic potential of plant-derived extracts in hepatocellular carcinoma treatment, with a focus on minimizing side effects while enhancing efficacy. Methods: This research investigates the in vitro synergistic effect of silver bio-nanoparticles synthesized from Clematis vitalba, Melissa officinalis, and Taraxacum officinale extracts (Clematis vitalbae extractum-CVE, Melissae extractum-ME, Taraxaci extractum-TE) in combination with liver cancer drugs, sunitinib (SNTB) and imatinib (IMTB), on HepG2 (human hepatocellular carcinoma) and HUVEC (human umbilical vein endothelial) cell lines. The silver nanoparticles (AgNPs) were characterized using UV-Vis spectroscopy, dynamic light scattering (DLS), zeta potential analysis, and scanning electron microscopy (SEM). The antitumor effects were evaluated through cell viability assays after 24 and 48 h of exposure, with additional cytotoxicity tests on HUVEC cells. Results: Results indicated that Melissa officinalis-derived silver nanoparticles (ME AgNPs) and Clematis vitalba extract with silver nanoparticles (CVE AgNPs) significantly reduced HepG2 cell viability. Their efficacy improved when combined with conventional therapies (SNTB + ME AgNPs 1:1 vs. SNTB: 20.01% vs. 25.73%, p = 0.002; IMTB + ME AgNPs 1:1 vs. IMTB: 17.80% vs. 18.08%, p = 0.036; SNTB + CVE AgNPs 1:1 vs. SNTB: 18.73% vs. 25.73%, p = 0.000; SNTB + CVE AgNPs 1:2 vs. SNTB: 26.62% vs. 41.00%, p = 0.018; IMTB + CVE AgNPs 1:1 vs. IMTB: 12.99% vs. 18.08%, p = 0.001). Taraxacum extract exhibited similar cytotoxicity to its nanoparticle formulation but did not exceed the efficacy of the extract alone at 24 h. Selectivity index assessments confirmed that AgNPs-based formulations significantly improve cytotoxicity and selectivity to HepG2 cells. Among the tested extracts, CVE demonstrated the strongest antitumor effect, enhancing the efficacy of synthetic drugs (CI < 1). SNTB + TE AgNPs (5% EtOH) also demonstrated consistent synergy at high doses, while SNTB + CVE AgNPs provided broad-range synergy, making it suitable for dose-escalation strategies. Conclusions: These findings underscore the potential of nanoparticle-based formulations in combination therapies with targeted kinase inhibitors such as sunitinib and imatinib. Future research should focus on in vivo validation and clinical trials to confirm these findings.
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Affiliation(s)
- Mirela Claudia Rîmbu
- Medical Doctoral School, Titu Maiorescu University of Bucharest, 040317 Bucharest, Romania; (M.C.R.); (F.D.U.)
| | - Liliana Popescu
- Faculty of Pharmacy, Titu Maiorescu University, Gheorghe Sincai Blv. 16, 040314 Bucharest, Romania; (L.P.); (M.M.); (R.C.S.); (M.L.G.); (M.P.); (C.-E.M.); (M.P.); (E.T.)
| | - Mirela Mihăilă
- Faculty of Pharmacy, Titu Maiorescu University, Gheorghe Sincai Blv. 16, 040314 Bucharest, Romania; (L.P.); (M.M.); (R.C.S.); (M.L.G.); (M.P.); (C.-E.M.); (M.P.); (E.T.)
- Ștefan S. Nicolau Institute of Virology, 285 Mihai Bravu Street, 030304 Bucharest, Romania
| | - Roxana Colette Sandulovici
- Faculty of Pharmacy, Titu Maiorescu University, Gheorghe Sincai Blv. 16, 040314 Bucharest, Romania; (L.P.); (M.M.); (R.C.S.); (M.L.G.); (M.P.); (C.-E.M.); (M.P.); (E.T.)
| | - Daniel Cord
- Medical Doctoral School, Titu Maiorescu University of Bucharest, 040317 Bucharest, Romania; (M.C.R.); (F.D.U.)
| | - Carmen-Marinela Mihăilescu
- Faculty of Pharmacy, Titu Maiorescu University, Gheorghe Sincai Blv. 16, 040314 Bucharest, Romania; (L.P.); (M.M.); (R.C.S.); (M.L.G.); (M.P.); (C.-E.M.); (M.P.); (E.T.)
- National Institute for Research and Development in Microtechnologies (IMT Bucharest), 072996 Bucharest, Romania; (A.B.); (O.B.); (M.S.); (A.G.)
- Faculty of Pharmacy, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania;
| | - Mona Luciana Gălățanu
- Faculty of Pharmacy, Titu Maiorescu University, Gheorghe Sincai Blv. 16, 040314 Bucharest, Romania; (L.P.); (M.M.); (R.C.S.); (M.L.G.); (M.P.); (C.-E.M.); (M.P.); (E.T.)
| | - Mariana Panțuroiu
- Faculty of Pharmacy, Titu Maiorescu University, Gheorghe Sincai Blv. 16, 040314 Bucharest, Romania; (L.P.); (M.M.); (R.C.S.); (M.L.G.); (M.P.); (C.-E.M.); (M.P.); (E.T.)
| | - Carmen-Elisabeta Manea
- Faculty of Pharmacy, Titu Maiorescu University, Gheorghe Sincai Blv. 16, 040314 Bucharest, Romania; (L.P.); (M.M.); (R.C.S.); (M.L.G.); (M.P.); (C.-E.M.); (M.P.); (E.T.)
- Horia Hulubei National Institute for R&D in Physics and Nuclear Engineering (IFIN-HH), 30 Reactorului Street, 077125 Măgurele, Romania
| | - Adina Boldeiu
- National Institute for Research and Development in Microtechnologies (IMT Bucharest), 072996 Bucharest, Romania; (A.B.); (O.B.); (M.S.); (A.G.)
| | - Oana Brîncoveanu
- National Institute for Research and Development in Microtechnologies (IMT Bucharest), 072996 Bucharest, Romania; (A.B.); (O.B.); (M.S.); (A.G.)
| | - Mihaela Savin
- National Institute for Research and Development in Microtechnologies (IMT Bucharest), 072996 Bucharest, Romania; (A.B.); (O.B.); (M.S.); (A.G.)
| | - Alexandru Grigoroiu
- National Institute for Research and Development in Microtechnologies (IMT Bucharest), 072996 Bucharest, Romania; (A.B.); (O.B.); (M.S.); (A.G.)
| | - Florin Dan Ungureanu
- Medical Doctoral School, Titu Maiorescu University of Bucharest, 040317 Bucharest, Romania; (M.C.R.); (F.D.U.)
| | - Emilia Amzoiu
- Faculty of Pharmacy, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania;
| | - Mariana Popescu
- Faculty of Pharmacy, Titu Maiorescu University, Gheorghe Sincai Blv. 16, 040314 Bucharest, Romania; (L.P.); (M.M.); (R.C.S.); (M.L.G.); (M.P.); (C.-E.M.); (M.P.); (E.T.)
| | - Elena Truță
- Faculty of Pharmacy, Titu Maiorescu University, Gheorghe Sincai Blv. 16, 040314 Bucharest, Romania; (L.P.); (M.M.); (R.C.S.); (M.L.G.); (M.P.); (C.-E.M.); (M.P.); (E.T.)
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Yuki S, Yamazaki K, Sunakawa Y, Taniguchi H, Bando H, Shiozawa M, Nishina T, Yasui H, Kanazawa A, Ando K, Horita Y, Goto M, Okano N, Moriwaki T, Satoh T, Tsuji A, Yamashita K, Asano C, Abe Y, Nomura S, Yoshino T. Plasma Angiogenic Factors as Predictors of the Efficacy of Second-line Chemotherapy Combined with Angiogenesis Inhibitors in Metastatic Colorectal Cancer: Results From the GI-SCREEN CRC-Ukit Study. Clin Colorectal Cancer 2024; 23:147-159.e7. [PMID: 38331650 DOI: 10.1016/j.clcc.2024.01.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2023] [Revised: 01/12/2024] [Accepted: 01/13/2024] [Indexed: 02/10/2024]
Abstract
BACKGROUND The significance of angiogenic factors as predictors of second-line (2L) chemotherapy efficacy when combined with angiogenesis inhibitors for metastatic colorectal cancer (mCRC) remains unestablished. PATIENTS AND METHODS In this multicenter prospective observational study, 17 angiogenic factors were analyzed in plasma samples collected at pretreatment and progression stages using a Luminex multiplex assay. Patients who received chemotherapy plus bevacizumab (BEV group), FOLFIRI plus ramucirumab (RAM group), or FOLFIRI plus aflibercept (AFL group) as the 2L treatment were included. Interactions between pretreatment and treatment groups for progression-free survival (PFS), overall survival (OS), and response rate (RR) were assessed using the propensity-score weighted Cox proportional hazards model. RESULTS From February 2018 to September 2020, 283 patients were analyzed in the 2L cohort. A strong interaction was observed for PFS between BEV and RAM with HGF, sNeuropilin-1, sVEGFR-1, and sVEGFR-3. Interactions for RR between the BEV and RAM groups were observed for sNeuropilin-1 and sVEGFR-1. Contrarily, OS, PlGF, sVEGFR-1, and sVEGFR-3 differentiated the treatment effect between BEV and AFL. Plasma samples were evaluable for dynamic analysis in 203 patients. At progression, VEGF-A levels significantly decreased in the BEV group and increased in the RAM and AFL groups. CONCLUSION The pretreatment plasma sVEGFR-1 and sVEGFR-3 levels could be predictive biomarkers for distinguishing BEV and RAM when combined with chemotherapy in 2L mCRC treatment. Based on the VEGF-A dynamics at progression, selecting RAM or AFL for patients with significantly elevated VEGF-A levels may be a 2L treatment strategy, with BEV considered for the third-line treatment. CLINICAL TRIAL NUMBER UMIN000028616.
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Affiliation(s)
- Satoshi Yuki
- Department of Gastroenterology and Hepatology, Hokkaido University Hospital, Sapporo, Japan.
| | - Kentaro Yamazaki
- Division of Gastrointestinal Oncology, Shizuoka Cancer Center, Nagaizumi, Japan
| | - Yu Sunakawa
- Department of Clinical Oncology, St. Marianna University School of Medicine, Kawasaki, Japan
| | - Hiroya Taniguchi
- Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya, Japan
| | - Hideaki Bando
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Manabu Shiozawa
- Department of Gastrointestinal Surgery, Kanagawa Cancer Center, Yokohama, Japan
| | - Tomohiro Nishina
- Department of Gastrointestinal Medical Oncology, National Hospital Organization Shikoku Cancer Center, Matsuyama, Japan
| | - Hisateru Yasui
- Department of Medical Oncology, Kobe City Medical Center General Hospital, Kobe, Japan
| | - Akiyoshi Kanazawa
- Department of Surgery, Shimane Prefectural Central Hospital, Izumo, Japan
| | - Koji Ando
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yosuke Horita
- Department of Gastroenterological Oncology, Saitama Medical University International Medical Center, Hidaka, Japan
| | - Masahiro Goto
- Cancer Chemotherapy Center, Osaka Medical and Pharmaceutical University Hospital, Takatsuki, Japan
| | - Naohiro Okano
- Department of Medical Oncology, Kyorin University Faculty of Medicine, Mitaka, Japan
| | - Toshikazu Moriwaki
- Department of Gastroenterology, University of Tsukuba Hospital, Tsukuba, Japan
| | - Taroh Satoh
- Center for Cancer Genomics and Precision Medicine Osaka University Hospital, Osaka, Japan
| | - Akihito Tsuji
- Department of Clinical Oncology, Faculty of Medicine, Kagawa University, Takamatsu, Japan
| | - Kaname Yamashita
- Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan
| | - Chiharu Asano
- Institute of Health Science Innovation for Medical Care, Hokkaido University Hospital, Sapporo, Japan
| | - Yukiko Abe
- Board member, G&G Science Co., Ltd., Fukushima, Japan
| | - Shogo Nomura
- Department of Biostatistics and Bioinformatics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Takayuki Yoshino
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan
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Latcu SC, Bardan R, Cumpanas AA, Barbos V, Baderca F, Gaje PN, Ceausu RA, Comsa S, Dumitru CS, Dumache R, Cut TG, Lazureanu VE, Petrica L. Immunotherapy Applications for Thymine Dimers and WT1 Antigen in Renal Cancers: A Comparative Statistical Analysis. J Pers Med 2024; 14:557. [PMID: 38929778 PMCID: PMC11205122 DOI: 10.3390/jpm14060557] [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: 04/18/2024] [Revised: 05/16/2024] [Accepted: 05/20/2024] [Indexed: 06/28/2024] Open
Abstract
Renal cell carcinoma (RCC) remains incurable in advanced stages. Biomarkers have proven to be quite useful in cancer therapeutics. Herein, we provide a comparative/integrative statistical analysis of seminal immunohistochemistry (IHC) findings for Wilms' Tumor 1 antigen (WT1) and thymine dimers (TDs), emerging as atypical, yet promising, potential biomarkers for RCCs. We assessed WT1/TD reactivity in adult RCC tumor cells, tumor microenvironment (TME), and tumor-adjacent healthy renal tissue (HRT). WT1 positivity was scarce and strictly nuclear in tumor cells, whereas TD-reactive tumor tissues were prevalent. We report statistically significant positive correlations between the density of reactive RCC cellularity and the intensity of nuclear staining for both biomarkers (WT1 - rho = 0.341, p-value = 0.036; TDs - rho = 0.379, p-value = 0.002). RCC stromal TME TD-positivity was much more frequent than WT1 reactivity, apparently proportional to that of the proper RCC cellularity and facilitated by extensive RCC inflammatory infiltration. TDs exhibited nuclear reactivity for most TME cell lines, while RCC TME WT1 expression was rare and inconsistent. In HRTs, TDs were entirely restricted to renal tubular cells, the likely cellular progenitor of most conventional RCC subtypes. In lieu of proper validation, these early findings have significant implications regarding the origins/biology of RCCs and may inform RCC therapeutics, both accounting for the high frequency of immunotherapy-permissive frameshift indels in RCCs, but also hinting at novel predictive clinical tools for WT1-targeted immunotherapy. Overall, the current study represents a meek yet hopefully significant step towards understanding the molecular biology and potential therapeutic targets of RCCs.
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Affiliation(s)
- Silviu Constantin Latcu
- Doctoral School, Victor Babes University of Medicine and Pharmacy Timisoara, E. Murgu Square, No. 2, 300041 Timisoara, Romania; (S.C.L.); (V.B.)
- Department XV, Discipline of Urology, Victor Babes University of Medicine and Pharmacy Timisoara, E. Murgu Square, No. 2, 300041 Timisoara, Romania;
| | - Razvan Bardan
- Department XV, Discipline of Urology, Victor Babes University of Medicine and Pharmacy Timisoara, E. Murgu Square, No. 2, 300041 Timisoara, Romania;
| | - Alin Adrian Cumpanas
- Department XV, Discipline of Urology, Victor Babes University of Medicine and Pharmacy Timisoara, E. Murgu Square, No. 2, 300041 Timisoara, Romania;
| | - Vlad Barbos
- Doctoral School, Victor Babes University of Medicine and Pharmacy Timisoara, E. Murgu Square, No. 2, 300041 Timisoara, Romania; (S.C.L.); (V.B.)
| | - Flavia Baderca
- Department II of Microscopic Morphology, Victor Babes University of Medicine and Pharmacy Timisoara, E. Murgu Square, No. 2, 300041 Timisoara, Romania; (F.B.); (P.N.G.); (R.A.C.); (S.C.); (C.-S.D.)
- Angiogenesis Research Center, Victor Babes University of Medicine and Pharmacy Timisoara, E. Murgu Square, No. 2, 300041 Timisoara, Romania
| | - Pusa Nela Gaje
- Department II of Microscopic Morphology, Victor Babes University of Medicine and Pharmacy Timisoara, E. Murgu Square, No. 2, 300041 Timisoara, Romania; (F.B.); (P.N.G.); (R.A.C.); (S.C.); (C.-S.D.)
- Angiogenesis Research Center, Victor Babes University of Medicine and Pharmacy Timisoara, E. Murgu Square, No. 2, 300041 Timisoara, Romania
| | - Raluca Amalia Ceausu
- Department II of Microscopic Morphology, Victor Babes University of Medicine and Pharmacy Timisoara, E. Murgu Square, No. 2, 300041 Timisoara, Romania; (F.B.); (P.N.G.); (R.A.C.); (S.C.); (C.-S.D.)
- Angiogenesis Research Center, Victor Babes University of Medicine and Pharmacy Timisoara, E. Murgu Square, No. 2, 300041 Timisoara, Romania
| | - Serban Comsa
- Department II of Microscopic Morphology, Victor Babes University of Medicine and Pharmacy Timisoara, E. Murgu Square, No. 2, 300041 Timisoara, Romania; (F.B.); (P.N.G.); (R.A.C.); (S.C.); (C.-S.D.)
- Angiogenesis Research Center, Victor Babes University of Medicine and Pharmacy Timisoara, E. Murgu Square, No. 2, 300041 Timisoara, Romania
| | - Cristina-Stefania Dumitru
- Department II of Microscopic Morphology, Victor Babes University of Medicine and Pharmacy Timisoara, E. Murgu Square, No. 2, 300041 Timisoara, Romania; (F.B.); (P.N.G.); (R.A.C.); (S.C.); (C.-S.D.)
- Angiogenesis Research Center, Victor Babes University of Medicine and Pharmacy Timisoara, E. Murgu Square, No. 2, 300041 Timisoara, Romania
| | - Raluca Dumache
- Department VIII, Discipline of Forensic Medicine, Bioethics, Deontology and Medical Law, Victor Babes University of Medicine and Pharmacy Timisoara, E. Murgu Square, No. 2, 300041 Timisoara, Romania;
- Center for Ethics in Human Genetic Identifications, Victor Babes University of Medicine and Pharmacy Timisoara, E. Murgu Square, No. 2, 300041 Timisoara, Romania;
| | - Talida Georgiana Cut
- Center for Ethics in Human Genetic Identifications, Victor Babes University of Medicine and Pharmacy Timisoara, E. Murgu Square, No. 2, 300041 Timisoara, Romania;
- Department XIII, Discipline of Infectious Diseases, Victor Babes University of Medicine and Pharmacy Timisoara, E. Murgu Square, No. 2, 300041 Timisoara, Romania;
| | - Voichita Elena Lazureanu
- Department XIII, Discipline of Infectious Diseases, Victor Babes University of Medicine and Pharmacy Timisoara, E. Murgu Square, No. 2, 300041 Timisoara, Romania;
| | - Ligia Petrica
- Department of Internal Medicine II, Division of Nephrology, Victor Babes University of Medicine and Pharmacy Timisoara, County Emergency Hospital Timisoara, E. Murgu Square, No. 2, 300041 Timisoara, Romania;
- Centre for Molecular Research in Nephrology and Vascular Disease, Faculty of Medicine, Victor Babes University of Medicine and Pharmacy Timisoara, E. Murgu Square, No. 2, 300041 Timisoara, Romania
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Zhang X, Ma L, Xue M, Sun Y, Wang Z. Advances in lymphatic metastasis of non-small cell lung cancer. Cell Commun Signal 2024; 22:201. [PMID: 38566083 PMCID: PMC10986052 DOI: 10.1186/s12964-024-01574-1] [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: 12/23/2023] [Accepted: 03/16/2024] [Indexed: 04/04/2024] Open
Abstract
Lung cancer is a deeply malignant tumor with high incidence and mortality. Despite the rapid development of diagnosis and treatment technology, abundant patients with lung cancer are still inevitably faced with recurrence and metastasis, contributing to death. Lymphatic metastasis is the first step of distant metastasis and an important prognostic indicator of non-small cell lung cancer. Tumor-induced lymphangiogenesis is involved in the construction of the tumor microenvironment, except promoting malignant proliferation and metastasis of tumor cells, it also plays a crucial role in individual response to treatment, especially immunotherapy. Thus, this article reviews the current research status of lymphatic metastasis in non-small cell lung cancer, in order to provide some insights for the basic research and clinical and translational application in this field.
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Affiliation(s)
- Xiaofei Zhang
- Cancer Medical Center, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, 210011, China
| | - Li Ma
- Cancer Medical Center, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, 210011, China
| | - Man Xue
- Cancer Medical Center, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, 210011, China
| | - Yanning Sun
- Cancer Medical Center, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, 210011, China
| | - Zhaoxia Wang
- Cancer Medical Center, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, 210011, China.
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Mei C, Gong W, Wang X, Lv Y, Zhang Y, Wu S, Zhu C. Anti-angiogenic therapy in ovarian cancer: Current understandings and prospects of precision medicine. Front Pharmacol 2023; 14:1147717. [PMID: 36959862 PMCID: PMC10027942 DOI: 10.3389/fphar.2023.1147717] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2023] [Accepted: 02/23/2023] [Indexed: 03/09/2023] Open
Abstract
Ovarian cancer (OC) remains the most fatal disease of gynecologic malignant tumors. Angiogenesis refers to the development of new vessels from pre-existing ones, which is responsible for supplying nutrients and removing metabolic waste. Although not yet completely understood, tumor vascularization is orchestrated by multiple secreted factors and signaling pathways. The most central proangiogenic signal, vascular endothelial growth factor (VEGF)/VEGFR signaling, is also the primary target of initial clinical anti-angiogenic effort. However, the efficiency of therapy has so far been modest due to the low response rate and rapidly emerging acquiring resistance. This review focused on the current understanding of the in-depth mechanisms of tumor angiogenesis, together with the newest reports of clinical trial outcomes and resistance mechanism of anti-angiogenic agents in OC. We also emphatically summarized and analyzed previously reported biomarkers and predictive models to describe the prospect of precision therapy of anti-angiogenic drugs in OC.
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Affiliation(s)
- Chao Mei
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Weijing Gong
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Province Clinical Research Center for Precision Medicine for Critical Illness, Wuhan, China
| | - Xu Wang
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yongning Lv
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yu Zhang
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Sanlan Wu
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Province Clinical Research Center for Precision Medicine for Critical Illness, Wuhan, China
| | - Chunqi Zhu
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Circulating Biomarkers in Patients With Locally Advanced or Metastatic Renal Cell Carcinoma Treated With Everolimus in the Pre-nephrectomy Setting. Clin Oncol (R Coll Radiol) 2023; 35:e245-e255. [PMID: 36526521 DOI: 10.1016/j.clon.2022.11.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2022] [Revised: 09/28/2022] [Accepted: 11/18/2022] [Indexed: 12/23/2022]
Abstract
Many drugs are available in renal cell carcinoma (RCC), yet clinicians are still looking for predictive biomarkers of disease recurrence or progression supporting more personalised treatments. An assessment of circulating biomarkers over time was carried out in this French, open-label, single-arm, multicentre trial conducted in 25 patients with either locally advanced (n = 14) or metastatic RCC (n = 11) who received everolimus (10 mg daily) for 6 weeks prior to nephrectomy (NEORAD, NCT01715935). Circulating biomarkers, including circulating tumour cells, haematopoietic and endothelial cells, plasma angiogenesis and inflammatory markers were quantified at baseline, upon everolimus and post-nephrectomy. We assessed tumour burden, objective response rate upon RECIST1.1, disease-free survival (DFS) and progression-free survival (PFS). The correlation between circulating biomarkers was evaluated with multiple factor analysis and biomarker association with DFS/PFS by Cox regression. No objective response rate was obtained before nephrectomy. Upon everolimus, neutrophils, platelets and sVEGFR2 significantly decreased. We did not find any association between circulating biomarkers and DFS/PFS, but patients with the highest tumour burden at baseline had significantly higher plasma levels of interleukin-6, an inflammatory circulating biomarker, and lower levels of sVEGFR2, related to angiogenesis. Further understanding of the link between these circulating biomarkers could help to optimise drug combinations in RCC.
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Jin J, Xie Y, Zhang JS, Wang JQ, Dai SJ, He WF, Li SY, Ashby CR, Chen ZS, He Q. Sunitinib resistance in renal cell carcinoma: From molecular mechanisms to predictive biomarkers. Drug Resist Updat 2023; 67:100929. [PMID: 36739809 DOI: 10.1016/j.drup.2023.100929] [Citation(s) in RCA: 67] [Impact Index Per Article: 33.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2022] [Revised: 01/13/2023] [Accepted: 01/14/2023] [Indexed: 01/19/2023]
Abstract
Currently, renal cell carcinoma (RCC) is the most prevalent type of kidney cancer. Targeted therapy has replaced radiation therapy and chemotherapy as the main treatment option for RCC due to the lack of significant efficacy with these conventional therapeutic regimens. Sunitinib, a drug used to treat gastrointestinal tumors and renal cell carcinoma, inhibits the tyrosine kinase activity of a number of receptor tyrosine kinases, including vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), c-Kit, rearranged during transfection (RET) and fms-related receptor tyrosine kinase 3 (Flt3). Although sunitinib has been shown to be efficacious in the treatment of patients with advanced RCC, a significant number of patients have primary resistance to sunitinib or acquired drug resistance within the 6-15 months of therapy. Thus, in order to develop more efficacious and long-lasting treatment strategies for patients with advanced RCC, it will be crucial to ascertain how to overcome sunitinib resistance that is produced by various drug resistance mechanisms. In this review, we discuss: 1) molecular mechanisms of sunitinib resistance; 2) strategies to overcome sunitinib resistance and 3) potential predictive biomarkers of sunitinib resistance.
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Affiliation(s)
- Juan Jin
- Department of Nephrology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Traditional Chinese Medicine), Hangzhou, Zhejiang 310003, China
| | - Yuhao Xie
- Institute for Biotechnology, St. John's University, Queens, NY 11439, USA; Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USA
| | - Jin-Shi Zhang
- Urology & Nephrology Center, Department of Nephrology, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang 310014, China
| | - Jing-Quan Wang
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USA
| | - Shi-Jie Dai
- Zhejiang Eyoung Pharmaceutical Research and Development Center, Hangzhou, Zhejiang 311258, China
| | - Wen-Fang He
- Department of Nephrology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Traditional Chinese Medicine), Hangzhou, Zhejiang 310003, China
| | - Shou-Ye Li
- Zhejiang Eyoung Pharmaceutical Research and Development Center, Hangzhou, Zhejiang 311258, China
| | - Charles R Ashby
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USA
| | - Zhe-Sheng Chen
- Institute for Biotechnology, St. John's University, Queens, NY 11439, USA; Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USA.
| | - Qiang He
- Department of Nephrology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Traditional Chinese Medicine), Hangzhou, Zhejiang 310003, China.
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8
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Brackenier C, Kinget L, Cappuyns S, Verslype C, Beuselinck B, Dekervel J. Unraveling the Synergy between Atezolizumab and Bevacizumab for the Treatment of Hepatocellular Carcinoma. Cancers (Basel) 2023; 15:348. [PMID: 36672297 PMCID: PMC9856647 DOI: 10.3390/cancers15020348] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2022] [Revised: 12/24/2022] [Accepted: 12/27/2022] [Indexed: 01/06/2023] Open
Abstract
Tyrosine kinase inhibitors (TKIs) with antiangiogenic properties, such as sorafenib, have been the standard choice to systemically treat hepatocellular carcinoma for over a decade. More recently, encouraging results were obtained using immune checkpoint inhibitors, although head-to-head comparisons with sorafenib in phase 3 trials could not demonstrate superiority in terms of overall survival. The IMbrave150 was a breakthrough study that resulted in atezolizumab/bevacizumab, a combination of an antiangiogenic and an immune checkpoint inhibitor, as a new standard of care for advanced HCC. This review discusses the mode of action, clinical efficacy, and biomarker research for both drug classes and for the combination therapy. Moreover, the synergy between atezolizumab and bevacizumab is highlighted, unraveling pathophysiological mechanisms underlying an enhanced anticancer immunity by changing the immunosuppressed to a more immunoreactive tumor microenvironment (TME). This is achieved by upregulation of antigen presentation, upregulation of T-cell proliferation, trafficking and infiltration, impairing recruitment, and proliferation of immunosuppressive cells in the TME. However, more insights are needed to identify biomarkers of response that may improve patient selection and outcome.
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Affiliation(s)
- Cedric Brackenier
- Department of Gastro-Enterology and Hepatology, University Hospitals Leuven, Herestraat 49, 3000 Leuven, Belgium
| | - Lisa Kinget
- Department of General Medical Oncology, Leuven Cancer Institute, University Hospitals Leuven, Herestraat 49, 3000 Leuven, Belgium
- Laboratory of Experimental Oncology, Department of Oncology, KU Leuven, Herestraat 49, 3000 Leuven, Belgium
| | - Sarah Cappuyns
- Department of Gastro-Enterology and Hepatology, University Hospitals Leuven, Herestraat 49, 3000 Leuven, Belgium
- Laboratory of Digestive Oncology, Department of Oncology, KU Leuven, Herestraat 49, 3000 Leuven, Belgium
| | - Chris Verslype
- Department of Gastro-Enterology and Hepatology, University Hospitals Leuven, Herestraat 49, 3000 Leuven, Belgium
- Laboratory of Digestive Oncology, Department of Oncology, KU Leuven, Herestraat 49, 3000 Leuven, Belgium
| | - Benoit Beuselinck
- Department of General Medical Oncology, Leuven Cancer Institute, University Hospitals Leuven, Herestraat 49, 3000 Leuven, Belgium
- Laboratory of Experimental Oncology, Department of Oncology, KU Leuven, Herestraat 49, 3000 Leuven, Belgium
| | - Jeroen Dekervel
- Department of Gastro-Enterology and Hepatology, University Hospitals Leuven, Herestraat 49, 3000 Leuven, Belgium
- Laboratory of Digestive Oncology, Department of Oncology, KU Leuven, Herestraat 49, 3000 Leuven, Belgium
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9
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Pan Y, Lu X, Shu G, Cen J, Lu J, Zhou M, Huang K, Dong J, Li J, Lin H, Song H, Xu Q, Han H, Chen Z, Chen W, Luo J, Wei J, Zhang J. Extracellular Vesicle-Mediated Transfer of LncRNA IGFL2-AS1 Confers Sunitinib Resistance in Renal Cell Carcinoma. Cancer Res 2023; 83:103-116. [PMID: 36264173 PMCID: PMC9811158 DOI: 10.1158/0008-5472.can-21-3432] [Citation(s) in RCA: 28] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2021] [Revised: 01/24/2022] [Accepted: 10/12/2022] [Indexed: 02/03/2023]
Abstract
Sunitinib resistance remains a serious challenge to the treatment of advanced and metastatic renal cell carcinoma (RCC), yet the mechanisms underlying this resistance are not fully understood. Here, we report that the long noncoding RNA IGFL2-AS1 is a driver of therapy resistance in RCC. IGFL2-AS1 was highly upregulated in sunitinib-resistant RCC cells and was associated with poor prognosis in patients with clear cell RCC (ccRCC) who received sunitinib therapy. IGFL2-AS1 enhanced TP53INP2 expression by competitively binding to hnRNPC, a multifunctional RNA-binding protein that posttranscriptionally suppresses TP53INP2 expression through alternative splicing. Upregulated TP53INP2 enhanced autophagy and ultimately led to sunitinib resistance. Meanwhile, IGFL2-AS1 was packaged into extracellular vesicles through hnRNPC, thus transmitting sunitinib resistance to other cells. N6-methyladenosine modification of IGFL2-AS1 was critical for its interaction with hnRNPC. In a patient-derived xenograft model of sunitinib-resistant ccRCC, injection of chitosan-solid lipid nanoparticles containing antisense oligonucleotide-IGFL2-AS1 successfully reversed sunitinib resistance. These findings indicate a novel molecular mechanism of sunitinib resistance in RCC and suggest that IGFL2-AS1 may serve as a prognostic indicator and potential therapeutic target to overcome resistance. SIGNIFICANCE Extracellular vesicle-packaged IGFL2-AS1 promotes sunitinib resistance by regulating TP53INP2-triggered autophagy, implicating this lncRNA as a potential therapeutic target in renal cell carcinoma.
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Affiliation(s)
- Yihui Pan
- Department of Urology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Xuanxuan Lu
- Department of Food Science and Engineering, Jinan University, Guangzhou, China
| | - Guannan Shu
- Department of Urology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Junjie Cen
- Department of Urology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Jun Lu
- Department of Urology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Mi Zhou
- Department of Oncology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Kangbo Huang
- Department of Urology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Department of Urology, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Jiaqi Dong
- Department of Oncology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Jiaying Li
- Department of Urology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Haishan Lin
- Department of Urology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Hongde Song
- Department of Urology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Quanhui Xu
- Department of Urology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Hui Han
- Department of Urology, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Zhenhua Chen
- Department of Urology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Wei Chen
- Department of Urology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Junhang Luo
- Department of Urology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Corresponding Authors: Jiaxing Zhang, Department of Oncology, First Affiliated Hospital of Sun Yat-sen University, No. 58, Zhongshan Second Road, Guangzhou, Guangdong, 510000, China. E-mail: ; Jinhuan Wei, ; and Junhang Luo,
| | - Jinhuan Wei
- Department of Urology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Corresponding Authors: Jiaxing Zhang, Department of Oncology, First Affiliated Hospital of Sun Yat-sen University, No. 58, Zhongshan Second Road, Guangzhou, Guangdong, 510000, China. E-mail: ; Jinhuan Wei, ; and Junhang Luo,
| | - Jiaxing Zhang
- Department of Oncology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Corresponding Authors: Jiaxing Zhang, Department of Oncology, First Affiliated Hospital of Sun Yat-sen University, No. 58, Zhongshan Second Road, Guangzhou, Guangdong, 510000, China. E-mail: ; Jinhuan Wei, ; and Junhang Luo,
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10
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Patel SA, Nilsson MB, Le X, Cascone T, Jain RK, Heymach JV. Molecular Mechanisms and Future Implications of VEGF/VEGFR in Cancer Therapy. Clin Cancer Res 2023; 29:30-39. [PMID: 35969170 DOI: 10.1158/1078-0432.ccr-22-1366] [Citation(s) in RCA: 178] [Impact Index Per Article: 89.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Revised: 06/28/2022] [Accepted: 08/03/2022] [Indexed: 02/06/2023]
Abstract
Angiogenesis, the sprouting of new blood vessels from existing vessels, is one of six known mechanisms employed by solid tumors to recruit blood vessels necessary for their initiation, growth, and metastatic spread. The vascular network within the tumor facilitates the transport of nutrients, oxygen, and immune cells and is regulated by pro- and anti-angiogenic factors. Nearly four decades ago, VEGF was identified as a critical factor promoting vascular permeability and angiogenesis, followed by identification of VEGF family ligands and their receptors (VEGFR). Since then, over a dozen drugs targeting the VEGF/VEGFR pathway have been approved for approximately 20 solid tumor types, usually in combination with other therapies. Initially designed to starve tumors, these agents transiently "normalize" tumor vessels in preclinical and clinical studies, and in the clinic, increased tumor blood perfusion or oxygenation in response to these agents is associated with improved outcomes. Nevertheless, the survival benefit has been modest in most tumor types, and there are currently no biomarkers in routine clinical use for identifying which patients are most likely to benefit from treatment. However, the ability of these agents to reprogram the immunosuppressive tumor microenvironment into an immunostimulatory milieu has rekindled interest and has led to the FDA approval of seven different combinations of VEGF/VEGFR pathway inhibitors with immune checkpoint blockers for many solid tumors in the past 3 years. In this review, we discuss our understanding of the mechanisms of response and resistance to blocking VEGF/VEGFR, and potential strategies to develop more effective therapeutic approaches.
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Affiliation(s)
- Sonia A Patel
- Department of Thoracic/Head and Neck Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Monique B Nilsson
- Department of Thoracic/Head and Neck Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Xiuning Le
- Department of Thoracic/Head and Neck Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Tina Cascone
- Department of Thoracic/Head and Neck Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Rakesh K Jain
- Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
| | - John V Heymach
- Department of Thoracic/Head and Neck Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas
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11
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Contemporary Clinical Definitions, Differential Diagnosis, and Novel Predictive Tools for Renal Cell Carcinoma. Biomedicines 2022; 10:biomedicines10112926. [PMID: 36428491 PMCID: PMC9687297 DOI: 10.3390/biomedicines10112926] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Revised: 10/26/2022] [Accepted: 11/11/2022] [Indexed: 11/16/2022] Open
Abstract
Despite significant progress regarding clinical detection/imaging evaluation modalities and genetic/molecular characterization of pathogenesis, advanced renal cell carcinoma (RCC) remains an incurable disease and overall RCC mortality has been steadily rising for decades. Concomitantly, clinical definitions have been greatly nuanced and refined. RCCs are currently viewed as a heterogeneous series of cancers, with the same anatomical origin, but fundamentally different metabolisms and clinical behaviors. Thus, RCC pathological diagnosis/subtyping guidelines have become increasingly intricate and cumbersome, routinely requiring ancillary studies, mainly immunohistochemistry. Meanwhile, RCC-associated-antigen targeted systemic therapy has been greatly diversified and emerging, novel clinical applications for RCC immunotherapy have already reported significant survival benefits, at least in the adjuvant setting. Even so, systemically disseminated RCCs still associate very poor clinical outcomes, with currently available therapeutic modalities only being able to prolong survival. In lack of a definitive cure for advanced RCCs, integration of the amounting scientific knowledge regarding RCC pathogenesis into RCC clinical management has been paramount for improving patient outcomes. The current review aims to offer an integrative perspective regarding contemporary RCC clinical definitions, proper RCC clinical work-up at initial diagnosis (semiology and multimodal imaging), RCC pathological evaluation, differential diagnosis/subtyping protocols, and novel clinical tools for RCC screening, risk stratification and therapeutic response prediction.
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12
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Chen WK, Oon CE, Kaur G, Sainson RC, Li JL. Downregulation of Manic fringe impedes angiogenesis and cell migration of renal carcinoma. Microvasc Res 2022; 142:104341. [DOI: 10.1016/j.mvr.2022.104341] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 01/14/2022] [Accepted: 02/08/2022] [Indexed: 12/12/2022]
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13
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The Role of Circulating Biomarkers in the Oncological Management of Metastatic Renal Cell Carcinoma: Where Do We Stand Now? Biomedicines 2021; 10:biomedicines10010090. [PMID: 35052770 PMCID: PMC8773056 DOI: 10.3390/biomedicines10010090] [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: 12/03/2021] [Revised: 12/25/2021] [Accepted: 12/29/2021] [Indexed: 01/08/2023] Open
Abstract
Renal cell carcinoma (RCC) is an increasingly common malignancy that can progress to metastatic renal cell carcinoma (mRCC) in approximately one-third of RCC patients. The 5-year survival rate for mRCC is abysmally low, and, at the present time, there are sparingly few if any effective treatments. Current surgical and pharmacological treatments can have a long-lasting impact on renal function, as well. Thus, there is a compelling unmet need to discover novel biomarkers and surveillance methods to improve patient outcomes with more targeted therapies earlier in the course of the disease. Circulating biomarkers, such as circulating tumor DNA, noncoding RNA, proteins, extracellular vesicles, or cancer cells themselves potentially represent a minimally invasive tool to fill this gap and accelerate both diagnosis and treatment. Here, we discuss the clinical relevance of different circulating biomarkers in metastatic renal cell carcinoma by clarifying their potential role as novel biomarkers of response or resistance to treatments but also by guiding clinicians in novel therapeutic approaches.
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14
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He F, Xiao H, Cai Y, Zhang N. ATF5 and HIF1α cooperatively activate HIF1 signaling pathway in esophageal cancer. Cell Commun Signal 2021; 19:53. [PMID: 33980247 PMCID: PMC8117505 DOI: 10.1186/s12964-021-00734-x] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Accepted: 03/22/2021] [Indexed: 11/17/2022] Open
Abstract
Background Esophageal cancer (ESCA) is one of the most common cancers worldwide and has a very poor prognosis. Hypoxia-inducible factor 1 (HIF1) signaling pathway plays a critical role in tumorigenesis and is therefore considered a potential therapeutic target in the treatment of many cancers. Activating transcription factor 5 (ATF5) facilitates the expression of various genes and has been extensively studied for its potential role in cancer treatment. Methods The expression level of ATF5 in clinic sample was detected by quantitative real time PCR and immunohistochemistry. ATF5 biological function was investigated by western blot, cell cycle analysis, cell viability assay, luciferase reporter assays, colony formation assay, transwell assay, wound healing assay, tube formation assay, and ELISA assay. CHIP and Re-CHIP assay, GST-pulldown, and RNA-sequencing were used to study the cross-talks between ATF5 and HIF1 complex. Mouse xenograft study was utilized to study the correlation of ATF5 and tumor growth in vivo. Student’s t-test or Chi-square test was used for statistical analysis. Results Here, we first found ATF5 was dramatically upregulated in ESCA cancer and related with poor survival time. Next, we found that the expression level of ATF5 had a positive relationship with the proliferation, migration, and invasion ability of ESCA cells. Besides, we innovatively found that ATF5 functions as a novel coactivator in HIF1 transcription complex by binding to HIF1α. Further, we demonstrated that silencing ATF5 phenocopies HIF1α knockdown in tumorigenic properties in vitro and inhibited ESCA tumor angiogenesis and proliferation in vivo. Conclusion Herein, we found ATF5 as a novel component of the HIF1 transcription complex. The findings of the present study may provide new insights into the development of a novel and more efficient therapeutic strategy against ESCA.
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Video abstract
- Feng He
- Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College Huazhong University of Science and Technology, Wuhan, 430030, China
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- Hang Xiao
- Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College Huazhong University of Science and Technology, Wuhan, 430030, China
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- Yixin Cai
- Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College Huazhong University of Science and Technology, Wuhan, 430030, China
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- Ni Zhang
- Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College Huazhong University of Science and Technology, Wuhan, 430030, China.
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15
Anti-Angiogenic Therapy: Current Challenges and Future Perspectives.
Int J Mol Sci 2021;
22:ijms22073765. [PMID:
33916438 PMCID:
PMC8038573 DOI:
10.3390/ijms22073765]
[Citation(s) in RCA: 216] [Impact Index Per Article: 54.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Revised: 03/29/2021] [Accepted: 03/31/2021] [Indexed: 02/07/2023] Open
Abstract
Anti-angiogenic therapy is an old method to fight cancer that aims to abolish the nutrient and oxygen supply to the tumor cells through the decrease of the vascular network and the avoidance of new blood vessels formation. Most of the anti-angiogenic agents approved for cancer treatment rely on targeting vascular endothelial growth factor (VEGF) actions, as VEGF signaling is considered the main angiogenesis promotor. In addition to the control of angiogenesis, these drugs can potentiate immune therapy as VEGF also exhibits immunosuppressive functions. Despite the mechanistic rational that strongly supports the benefit of drugs to stop cancer progression, they revealed to be insufficient in most cases. We hypothesize that the rehabilitation of old drugs that interfere with mechanisms of angiogenesis related to tumor microenvironment might represent a promising strategy. In this review, we deepened research on the molecular mechanisms underlying anti-angiogenic strategies and their failure and went further into the alternative mechanisms that impact angiogenesis. We concluded that the combinatory targeting of alternative effectors of angiogenic pathways might be a putative solution for anti-angiogenic therapies.
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16
Bonfiglio V, Platania CBM, Lazzara F, Conti F, Pizzo C, Reibaldi M, Russo A, Fallico M, Ortisi E, Pignatelli F, Longo A, Avitabile T, Drago F, Bucolo C. TGF-β Serum Levels in Diabetic Retinopathy Patients and the Role of Anti-VEGF Therapy.
Int J Mol Sci 2020;
21:ijms21249558. [PMID:
33334029 PMCID:
PMC7765505 DOI:
10.3390/ijms21249558]
[Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2020] [Revised: 12/04/2020] [Accepted: 12/12/2020] [Indexed: 12/16/2022] Open
Abstract
Transforming growth factor β1 (TGFβ1) is a proinflammatory cytokine that has been implicated in the pathogenesis of diabetic retinopathy (DR), particularly in the late phase of disease. The aim of the present study was to validate serum TGFβ1 as a diagnostic and prognostic biomarker of DR stages. Thirty-eight subjects were enrolled and, after diagnosis and evaluation of inclusion and exclusion criteria, were assigned to six groups: (1) healthy age-matched control, (2) diabetic without DR, (3) non-proliferative diabetic retinopathy (NPDR) naïve to treatment, (4) NPDR treated with intravitreal (IVT) aflibercept, (5) proliferative diabetic retinopathy (PDR) naïve to treatment and (6) PDR treated with IVT aflibercept. Serum levels of vascular endothelial growth factor A (VEGF-A), placental growth factor (PlGF) and TGFβ1 were measured by means of enzyme-linked immunosorbent assay (ELISA). Foveal macular thickness (FMT) in enrolled subjects was evaluated by means of structural-optical coherence tomography (S-OCT). VEGF-A serum levels decreased in NPDR and PDR patients treated with aflibercept, compared to naïve DR patients. PlGF serum levels were modulated only in aflibercept-treated NPDR patients. Particularly, TGFβ1 serum levels were predictive of disease progression from NPDR to PDR. A Multivariate ANOVA analysis (M-ANOVA) was also carried out to assess the effects of fixed factors on glycated hemoglobin (HbA1c) levels, TGFβ1, and diabetes duration. In conclusion, our data have strengthened the hypothesis that TGFβ1 would be a biomarker and pharmacological target of diabetic retinopathy.
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Affiliation(s)
- Vincenza Bonfiglio
- Department of Experimental Biomedicine and Clinical Neuroscience, Ophthalmology Section, University of Palermo, 90133 Palermo, Italy;
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- Chiara Bianca Maria Platania
- Department of Biomedical and Biotechnological Sciences, School of Medicine, University of Catania, 95123 Catania, Italy; (C.B.M.P.); (F.L.); (F.C.); (F.D.)
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- Francesca Lazzara
- Department of Biomedical and Biotechnological Sciences, School of Medicine, University of Catania, 95123 Catania, Italy; (C.B.M.P.); (F.L.); (F.C.); (F.D.)
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- Federica Conti
- Department of Biomedical and Biotechnological Sciences, School of Medicine, University of Catania, 95123 Catania, Italy; (C.B.M.P.); (F.L.); (F.C.); (F.D.)
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- Corrado Pizzo
- Department of Ophthalmology, University of Catania, 95123 Catania, Italy; (C.P.); (A.R.); (M.F.); (E.O.); (A.L.); (T.A.)
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- Michele Reibaldi
- Department of Surgical Science, Eye Clinic, University of Torino, 10124 Torino, Italy;
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- Andrea Russo
- Department of Ophthalmology, University of Catania, 95123 Catania, Italy; (C.P.); (A.R.); (M.F.); (E.O.); (A.L.); (T.A.)
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- Matteo Fallico
- Department of Ophthalmology, University of Catania, 95123 Catania, Italy; (C.P.); (A.R.); (M.F.); (E.O.); (A.L.); (T.A.)
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- Elina Ortisi
- Department of Ophthalmology, University of Catania, 95123 Catania, Italy; (C.P.); (A.R.); (M.F.); (E.O.); (A.L.); (T.A.)
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- Antonio Longo
- Department of Ophthalmology, University of Catania, 95123 Catania, Italy; (C.P.); (A.R.); (M.F.); (E.O.); (A.L.); (T.A.)
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- Teresio Avitabile
- Department of Ophthalmology, University of Catania, 95123 Catania, Italy; (C.P.); (A.R.); (M.F.); (E.O.); (A.L.); (T.A.)
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- Filippo Drago
- Department of Biomedical and Biotechnological Sciences, School of Medicine, University of Catania, 95123 Catania, Italy; (C.B.M.P.); (F.L.); (F.C.); (F.D.)
- Center for Research in Ocular Pharmacology-CERFO, University of Catania, 95123 Catania, Italy
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- Claudio Bucolo
- Department of Biomedical and Biotechnological Sciences, School of Medicine, University of Catania, 95123 Catania, Italy; (C.B.M.P.); (F.L.); (F.C.); (F.D.)
- Center for Research in Ocular Pharmacology-CERFO, University of Catania, 95123 Catania, Italy
- Correspondence:
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17
Honma N, Inoue T, Tsuchiya N, Koizumi A, Yamamoto R, Nara T, Kanda S, Huang M, Numakura K, Saito M, Narita S, Satoh S, Habuchi T. Prognostic value of plasminogen activator inhibitor-1 in biomarker exploration using multiplex immunoassay in patients with metastatic renal cell carcinoma treated with axitinib.
Health Sci Rep 2020;
3:e197. [PMID:
33088925 PMCID:
PMC7559632 DOI:
10.1002/hsr2.197]
[Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2020] [Revised: 08/24/2020] [Accepted: 09/17/2020] [Indexed: 11/08/2022] Open
Abstract
Background and Aims
Vascular endothelial growth factor‐directed therapies play a significant role in patients with metastatic renal cell carcinoma (mRCC). Biomarkers for predicting treatment efficacy and resistance are required to develop personalized medicine. We evaluated multiple serum cytokine levels in patients with mRCC treated with axitinib to explore predictive biomarkers.
Methods
From September 2012 to October 2015, serum samples were collected from 44 patients with mRCC before treatment and 4 weeks after axitinib initiation. Bio‐Plex Pro Human Cancer Biomarker Panels 1 and 2 were used to measure levels of 34 serum biomarkers related to angiogenesis and cell proliferation.
Results
Patients with partial response or stable disease had significantly decreased serum plasminogen activator inhibitor‐1 (PAI‐1) level from pre‐treatment to 4 weeks after axitinib initiation compared with those with progressive disease (P = .022). The median progression‐free survival (PFS) and median overall survival (OS) in patients with increased serum PAI‐1 level from pre‐treatment to 4 weeks after axitinib initiation were significantly shorter than those with decreased serum PAI‐1 level (P = .027 and P = .026, respectively). Increased serum PAI‐1 level from pre‐treatment to 4 weeks after axitinib initiation was an independent prognostic marker for shorter PFS and OS in multivariate analyses (P = .015 and P = .032, respectively). The immunohistochemical staining intensity of PAI‐1 in tumor specimens was significantly associated with Fuhrman grade and presence of distant metastasis (P = .026 and P = .010, respectively).
Conclusions
The initial change in serum PAI‐1 level in the early stage of axitinib treatment could be a useful prognostic biomarker in patients with mRCC.
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Affiliation(s)
- Naoko Honma
- Department of Urology Akita University Graduate School of Medicine Akita Japan
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- Takamitsu Inoue
- Department of Urology Akita University Graduate School of Medicine Akita Japan.,AMED-CREST Japan Science and Technology Agency Tokyo Japan
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- Norihiko Tsuchiya
- Department of Urology Akita University Graduate School of Medicine Akita Japan.,Department of Urology Yamagata University Faculty of Medicine Yamagata Japan
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- Atsushi Koizumi
- Department of Urology Akita University Graduate School of Medicine Akita Japan
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- Ryohei Yamamoto
- Department of Urology Akita University Graduate School of Medicine Akita Japan
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- Taketoshi Nara
- Department of Urology Akita University Graduate School of Medicine Akita Japan
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- Sohei Kanda
- Department of Urology Akita University Graduate School of Medicine Akita Japan
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- Mingguo Huang
- Department of Urology Akita University Graduate School of Medicine Akita Japan
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- Kazuyuki Numakura
- Department of Urology Akita University Graduate School of Medicine Akita Japan
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- Mitsuru Saito
- Department of Urology Akita University Graduate School of Medicine Akita Japan
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- Shintaro Narita
- Department of Urology Akita University Graduate School of Medicine Akita Japan.,AMED-CREST Japan Science and Technology Agency Tokyo Japan
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- Shigeru Satoh
- Center for Kidney Disease and Transplantation Akita University Hospital Akita Japan
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- Tomonori Habuchi
- Department of Urology Akita University Graduate School of Medicine Akita Japan.,AMED-CREST Japan Science and Technology Agency Tokyo Japan
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18
Di Paolo V, Colletti M, Ferruzzi V, Russo I, Galardi A, Alessi I, Milano GM, Di Giannatale A. Circulating Biomarkers for Tumor Angiogenesis: Where Are We?
Curr Med Chem 2020;
27:2361-2380. [PMID:
30129403 DOI:
10.2174/0929867325666180821151409]
[Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2018] [Revised: 07/10/2018] [Accepted: 07/17/2018] [Indexed: 01/26/2023]
Abstract
BACKGROUND
In recent years, several anti-angiogenic drugs have been developed and their addition to standard treatment has been associated with clinical benefits. However, the response to anti-angiogenic therapy is characterized by considerable variability. In this context, the development of dynamic non-invasive biomarkers would be helpful to elucidate the emergence of anti-angiogenic resistance as well as to correctly address the treatment.
OBJECTIVES
The purpose of this review is to describe current reports on circulating diagnostic and prognostic biomarkers related to angiogenesis. We further discuss how this non-invasive strategy could improve the monitoring of tumor treatment and help clinical strategy.
RESULTS
We discuss the latest evidence in the literature regarding circulating anti-angiogenic markers. Besides growth factor proteins, different circulating miRNAs could exert a pro- or anti-angiogenic activity so as to represent suitable candidates for a non-invasive strategy. Recent reports indicate that tumor-derived exosomes, which are small membrane vesicles abundant in biological fluids, also have an impact on vascular remodeling.
CONCLUSION
Numerous circulating biomarkers related to angiogenesis have been recently identified. Their use will allow identifying patients who are more likely to benefit from a specific anti-angiogenic treatment, as well as detecting those who will develop resistance and/or adverse effects. Nonetheless, further studies are required to elucidate the role of these biomarkers in clinical settings.
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Affiliation(s)
- Virginia Di Paolo
- Department of Hematology/Oncology and Stem Cell Transplantation, Bambino Gesù Children's Hospital, IRCCS, Piazza di Sant'Onofrio, 4-00165 Rome, Italy
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- Marta Colletti
- Department of Hematology/Oncology and Stem Cell Transplantation, Bambino Gesù Children's Hospital, IRCCS, Piazza di Sant'Onofrio, 4-00165 Rome, Italy
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- Valentina Ferruzzi
- Department of Hematology/Oncology and Stem Cell Transplantation, Bambino Gesù Children's Hospital, IRCCS, Piazza di Sant'Onofrio, 4-00165 Rome, Italy
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- Ida Russo
- Department of Hematology/Oncology and Stem Cell Transplantation, Bambino Gesù Children's Hospital, IRCCS, Piazza di Sant'Onofrio, 4-00165 Rome, Italy
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- Angela Galardi
- Department of Hematology/Oncology and Stem Cell Transplantation, Bambino Gesù Children's Hospital, IRCCS, Piazza di Sant'Onofrio, 4-00165 Rome, Italy
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- Iside Alessi
- Department of Hematology/Oncology and Stem Cell Transplantation, Bambino Gesù Children's Hospital, IRCCS, Piazza di Sant'Onofrio, 4-00165 Rome, Italy
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- Giuseppe Maria Milano
- Department of Hematology/Oncology and Stem Cell Transplantation, Bambino Gesù Children's Hospital, IRCCS, Piazza di Sant'Onofrio, 4-00165 Rome, Italy
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- Angela Di Giannatale
- Department of Hematology/Oncology and Stem Cell Transplantation, Bambino Gesù Children's Hospital, IRCCS, Piazza di Sant'Onofrio, 4-00165 Rome, Italy
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19
Anti-angiogenesis and Immunotherapy: Novel Paradigms to Envision Tailored Approaches in Renal Cell-Carcinoma.
J Clin Med 2020;
9:jcm9051594. [PMID:
32456352 PMCID:
PMC7291047 DOI:
10.3390/jcm9051594]
[Citation(s) in RCA: 50] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2020] [Revised: 05/18/2020] [Accepted: 05/20/2020] [Indexed: 12/16/2022] Open
Abstract
Although decision making strategy based on clinico-histopathological criteria is well established, renal cell carcinoma (RCC) represents a spectrum of biological ecosystems characterized by distinct genetic and molecular alterations, diverse clinical courses and potential specific therapeutic vulnerabilities. Given the plethora of drugs available, the subtype-tailored treatment to RCC subtype holds the potential to improve patient outcome, shrinking treatment-related morbidity and cost. The emerging knowledge of the molecular taxonomy of RCC is evolving, whilst the antiangiogenic and immunotherapy landscape maintains and reinforces their potential. Although several prognostic factors of survival in patients with RCC have been described, no reliable predictive biomarkers of treatment individual sensitivity or resistance have been identified. In this review, we summarize the available evidence able to prompt more precise and individualized patient selection in well-designed clinical trials, covering the unmet need of medical choices in the era of next-generation anti-angiogenesis and immunotherapy.
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20
Evaluation of Vascular Endothelial Growth Factor (VEGF) and Thrombospondin-1 as Biomarkers of Metronomic Chemotherapy in Progressive Pediatric Solid Malignancies.
Indian Pediatr 2020. [DOI:
10.1007/s13312-020-1845-3]
[Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
21
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.
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Affiliation(s)
- Yolla Haibe
- Division of Hematology/Oncology, Department of Internal Medicine, American University of Beirut-Medical Center, Beirut, Lebanon
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- Malek Kreidieh
- Division of Hematology/Oncology, Department of Internal Medicine, American University of Beirut-Medical Center, Beirut, Lebanon
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- 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
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- Ibrahim Khalifeh
- Department of Pathology and Laboratory Medicine, American University of Beirut Medical Center, Beirut, Lebanon
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- Deborah Mukherji
- Division of Hematology/Oncology, Department of Internal Medicine, American University of Beirut-Medical Center, Beirut, Lebanon
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- Sally Temraz
- Division of Hematology/Oncology, Department of Internal Medicine, American University of Beirut-Medical Center, Beirut, Lebanon
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- Ali Shamseddine
- Division of Hematology/Oncology, Department of Internal Medicine, American University of Beirut-Medical Center, Beirut, Lebanon
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22
D'Aniello C, Berretta M, Cavaliere C, Rossetti S, Facchini BA, Iovane G, Mollo G, Capasso M, Pepa CD, Pesce L, D'Errico D, Buonerba C, Di Lorenzo G, Pisconti S, De Vita F, Facchini G. Biomarkers of Prognosis and Efficacy of Anti-angiogenic Therapy in Metastatic Clear Cell Renal Cancer.
Front Oncol 2019;
9:1400. [PMID:
31921657 PMCID:
PMC6917607 DOI:
10.3389/fonc.2019.01400]
[Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2019] [Accepted: 11/27/2019] [Indexed: 12/30/2022] Open
Abstract
In the last decades, the prognosis of metastatic renal cell carcinoma (mRCC) has remarkably improved following the advent of the "targeted therapy" era. The expanding knowledge on the prominent role played by angiogenesis in RCC pathogenesis has led to approval of multiple anti-angiogenic agents such as sunitinib, pazopanib, axitinib, cabozantinib, sorafenib, and bevacizumab. These agents can induce radiological responses and delay cancer progression for months or years before onset of resistance, with a clinically meaningful activity. The need for markers of prognosis and efficacy of anti-angiogenic agents has become more compelling as novel systemic immunotherapy agents have also been approved in RCC and can be administered as an alternative to angiogenesis inhibitors. Anti PD-1 monoclonal antibody nivolumab has been approved in the second-line setting after tyrosine kinase inhibitors failure, while combination of nivolumab plus anti CTLA-4 monoclonal antibody ipilimumab has been approved as first-line therapy of RCC patients at intermediate or poor prognosis. In this review article, biomarkers of prognosis and efficacy of antiangiogenic therapies are summarized with a focus on those that have the potential to affect treatment decision-making in RCC. Biomarkers predictive of toxicity of anti-angiogenic agents have also been discussed.
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Affiliation(s)
- Carmine D'Aniello
- Division of Medical Oncology, A.O.R.N. dei COLLI “Ospedali Monaldi-Cotugno-CTO,”Naples, Italy
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- Massimiliano Berretta
- Division of Medical Oncology, Istituto Nazionale Tumori, IRCCS CRO Aviano (PN), Milan, Italy
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- Carla Cavaliere
- UOC of Medical Oncology, ASL NA 3 SUD, Ospedali Riuniti Area Nolana, Nola, Italy
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- Sabrina Rossetti
- Departmental Unit of Experimental Uro-Andrologic Clinical Oncology, Istituto Nazionale Tumori Fondazione G. Pascale—IRCCS, Naples, Italy
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- Bianca Arianna Facchini
- Division of Medical Oncology, Department of Precision Medicine, University of Campania 'Luigi Vanvitelli', Naples, Italy
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- Gelsomina Iovane
- Departmental Unit of Experimental Uro-Andrologic Clinical Oncology, Istituto Nazionale Tumori Fondazione G. Pascale—IRCCS, Naples, Italy
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- Giovanna Mollo
- Departmental Unit of Experimental Uro-Andrologic Clinical Oncology, Istituto Nazionale Tumori Fondazione G. Pascale—IRCCS, Naples, Italy
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- Mariagrazia Capasso
- Departmental Unit of Experimental Uro-Andrologic Clinical Oncology, Istituto Nazionale Tumori Fondazione G. Pascale—IRCCS, Naples, Italy
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- Laura Pesce
- Oncology Unit, San Luca Hospital, Vallo Della Lucania, Italy
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- Davide D'Errico
- Departmental Unit of Experimental Uro-Andrologic Clinical Oncology, Istituto Nazionale Tumori Fondazione G. Pascale—IRCCS, Naples, Italy
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- Carlo Buonerba
- CRTR Rare Tumors Reference Center, AOU Federico II, Naples, Italy
- Environment & Health Operational Unit, Zoo-Prophylactic Institute of Southern Italy, Portici, Italy
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- Giuseppe Di Lorenzo
- Department of Clinical Medicine and Surgery, University Federico II, Naples, Italy
- Department of Medicine, University of Molise, Campobasso, Italy
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- Salvatore Pisconti
- Department of Onco-Hematology, Medical Oncology, S.G. Moscati Hospital, Taranto, Italy
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- Ferdinando De Vita
- Division of Medical Oncology, Department of Precision Medicine, University of Campania 'Luigi Vanvitelli', Naples, Italy
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- Gaetano Facchini
- Departmental Unit of Experimental Uro-Andrologic Clinical Oncology, Istituto Nazionale Tumori Fondazione G. Pascale—IRCCS, Naples, Italy
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23
Allman KD, Ryan JC, Clair A, Yenser-Wood S. Therapy Management Using Modified 2-Weeks-On/1-Week-Off Dosing Schedule in Patients With Metastatic Renal Cell Carcinoma Receiving Sunitinib: A Hypothetical, Illustrative Case Scenario.
J Adv Pract Oncol 2019;
10:483-493. [PMID:
33457061 PMCID:
PMC7779571 DOI:
10.6004/jadpro.2019.10.5.6]
[Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
This patient case is fictional and does not represent events or a response from an actual patient. The authors developed this fictional case for educational purposes only.
Brady, a 54-year-old white male, was diagnosed with metastatic renal cell carcinoma (mRCC). Two and a half years prior, he had undergone a complete left nephrectomy for clear-cell RCC, with clean margins and negative lymph nodes. Post nephrectomy, he was routinely surveyed (every 3–6 months) by radiologic imaging. After 15 months of monitoring, a CT scan revealed small nodules in the left lung. Repeated scans were ordered to be taken in 6 weeks to assess growth kinetics, wherein an increase in the size of a number of nodules was detected. Of particular concern was the location of one of the larger nodules very close to a bronchus. Consequently, a needle biopsy was performed, which recovered malignant cells consistent with mRCC. It was then decided to begin systemic treatment for mRCC. Prior to starting treatment, Brady’s Eastern Cooperative Oncology Group performance status (ECOG PS) was 0, and he had a Karnofsky score of 90, as he had only slightly diminished stamina that was considered disease related. Accordingly, he was classified as favorable risk by both Memorial Sloan Kettering Cancer Center and International Metastatic Renal Cell Carcinoma Database Consortium criteria (Table 1).
Brady is married and lives with his wife. He drinks alcohol occasionally but does not have a history of smoking. For the past 22 years, he has been employed full time as a factory assembly line worker, performing skilled, light assembly. In this capacity, Brady works with his hands and must remain on his feet approximately 30% of the working day. As Brady is eligible for early retirement in 11 months, he intends to continue working full time during treatment, if possible. Brady’s medical history includes nonvalvular atrial fibrillation, which is treated with apixaban; hypertension that is adequately controlled (blood pressure 137/79 mm Hg) with lisinopril at 20 mg/day; coronary artery disease; and hyperlipidemia that is treated with atorvastatin at 20 mg/day. He is also taking daily low-dose aspirin (81 mg).
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Affiliation(s)
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- Joanne C Ryan
- Pfizer Oncology, US Medical Affairs, New York, New York
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- Andrew Clair
- Pfizer Oncology, US Medical Affairs, New York, New York
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24
Jannin A, Penel N, Ladsous M, Vantyghem MC, Do Cao C. Tyrosine kinase inhibitors and immune checkpoint inhibitors-induced thyroid disorders.
Crit Rev Oncol Hematol 2019;
141:23-35. [PMID:
31202955 DOI:
10.1016/j.critrevonc.2019.05.015]
[Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2018] [Revised: 04/21/2019] [Accepted: 05/27/2019] [Indexed: 12/11/2022] Open
Abstract
Recently, tyrosine kinase inhibitors (TKI) and immune checkpoint inhibitors (ICPIs) have emerged as new classes of anticancer therapies. Although generally considered less toxic than cytotoxic chemotherapy, these new drugs can cause significant unanticipated side effects including thyroid dysfunction. This review provides a literature assessment of thyroid dysfunctions induced by TKI and ICPIs. We intend to define for these two classes the frequency of thyroid involvement, the potential mechanisms that result in this toxicity, the clinical-biological impact and the therapeutic management. Detection of thyroid dysfunction requires monitoring of TSH, in combination with free T4 if needed and, depending on the clinical impact and the kinetics of biological abnormalities, starting symptomatic treatment of hyperthyroidism and/or correcting hypothyroidism.
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Affiliation(s)
- Arnaud Jannin
- Department of Endocrinology and Metabolism, CHU Lille, 59037 Lille, France.
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- Nicolas Penel
- Medical Oncology Department, Oscar Lambret Cancer Centre, Lille, France; Medical Oncology Department, CHU Lille, 59037, Lille France.
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- Miriam Ladsous
- Department of Endocrinology and Metabolism, CHU Lille, 59037 Lille, France.
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- Marie Christine Vantyghem
- Department of Endocrinology and Metabolism, CHU Lille, 59037 Lille, France; UMR 1190 Translational Research in Diabetes INSERM, 59000 Lille, France.
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- Christine Do Cao
- Department of Endocrinology and Metabolism, CHU Lille, 59037 Lille, France.
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25
Ndiaye PD, Dufies M, Giuliano S, Douguet L, Grépin R, Durivault J, Lenormand P, Glisse N, Mintcheva J, Vouret-Craviari V, Mograbi B, Wurmser M, Ambrosetti D, Rioux-Leclercq N, Maire P, Pagès G. VEGFC acts as a double-edged sword in renal cell carcinoma aggressiveness.
Am J Cancer Res 2019;
9:661-675. [PMID:
30809300 PMCID:
PMC6376471 DOI:
10.7150/thno.27794]
[Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2018] [Accepted: 07/30/2018] [Indexed: 12/17/2022] Open
Abstract
Hypoxic zones are common features of metastatic tumors. Due to inactivation of the von Hippel-Lindau gene (VHL), renal cell carcinomas (RCC) show constitutive stabilization of the alpha subunit of the hypoxia-inducible factor (HIF). Thus, RCC represents a model of chronic hypoxia. Development of the lymphatic network is dependent on vascular endothelial growth factor C (VEGFC) and lies at the front line of metastatic spreading. Here, we addressed the role of VEGFC in RCC aggressiveness and the regulation of its expression in hypoxia. Methods: Transcriptional and post transcriptional regulation of VEGFC expression was evaluated by qPCR and with reporter genes. The involvement of HIF was evaluated using a siRNA approach. Experimental RCC were performed with immuno-competent/deficient mice using human and mouse cells knocked-out for the VEGFC gene by a CRISPR/Cas9 method. The VEGFC axis was analyzed with an online available data base (TCGA) and using an independent cohort of patients. Results: Hypoxia induced VEGFC protein expression but down-regulated VEGFC gene transcription and mRNA stability. Increased proliferation, migration, over-activation of the AKT signaling pathway and enhanced expression of mesenchymal markers characterized VEGFC-/- cells. VEGFC-/- cells did not form tumors in immuno-deficient mice but developed aggressive tumors in immuno-competent mice. These tumors showed down-regulation of markers of activated lymphocytes and M1 macrophages, and up-regulation of M2 macrophages markers and programmed death ligand 1 (PDL1). Over-expression of lymphangiogenic genes including VEGFC was linked to increased disease-free and overall survival in patients with non-metastatic tumors, whereas its over-expression correlated with decreased progression-free and overall survival of metastatic patients. Conclusion: Our study revisited the admitted dogma linking VEGFC to tumor aggressiveness. We conclude that targeting VEGFC for therapy must be considered with caution.
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26
Lacal PM, Graziani G. Therapeutic implication of vascular endothelial growth factor receptor-1 (VEGFR-1) targeting in cancer cells and tumor microenvironment by competitive and non-competitive inhibitors.
Pharmacol Res 2018;
136:97-107. [PMID:
30170190 DOI:
10.1016/j.phrs.2018.08.023]
[Citation(s) in RCA: 120] [Impact Index Per Article: 17.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2018] [Revised: 08/24/2018] [Accepted: 08/26/2018] [Indexed: 12/12/2022]
Abstract
The vascular endothelial growth factor receptor-1 (VEGFR-1) is a tyrosine kinase receptor for VEGF-A, VEGF-B, and placental growth factor (PlGF) ligands that is expressed in endothelial, myelomonocytic and tumor cells. VEGF-B and PlGF exclusively bind to VEGFR-1, whereas VEGF-A also binds to VEGFR-2. At variance with VEGFR-2, VEGFR-1 does not play a relevant role in physiological angiogenesis in the adult, while it is important in tumor-associated angiogenesis. VEGFR-1 and PlGF are expressed in a variety of tumors, promote invasiveness and contribute to resistance to anti-VEGF-A therapy. The currently approved antiangiogenic therapies for the treatment of a variety of solid tumors hamper VEGF-A signaling mediated by both VEGFR-2 and VEGFR-1 [i.e., the monoclonal antibody (mAb) anti-VEGF-A bevacizumab, the chimeric molecule aflibercept and several small molecule tyrosine kinase inhibitors] or exclusively by VEGFR-2 (i.e., the mAb anti-VEGFR-2 ramucirumab). However, molecules that interfere with VEGF-A/VEGFR-2 signaling determine severe adverse effects due to inhibition of physiological angiogenesis and their efficacy is hampered by tumor infiltration of protumoral myeloid cells. Blockade of VEGFR-1 may exert anti-tumor activity by multiple mechanisms: a) inhibition of tumor-associated angiogenesis; b) reduction of myeloid progenitor mobilization and tumor infiltration by VEGFR-1 expressing M2 macrophages, which contribute to tumor progression and spreading; c) inhibition of invasiveness, vasculogenic mimicry and survival of VEGFR-1 positive tumor cells. As a consequence of these properties, molecules targeting VEGFR-1 are expected to produce less adverse effects and to counteract resistance towards anti-VEGF-A therapies. More interestingly, selective VEGFR-1 inhibition might enhance the efficacy of immunotherapy with immune checkpoint inhibitors. In this review, we will examine the experimental evidence available so far that supports targeting VEGFR-1 signal transduction pathway for cancer treatment by competitive inhibitors that prevent growth factor interaction with the receptor and non-competitive inhibitors that hamper receptor activation without affecting ligand binding.
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Affiliation(s)
- Pedro Miguel Lacal
- Laboratory of Molecular Oncology, Istituto Dermopatico dell'Immacolata, IDI-IRCCS, Via Monti di Creta 104, 00167 Rome, Italy.
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- Grazia Graziani
- Department of Systems Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy.
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27
Zhang X, Shen P, Yao J, Chen N, Liu J, Zeng H. Sunitinib rechallenge with dose escalation in progressive metastatic renal cell carcinoma: A case report and literature review.
Medicine (Baltimore) 2018;
97:e11565. [PMID:
30075524 PMCID:
PMC6081141 DOI:
10.1097/md.0000000000011565]
[Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
RATIONALE
We aimed to present a case of sunitinib rechallenge with dosage escalation after disease progression, hopefully, providing an optional approach to the personalized medication management of progressive metastatic renal cell carcinoma (mRCC).
PATIENT CONCERNS
The patient was admitted to hospital due to right kidney mass, with merged enlargement of retroperitoneal lymph nodes. Subsequent surgery and sunitinib treatment was administered.
DIAGNOSES
Postoperative pathologic diagnosis was type II papillary renal cell carcinoma (pRCC) (Fuhrman grade 3) with metastases of retroperitoneal lymph nodes (T1aN1M0).
INTERVENTIONS
The patient underwent cytoreductive nephrectomy followed by treatment of sunitinib standard therapy (4/2 schedule) and alternative schedules according to different disease status. The patient received alternative 2/1 schedule while experiencing grade 3/4 adverse events. Re-challenge with sunitinib upon disease progression and metastasectomy were given. After second disease progression, sunitinib rechallenge with dose escalation was administered. Around 2/1 schedule showed desirable efficacy and better tolerance.
OUTCOMES
After 4 months of sunitinib individualized treatment, a complete response with retroperitoneal metastases was achieved. Rechallenge with sunitinib after disease progression and also rechallenge with dose escalation after second disease progression were effective.
LESSONS
Cessation of sunitinib in patients with complete response is not suggested. Also, strategy of subsequently administered sunitinib after metastasectomy is seemed to be effective. What is more, sunitinib rechallenge with escalation to 62.5 mg probably possess value in progressive mRCC and has a well tolerance when sunitinib is rechallenged. Based on this case, we probe a feasible alternative strategy in personalized therapy of sunitinib, hoping for providing referable insights into the detailed strategies of individual treatment for patients with mRCC.
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Affiliation(s)
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- Jiyan Liu
- Department of Oncology, West China Hospital, Sichuan University, Chengdu, China
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- Hao Zeng
- Department of Urology, Institute of Urology
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28
Mauge L, Mejean A, Fournier L, Pereira H, Etienne-Grimaldi MC, Levionnois E, Caty A, Abadie-Lacourtoisie S, Culine S, Le Moulec S, Linassier C, Théodore C, Ravaud A, Albiges L, Grine A, Tartour E, Milano G, Gille AS, Verkarre V, Helley D, Oudard S. Sunitinib Prior to Planned Nephrectomy in Metastatic Renal Cell Carcinoma: Angiogenesis Biomarkers Predict Clinical Outcome in the Prospective Phase II PREINSUT Trial.
Clin Cancer Res 2018;
24:5534-5542. [PMID:
30061359 DOI:
10.1158/1078-0432.ccr-18-1045]
[Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2018] [Revised: 06/22/2018] [Accepted: 07/24/2018] [Indexed: 11/16/2022]
Abstract
Purpose: The PREINSUT study characterized factors predictive of response to sunitinib given before planned nephrectomy in patients with metastatic renal cell carcinoma (mRCC).Patients and Methods: This French multicenter, prospective, open-label, phase II trial (NCT00930345) included treatment-naïve patients with clear-cell mRCC. Patients received two cycles of sunitinib before nephrectomy. The primary objective was to evaluate the potential of circulating angiogenesis-related biomarkers measured before and on treatment for identifying responders based on primary renal tumor (PRT) size change. Secondary objectives were to evaluate the ability of biomarkers to predict progression-free survival (PFS) and overall survival (OS).Results: Thirty-two patients were enrolled. The median PFS was 4.5 months, and the median OS was 12.4 months. OS was significantly longer in responding patients (28.8 vs. 11.1 months; P = 0.03). Of 27 patients evaluable for PRT response, nine (33.3%) had a ≥10% decrease in PRT size. Baseline biomarkers significantly associated with outcome were endothelial progenitor cells (PRT response); vascular endothelial growth factor (VEGF)-A, stromal cell-derived factor-1 (SDF-1), soluble VEGF receptors (sVEGFR)1 and 2 (PFS); and SDF-1 and sVEGFR1 (OS). During treatment, changes in biomarkers associated with outcome were SDF-1 and platelet-derived growth factor (PDGF)-BB (PRT response), sVEGFR2 (PFS), and SDF-1 and sVEGFR1 (OS). There was no correlation between plasma sunitinib or its active metabolite steady-state trough concentrations and clinical outcome.Conclusions: Angiogenesis-related parameters that could reflect hypoxia seem to be associated with worse outcome in mRCC. As blood biomarkers are not subjected to tumor heterogeneity and allow longitudinal follow-up, circulating angiogenesis profile has a promising place in antiangiogenic therapy guidance. Clin Cancer Res; 24(22); 5534-42. ©2018 AACR.
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Affiliation(s)
- Laetitia Mauge
- Department of Biological Hematology, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris; Université Paris-Descartes; UMR-S970, Paris, France
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- Arnaud Mejean
- Department of Urology, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris; Université Paris-Descartes, Paris, France
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- Laure Fournier
- Department of Radiology, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris; Université Paris-Descartes; UMR-S970, Paris, France
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- Helena Pereira
- Department of Epidemiology and Clinical Research, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris, INSERM U1418, Paris, France
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- Emeline Levionnois
- Department of Biological Hematology, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris; Université Paris-Descartes; UMR-S970, Paris, France
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- Armelle Caty
- Department of Medical Oncology, Hôpital Privé La Louvière, Lille, France
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- Stéphane Culine
- Department of Medical Oncology, Hôpital Saint-Louis, Assistance Publique-Hôpitaux de Paris; Université Paris-Diderot, Paris, France
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- Sylvestre Le Moulec
- Department of Medical Oncology, Hôpital d'Instruction des Armées du Val de Grâce, Paris, France
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- Claude Linassier
- Department of Medical Oncology, Hôpital Bretonneau, Tours, France
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- Alain Ravaud
- Department of Medical Oncology, Hôpital Saint-André, Bordeaux, France
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- Laurence Albiges
- Department of Medical Oncology, Institut Gustave Roussy; INSERM U753, Villejuif, France
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- Abel Grine
- Department of Epidemiology and Clinical Research, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris, INSERM U1418, Paris, France
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- Eric Tartour
- Department of Immunotherapy, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris; Université Paris-Descartes; UMR-S970, Paris, France
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- Gérard Milano
- Department of Oncopharmacology, Centre Antoine Lacassagne, Nice, France
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- Anne-Sophie Gille
- Department of Biological Hematology, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris; Université Paris-Descartes; UMR-S970, Paris, France
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- Virginie Verkarre
- Department of Pathology, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris; Université Paris-Descartes, Paris, France
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- Dominique Helley
- Department of Biological Hematology, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris; Université Paris-Descartes; UMR-S970, Paris, France.
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- Stéphane Oudard
- Department of Medical Oncology, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris; Université Paris-Descartes; UMR-S970, Paris, France.
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29
Rini BI, Hutson TE, Figlin RA, Lechuga MJ, Valota O, Serfass L, Rosbrook B, Motzer RJ. Sunitinib in Patients With Metastatic Renal Cell Carcinoma: Clinical Outcome According to International Metastatic Renal Cell Carcinoma Database Consortium Risk Group.
Clin Genitourin Cancer 2018;
16:298-304. [PMID:
29853320 DOI:
10.1016/j.clgc.2018.04.005]
[Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2018] [Revised: 04/25/2018] [Accepted: 04/26/2018] [Indexed: 01/09/2023]
Abstract
BACKGROUND
Sunitinib malate, a targeted tyrosine kinase inhibitor, is standard of care for metastatic renal cell carcinoma (mRCC) and serves as the active comparator in several ongoing mRCC clinical trials. In this analysis we report benchmarks for clinical outcomes on the basis of International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk groups for patients treated with sunitinib for mRCC in a first-line setting.
MATERIALS AND METHODS
A retrospective analysis was performed on data from sunitinib-treated patients (n = 375) in the pivotal phase III trial of sunitinib versus interferon-α as first-line treatment for mRCC. Objective response rates (ORRs) were determined from independently reviewed radiologic assessments. The Kaplan-Meier method was used to estimate median progression-free survival (PFS) and median overall survival (OS) according to patient risk group.
RESULTS
Median PFS (95% confidence interval [CI]) was 14.1 (13.4-17.1), 10.7 (10.5-12.5), 2.4 (1.1-4.7), and 10.6 (8.1-10.9) months in sunitinib-treated patients in the IMDC favorable (n = 134), intermediate (n = 205), poor (n = 34), and intermediate + poor (n = 239) risk groups, respectively. Median OS (95% CI) was 23.0 (19.8-27.8), 5.1 (4.3-9.9), and 20.3 (16.8-23.0) months in sunitinib-treated patients in IMDC intermediate, poor, and intermediate + poor risk groups, respectively, and was not reached in the favorable risk group (>50% of patients were alive at data cutoff). ORRs (95% CI) was 53.0% (44.2%-61.7%), 33.7% (27.2%-40.6%), 11.8% (3.3%-27.5%), and 30.5% (24.8%-36.8%) in sunitinib-treated patients in IMDC favorable, intermediate, poor, and intermediate + poor risk groups, respectively.
CONCLUSION
Results of this retrospective analysis show differences in patient outcomes for PFS, OS, and ORR on the basis of IMDC prognostic risk group assignment for patients with mRCC.
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Affiliation(s)
- Brian I Rini
- Cleveland Clinic, Taussig Cancer Institute, Cleveland, OH.
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- Robert A Figlin
- Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA
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- Robert J Motzer
- Memorial Sloan Kettering Cancer Center, Department of Oncology, New York, NY
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30
Itatani Y, Kawada K, Yamamoto T, Sakai Y. Resistance to Anti-Angiogenic Therapy in Cancer-Alterations to Anti-VEGF Pathway.
Int J Mol Sci 2018;
19:ijms19041232. [PMID:
29670046 PMCID:
PMC5979390 DOI:
10.3390/ijms19041232]
[Citation(s) in RCA: 245] [Impact Index Per Article: 35.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2018] [Revised: 04/12/2018] [Accepted: 04/15/2018] [Indexed: 02/06/2023] Open
Abstract
Anti-angiogenic therapy is one of the promising strategies for many types of solid cancers. Bevacizumab (Avastin), a recombinant humanized monoclonal antibody of vascular endothelial growth factor (VEGF) A, was approved for the first time as an anti-angiogenic drug for the treatment of metastatic colorectal cancer (CRC) by the Food and Drug Administration (FDA) in 2004. In addition, the other VEGF pathway inhibitors including small molecule tyrosine kinase inhibitors (sunitinib, sorafenib, and pazopanib), a soluble VEGF decoy receptor (aflibercept), and a humanized monoclonal antibody of VEGF receptor 2 (VEGFR2) (ramucirumab) have been approved for cancer therapy. Although many types of VEGF pathway inhibitors can improve survival in most cancer patients, some patients have little or no beneficial effect from them. The primary or acquired resistance towards many oncological drugs, including anti-VEGF inhibitors, is a common problem in cancer treatment. This review summarizes the proposed alternative mechanisms of angiogenesis other than the VEGF pathway. These mechanisms are involved in the development of resistance to anti-VEGF therapies in cancer patients.
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Affiliation(s)
- Yoshiro Itatani
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan.
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- Kenji Kawada
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan.
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- Takamasa Yamamoto
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan.
- Moores Cancer Center, University of California San Diego, San Diego, CA 92093, USA.
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- Yoshiharu Sakai
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan.
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31
Abstract
Metastatic renal cell carcinoma (mRCC) is an incurable malignancy, characterized by its resistance to traditional chemotherapy, radiation, and hormonal therapy. Treatment perspectives and prognosis of patients with mRCC have been significantly improved by advances in the understanding of its molecular pathogenesis, which have led to the development of targeted therapeutics. Different molecular factors derived from the tumor or the host detected in both tissue or serum could be predictive of therapeutic benefit. Some of them suggest a rational selection of patients to be treated with certain therapies, though none have been validated for routine use. This article provides an overview of both clinical and molecular factors associated with predictive or prognostic value in mRCC and emphasizes that both should be considered in parallel to provide the most appropriate, individualized treatment and achieve the best outcomes in clinical practice.
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32
Rodriguez-Pascual J, Cubillo A. Dynamic Biomarkers of Response to Antiangiogenic Therapies in Colorectal Cancer: A Review.
ACTA ACUST UNITED AC 2018;
15:81-85. [PMID:
29657584 PMCID:
PMC5872368 DOI:
10.2174/1875692115666170815161754]
[Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2017] [Revised: 07/27/2017] [Accepted: 08/09/2017] [Indexed: 12/14/2022]
Abstract
Background:
Identification of clinical and molecular biomarkers to predict dynamic response or monitor in real-time the efficacy of antiangiogenic therapy represents a major point in the treatment of patients with advanced colorectal cancer. Several stu-dies have been conduced to identify some predictive biomarkers to select patients who will benefit from bevacizumab, the most widely used antiangiogenic monoclonal anti-body.
Conclusion:
After a decade since the introduction of bevacizumab, no effective predictive biomarkers are available in routine clinical practice. In this review, we summarized the potential candidate dynamic biomarkers that may play a role in this setting.
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Affiliation(s)
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- Antonio Cubillo
- Centro Integral Oncológico Clara Campal (CIOCC), Madrid, Spain
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33
von Klot CA, Dubrowinskaja N, Peters I, Hennenlotter J, Merseburger AS, Stenzl A, Kuczyk MA, Serth J. Rho GDP dissociation inhibitor-β in renal cell carcinoma.
Oncol Lett 2017;
14:8190-8196. [PMID:
29250194 DOI:
10.3892/ol.2017.7233]
[Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2017] [Accepted: 06/15/2017] [Indexed: 12/18/2022] Open
Abstract
Rho GDP dissociation inhibitor-β (ARHGDIB) is an important mediator of cell signaling. The expression of ARHGDIB is associated with tumor growth and metastasis in a variety of non-genitourinary cancers; however, the role of ARHGDIB in renal cell carcinoma (RCC) has not yet been evaluated. In the present study, tissue samples from 105 patients undergoing surgery for RCC were obtained. The expression levels of ARHGDIB mRNA in normal kidney tissues and in corresponding cancer tissues were analyzed by reverse transcription-quantitative polymerase chain reaction. Differences in relative mRNA expression levels were assessed using paired two-sample t-tests. Expression levels were analyzed with respect to various clinical parameters, and associations were tested using a bivariate logistic regression model. Relative mRNA expression levels in healthy renal tissues compared with cancerous tissues from the same kidney were assessed using paired t-tests. Expression data were compared with respect to survival data by the Kaplan-Meier method/Cox regression analysis. The results revealed that the relative mRNA expression level of ARHGDIB was significantly higher in the lysates of RCC tumor tissues (P<0.001) when compared with healthy renal tissues in a paired analysis of 74 samples; this finding was consistent with the analysis of ARHGDIB mRNA expression levels in all RCC samples, as well as in the subset of clear cell RCC (ccRCC) samples. The relative mRNA expression level of ARHGDIB was also increased in ccRCC tissues compared with papillary RCC tissues (P<0.001). On univariate Cox regression analysis, recurrence-free survival (RFS) was significantly associated with metastasis, locally advanced disease and tumor grade (P=0.018, P=0.002 and P<0.001, respectively). Furthermore, in the subgroup of patients with ccRCC, increased ARHGDIB mRNA expression was significantly associated with a longer RFS time (P=0.001). In summary, the results indicate that ARHGDIB mRNA is highly expressed in RCC tissues in general and is positively associated with RFS in ccRCC. As ARHGDIB has a known effect on angiogenesis and immune modulation, the present study suggests that the functional analysis of ARHGDIB should be performed in the future.
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Affiliation(s)
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- Natalia Dubrowinskaja
- Department of Urology and Urological Oncology, Hannover University Medical School, D-30625 Hannover, Germany
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- Inga Peters
- Department of Urology and Urological Oncology, Hannover University Medical School, D-30625 Hannover, Germany
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- Jörg Hennenlotter
- Department of Urology, Eberhard Karls University of Tübingen, D-72076 Tübingen, Germany
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- Axel S Merseburger
- Department of Urology, Campus Lübeck University Hospital Schleswig-Holstein, D-23538 Lübeck, Germany
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- Arnulf Stenzl
- Department of Urology, Campus Lübeck University Hospital Schleswig-Holstein, D-23538 Lübeck, Germany
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- Markus A Kuczyk
- Department of Urology and Urological Oncology, Hannover University Medical School, D-30625 Hannover, Germany
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- Jürgen Serth
- Department of Urology and Urological Oncology, Hannover University Medical School, D-30625 Hannover, Germany
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34
Kudo M, Cheng AL, Park JW, Park JH, Liang PC, Hidaka H, Izumi N, Heo J, Lee YJ, Sheen IS, Chiu CF, Arioka H, Morita S, Arai Y. Orantinib versus placebo combined with transcatheter arterial chemoembolisation in patients with unresectable hepatocellular carcinoma (ORIENTAL): a randomised, double-blind, placebo-controlled, multicentre, phase 3 study.
Lancet Gastroenterol Hepatol 2017;
3:37-46. [PMID:
28988687 DOI:
10.1016/s2468-1253(17)30290-x]
[Citation(s) in RCA: 144] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2017] [Revised: 08/22/2017] [Accepted: 08/29/2017] [Indexed: 02/06/2023]
Abstract
BACKGROUND
Orantinib is an oral multi-kinase inhibitor. This study was done to evaluate the efficacy of orantinib combined with conventional transcatheter arterial chemoembolisation (cTACE) in patients with unresectable hepatocellular carcinoma.
METHODS
This randomised, double-blind, placebo-controlled, phase 3 study was done at 75 sites in Japan, South Korea, and Taiwan. Patients with unresectable hepatocellular carcinoma, no extra-hepatic tumour spread, and Child-Pugh score of 6 or less were randomly assigned (1:1) by interactive web response system using a computer-generated sequence to receive orantinib or placebo, within 28 days of cTACE. Randomisation was stratified by region, Child-Pugh score (5 vs 6), alpha fetoprotein concentrations (<400 ng/mL vs ≥400 ng/mL), and size of the largest lesion (≤50 mm vs >50 mm). Orantinib at 200 mg, twice per day, or placebo was given orally until TACE failure or unacceptable toxicity. The patients, investigators, and study personnel were masked to treatment assignment. The primary endpoint was overall survival, analysed in the full analysis set (patients who had received at least one dose of study drug). This study is registered at ClinicalTrials.gov, number NCT01465464, and has been terminated.
FINDINGS
Between Dec 10, 2010, and Nov 21, 2013, 889 patients were randomly assigned to receive either orantinib (445 patients; 444 treated) or placebo (444 patients; all treated). The study was ended at interim analysis for futility evaluation. Median follow-up was 17·3 months (IQR 11·3-26·4). There was no improvement in overall survival with orantinib compared with placebo (median 31·1 months [95% CI 26·5-34·5] vs 32·3 months [28·4-not reached]; hazard ratio 1·090, 95% CI 0·878-1·352; p=0·435). The main adverse events in the orantinib group were oedema, ascites, and elevation of aspartate and alanine aminotransferases. The most frequent adverse events of grade 3 or worse in the orantinib group included elevated aspartate aminotransferase (189 [43%] patients in the oratinib group, 161 [36%] patients in the placebo group), elevated alanine aminotransferase (150 [34%] patients in the oratinib group, 132 (30%) patients in the placebo group), and hypertension (47 [11%] patients in the oratinib group, 39 [9%] patients in the placebo group). Serious adverse events were reported in 200 (45%) patients in the orantinib group and 134 (30%) patients in the placebo group.
INTERPRETATION
Orantinib combined with cTACE did not improve overall survival in patients with unresectable hepatocellular carcinoma.
FUNDING
Taiho Pharmaceutical.
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Affiliation(s)
- Masatoshi Kudo
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka, Japan.
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- Ann-Lii Cheng
- Department of Oncology, National Taiwan University Hospital, Taipei City, Taiwan
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- Joong-Won Park
- Center for Liver Cancer, National Cancer Center Korea, Gyeonggi-do, South Korea
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- Jae Hyung Park
- Department of Radiology, Seoul National University Hospital, Seoul, South Korea; Department of Radiology, Myongji Hospital, Gyeonggi-do, South Korea
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- Po-Chin Liang
- Division of Abdomen Radiology, National Taiwan University Hospital, Taipei City, Taiwan
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- Hisashi Hidaka
- Department of Gastroenterology, Internal Medicine, Kitasato University School of Medicine, Kanagawa, Japan
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- Namiki Izumi
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
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- Jeong Heo
- Department of Internal Medicine, College of Medicine, Pusan National University and Medical Research Institute, Pusan National University Hospital, Busan, South Korea
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- Youn Jae Lee
- Division of Gastroenterology, Inje University Busan Paik Hospital, Busan, South Korea
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- I-Shyan Sheen
- Department of Hepato-gastroenterology, Chang Gung Memorial Hospital-Linkou, Taoyuan County, Taiwan
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- Chang-Fang Chiu
- Division of Hematology/Oncology, China Medical University Hospital, Taichung City, Taiwan
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- Hitoshi Arioka
- Department of Medical Oncology, Yokohama Rosai Hospital, Kanagawa, Japan
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- Satoshi Morita
- Department of Biomedical Statistics and Bioinformatics, Kyoto University Graduate School of Medicine, Kyoto, Japan
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- Yasuaki Arai
- Department of Diagnostic Radiology, National Cancer Center Hospital, Tokyo, Japan
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35
Miao C, Cao J, Wang Y, Liu B, Wang Z. Effects of VEGF and VEGFR polymorphisms on the outcome of patients with metastatic renal cell carcinoma treated with sunitinib: a systematic review and meta-analysis.
Oncotarget 2017;
8:68854-68862. [PMID:
28978162 PMCID:
PMC5620302 DOI:
10.18632/oncotarget.19924]
[Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2017] [Accepted: 07/26/2017] [Indexed: 12/15/2022] Open
Abstract
To summarize and clarify the association between vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor (VEGFR) polymorphisms and the outcome in patients with metastatic renal cell carcinoma (mRCC) treated with sunitinib. A total of 8 studies including 900 patients were analyzed in this systematic review after screening the database of PubMed, EMBASE and Web of Science. Hazard ratios (HRs) with 95% confidence interval (CI) were used to evaluate the strength of the association. VEGFR1 rs9582036 AA/AC carriers and rs9554320 CC/AC carriers had more favorable overall survival (OS) in patients with mRCC treated with sunitinib (n = 3), but not in progression-free survival (PFS). In addition, VEGFA rs2010963 was associated with poorer PFS of mRCC (n = 1). VEGFA rs699947 was significant in predicting PFS by univariate analysis, but showed no statistical significance in OS (n = 1). VEGFR2 rs1870377 was verified to be associated with sunitinib OS (n = 1). Furthermore, patients with VEGFR3 rs307826 and rs307821 had shorter PFS and OS during sunitinib therapy (n = 2, respectively). Our results suggested that VEGF and VEGFR polymorphisms were associated with outcomes in sunitinib treated mRCC patients, especially VEGFR1 polymorphisms. However, considering the limited study numbers, its clinical application in sunitinib treated mRCC still needs further confirmation.
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Affiliation(s)
- Chenkui Miao
- State Key Laboratory of Reproductive Medicine and Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
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- Jingyi Cao
- Department of Urology, Xuzhou Cancer Hospital, Xuzhou, China
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- Yuhao Wang
- State Key Laboratory of Reproductive Medicine and Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
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- Bianjiang Liu
- State Key Laboratory of Reproductive Medicine and Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
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- Zengjun Wang
- State Key Laboratory of Reproductive Medicine and Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
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36
Decker T, Overkamp F, Rösel S, Nusch A, Göhler T, Indorf M, Sahlmann J, Trarbach T. A randomized phase II study of paclitaxel alone versus paclitaxel plus sorafenib in second- and third-line treatment of patients with HER2-negative metastatic breast cancer (PASO).
BMC Cancer 2017;
17:499. [PMID:
28743247 PMCID:
PMC5526236 DOI:
10.1186/s12885-017-3492-1]
[Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2016] [Accepted: 07/20/2017] [Indexed: 01/07/2023] Open
Abstract
Background
We conducted an open-label, randomized, two-arm multi-center study to assess the efficacy and safety of paclitaxel versus paclitaxel + sorafenib in patients with locally advanced or metastatic HER2-negative breast cancer.
Methods
Patients were randomly assigned to receive either paclitaxel monotherapy (80 mg/m2) weekly (3 weeks on, 1 week off) plus sorafenib 400 mg orally, twice a day taken continuously throughout 28 day cycles. Sorafenib dose was gradually escalated from a starting dose of 200 mg twice a day. The primary endpoint was progression free survival (PFS).
Results
A pre-planned efficacy interim analysis was performed on the data of 60 patients, 30 patients in each treatment arm. Median PFS was estimated at 6.6 months (95% CI: 5.1 to 9.0) in patients randomized to single-agent paclitaxel (Arm A) and 5.6 months (95% CI: 3.8 to 6.5) in patients randomized to paclitaxel-sorafenib combination (Arm B) therapy. Contrary to the hypothesis, the treatment effect was statistically significant in favor of paclitaxel monotherapy (hazard ratio 1.80, 95% CI: 1.02 to 3.20; log-rank test P = 0.0409). It was decided to stop the trial early for futility. Median OS was also in favor of Arm A (20.7 months (95% CI: 16.4 to 26.7) versus 12.1 months (95% CI: 5.8 to 20.4) in Arm B. Clinical control was achieved in 28 patients (93.3%) in Arm A and in 21 patients 70.0% in Arm B. Overall response rate was met in 43.3% of patients in Arm A and in 40.0% in Arm B. Toxicities were increased in Arm B with higher rates of diarrhea, nausea, neutropenia, hand-foot skin reaction (HFSR) and anorexia, Grad 3 and 4 toxicities were rare.
Conclusions
In this pre-planned interim analysis, paclitaxel-sorafenib combination therapy was not found to be superior to paclitaxel monotherapy with regard to the primary end point, progression-free survival. The trial was therefore discontinued early. There was no indication of more favorable outcomes for combination therapy in secondary efficacy end points. As expected, the safety and toxicity profile of the combination therapy was less favorable compared to monotherapy. Overall, this trial did not demonstrate that adding sorafenib to second- or third-line paclitaxel provides any clinical benefit to patients with HER2-negative advanced or metastatic breast cancer. Cautious dosing using a sorafenib ramp up schedule might have contributed to negative results.
Trial registration
The study was registered at EudraCT (No 2009–018025-73) and retrospectively registered at Clinical trials.gov on March 17, 2011 (NCT01320111).
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Affiliation(s)
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- Arnd Nusch
- Practice for Haematology and internal Oncology, Velbert, Germany
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- Tanja Trarbach
- iOMEDICO, Freiburg, Germany.,Center for Tumor Biology and Integrative Medicine Clinics Wilhelmshaven, Wilhelmshaven, Germany
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37
Tannir NM, Figlin RA, Gore ME, Michaelson MD, Motzer RJ, Porta C, Rini BI, Hoang C, Lin X, Escudier B. Long-Term Response to Sunitinib Treatment in Metastatic Renal Cell Carcinoma: A Pooled Analysis of Clinical Trials.
Clin Genitourin Cancer 2017;
16:S1558-7673(17)30171-4. [PMID:
28711490 PMCID:
PMC6736765 DOI:
10.1016/j.clgc.2017.06.005]
[Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2017] [Revised: 06/05/2017] [Accepted: 06/13/2017] [Indexed: 12/29/2022]
Abstract
BACKGROUND
We characterized clinical outcomes of patients with metastatic renal cell carcinoma (mRCC) treated with sunitinib who were long-term responders (LTRs), defined as patients having progression-free survival (PFS) > 18 months.
PATIENTS AND METHODS
A retrospective analysis of data from 5714 patients with mRCC treated with sunitinib in 8 phase II/III clinical trials and the expanded access program. Duration on-study and objective response rate (ORR) were compared between LTRs and patients with PFS ≤ 18 months ("others"). PFS and overall survival (OS) were summarized using Kaplan-Meier methodology.
RESULTS
Overall, 898 (15.7%) patients achieved a long-term response and 4816 (84.3%) patients did not achieve long-term response. The median (range) duration on-study was 28.6 (16.8-70.7) months in LTRs and 5.5 (0-68.8) months in others. ORR was 51% in LTRs versus 14% in others (P < .0001). Median PFS in LTRs was 32.11 months and median OS was not reached. LTRs had higher percentage of early tumor shrinkage ≥ 10% at the first scan (67.1% vs. 51.2%; P = .0018) and greater median maximum on-study tumor shrinkage from baseline (-56.9 vs. -27.1; P < .0001) versus others. White race, Eastern Cooperative Oncology Group performance status 0, time from diagnosis to treatment ≥ 1 year, clear cell histology, no liver metastasis, lactate dehydrogenase ≤ 1.5 upper limit of normal (ULN), corrected calcium ≤ 10 mg/dL, hemoglobin greater than the lower limit of normal, platelets less than or equal to ULN, body mass index ≥ 25 kg/m2, and low neutrophil-to-lymphocyte ratio were associated with LTR.
CONCLUSION
A subset of patients with mRCC treated with sunitinib achieved long-term response. LTRs had improved ORR, PFS, and OS.
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Affiliation(s)
- Nizar M Tannir
- Division of Cancer Medicine, Department of Genitourinary Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX.
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- Robert A Figlin
- Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA
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- Martin E Gore
- Royal Marsden Hospital NHS Trust, Fulham Road, London, UK
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- Camillo Porta
- Division of Medical Oncology, IRCCS San Matteo University Hospital Foundation, Pavia, Italy
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- Brian I Rini
- Cleveland Clinic Taussig Cancer Institute, Cleveland, OH
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- Xun Lin
- Pfizer Oncology, La Jolla, CA
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38
Wang JC, Li GY, Li PP, Sun X, Li WM, Li Y, Lu SY, Liu PJ. Suppression of hypoxia-induced excessive angiogenesis by metformin via elevating tumor blood perfusion.
Oncotarget 2017;
8:73892-73904. [PMID:
29088755 PMCID:
PMC5650310 DOI:
10.18632/oncotarget.18029]
[Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2017] [Accepted: 05/09/2017] [Indexed: 12/22/2022] Open
Abstract
The anti-diabetic metformin has been demonstrated to be effective in suppression of tumor progression via multiple mechanisms, in which angiogenic inhibition is involved. Hypoxia is a common feather of malignant tumor and promotes angiogenesis via induction of pro-angiogenic factors. However, the effect of metformin on tumor hypoxia and the association with angiogenic inhibition are still unclear. In the current study, we investigated the effects of metformin on both tumor blood perfusion and hypoxia-induced excessive angiogenesis. In the tumor region adjacent to necrosis, aberrantly excessive angiogenesis resulted from hypoperfusion-induced intense hypoxia and greatly contributed to the high average levels of both microvessel density and vascular branch density. Metformin administration increased the percentage of lectin-perfused vessels and reduced hypoxyprobe-positive area. This metformin-induced amelioration of hypoxia was accompanied by a significant reduction in expressions of both HIF-1α and angiogenesis-associated factors (AAFs). Consequently, inhibited excessive angiogenesis in hypoxic peri-necrotic region was observed in metformin-treated tumor. Further stable knockdown of HIF-1α abrogated hypoxia-induced AAFs in vitro and reduced both microvessel density and area of fitc-conjugated dextran that leaked outside the vascular lumen. Taken together, metformin ameliorated tumor hypoxia and restrained HIF-1α-induced expressions of AAFs through elevating tumor blood perfusion, thus suppressing the excessive tumor angiogenesis.
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Affiliation(s)
- Ji-Chang Wang
- Department of Vascular Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, 710061, P.R.China.,Center for Translational Medicine, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, 710061, P.R.China
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- Guang-Yue Li
- Department of Science and Technology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, 710061, P.R.China
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- Ping-Ping Li
- Center for Translational Medicine, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, 710061, P.R.China
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- Xin Sun
- Department of Thoracic Surgery and Oncology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, 710061, P.R.China
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- Wei-Ming Li
- Department of Vascular Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, 710061, P.R.China
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- Yan Li
- Department of Vascular Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, 710061, P.R.China
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- Shao-Ying Lu
- Department of Vascular Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, 710061, P.R.China
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- Pei-Jun Liu
- Center for Translational Medicine, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, 710061, P.R.China
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39
Ma Y, Zhou W, He S, Xu W, Xiao J. Tyrosine kinase inhibitor sunitinib therapy is effective in the treatment of bone metastasis from cancer of unknown primary: Identification of clinical and immunohistochemical biomarkers predicting survival.
Int J Cancer 2017;
139:1423-30. [PMID:
27164264 DOI:
10.1002/ijc.30176]
[Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2016] [Revised: 04/14/2016] [Accepted: 05/03/2016] [Indexed: 11/06/2022]
Abstract
Bone metastasis from cancer of unknown primary (BMCUP) brings poor survival prognosis and its management remains controversial. Sunitinib (SUTENT) proved effective in many sorts of solid tumors but has never been applied for patients with occult primary cancers, and there is no study to identify sensitive or resistant biomarkers for sunitinib therapy in CUP patients. An analysis was carried out to investigate the efficacy of sunitinib by multivariate survival analysis of 286 patients with BMCUP. We further carried out multivariate analysis to identify histological and clinical biomarkers that could predict sensitivity or resistance for sunitinib therapy. Of the 286 patients included from January 2011 to March 2016, sunitinib therapy proved effective to prolong survival in patients with BMCUP. Sensitive and resistant biomarkers were identified in histological specimen of patients receiving sunitinib therapy. Clinical factors were also identified that predict poor survival prognosis for sunitinib therapy. Sunitinib therapy proved effective to prolong survival in patients with BMCUP. Sensitive markers for sunitinib therapy include KDR positivity and early-developed treatment-induced hypertension. Resistance factors for sunitinib include VEGF positivity, CAIX positivity and squamous cell carcinoma pathology type. Prolonged symptom time and severe weight loss before therapy seemed to be associated with poor survival prognosis for sunitinib therapy.
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Affiliation(s)
- Yifei Ma
- Department of Orthorpedic Oncology, Changzheng Hospital, Second Military Medical University, Shanghai, China
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- Wang Zhou
- Department of Orthorpedic Oncology, Changzheng Hospital, Second Military Medical University, Shanghai, China
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- Shaohui He
- Department of Orthorpedic Oncology, Changzheng Hospital, Second Military Medical University, Shanghai, China
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- Wei Xu
- Department of Orthorpedic Oncology, Changzheng Hospital, Second Military Medical University, Shanghai, China
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- Jianru Xiao
- Department of Orthorpedic Oncology, Changzheng Hospital, Second Military Medical University, Shanghai, China
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40
Nassif E, Thibault C, Vano Y, Fournier L, Mauge L, Verkarre V, Timsit MO, Mejean A, Tartour E, Oudard S. Sunitinib in kidney cancer: 10 years of experience and development.
Expert Rev Anticancer Ther 2016;
17:129-142. [PMID:
27967249 DOI:
10.1080/14737140.2017.1272415]
[Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
INTRODUCTION
Sunitinib is a multi-target, anti-angiogenic tyrosine kinase inhibitor and a key molecule in the treatment of metastatic renal cell carcinoma (mRCC). Since it first demonstrated its efficacy ten years ago, overall survival of mRCC has more than doubled, in part due to sunitinib. In most recent years, progress has been made in the comprehension of its mechanism of action and resistance. Areas Covered: In this article, clinical trials involving sunitinib in kidney cancer have been reviewed, defining its different indications in metastatic and localized RCC. The rationale of sunitinib's efficacy, preclinical trials, past-clinical trials and ongoing clinical trials are summarized. Dose and scheme base are discussed, as the recommended dosage is frequently not well tolerated. Combination therapies appear to be toxic. Novel immunotherapies are changing the landscape of mRCC treatment and challenging sunitinib. Special attention has been paid towards cancer cell biology and immunity involved in treatment response. Expert Commentary: Sunitinib's place in the therapeutic arsenal is being redefined with the arrival of major challengers. Dosage and scheduling of sunitinib remains a major challenge.
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Affiliation(s)
- Elise Nassif
- a Oncology Department , Georges Pompidou European Hospital , Paris , France
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- Constance Thibault
- a Oncology Department , Georges Pompidou European Hospital , Paris , France.,g Université Paris Descartes Sorbonne Paris-Cité , Paris 5 , France
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- Yann Vano
- a Oncology Department , Georges Pompidou European Hospital , Paris , France.,b Cordeliers Research Center, UMRS1138 Team 13 Cancer, Immune Control and Escape , Paris , France .,g Université Paris Descartes Sorbonne Paris-Cité , Paris 5 , France
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- Laure Fournier
- c Radiology Department , Georges Pompidou European Hospital , Paris , France.,g Université Paris Descartes Sorbonne Paris-Cité , Paris 5 , France
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- Laetitia Mauge
- d Biological Hematology Department , Georges Pompidou European Hospital , Paris , France.,g Université Paris Descartes Sorbonne Paris-Cité , Paris 5 , France
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- Virginie Verkarre
- d Biological Hematology Department , Georges Pompidou European Hospital , Paris , France.,g Université Paris Descartes Sorbonne Paris-Cité , Paris 5 , France
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- Marc-Olivier Timsit
- e Urology Department , Georges Pompidou European Hospital , Paris , France.,g Université Paris Descartes Sorbonne Paris-Cité , Paris 5 , France
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- Arnaud Mejean
- e Urology Department , Georges Pompidou European Hospital , Paris , France.,g Université Paris Descartes Sorbonne Paris-Cité , Paris 5 , France
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- Eric Tartour
- f Immunology Department , Georges Pompidou European Hospital , Paris , France.,g Université Paris Descartes Sorbonne Paris-Cité , Paris 5 , France
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- Stéphane Oudard
- a Oncology Department , Georges Pompidou European Hospital , Paris , France.,g Université Paris Descartes Sorbonne Paris-Cité , Paris 5 , France
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41
Abstract
Sunitinib is an oral multi-targeted tyrosine kinase inhibitor (TKI) that targets various receptors, including vascular endothelial growth factor receptors (VEGFRs). Sunitinib received approval in 2006 and became a standard treatment option in the first-line treatment of metastatic renal cell cancer (mRCC) after a phase III trial showed superiority compared with interferon alpha (IFN-α). Sunitinib has also shown activity in second-line treatment in several trials. Most of the combination trials with sunitinib with various agents have led to considerable toxicity without improving efficacy. Sunitinib alone causes significant side effects and has a distinct profile with diarrhoea, hypertension, skin effects hypothyroidism, fatigue and nausea of special interest. The recommended dose of sunitinib in mRCC is 50 mg orally daily for 4 weeks, followed by 2 weeks off treatment (4/2 schedule). An alternative 2 weeks on, 1 week off schedule (2/1 schedule) seems to be of similar efficacy and better tolerability and could be more widely used in the future. An intermittent treatment strategy with a stop in remission and re-induction after progression showed efficacy in smaller trials and is currently being evaluated in a phase III trial. Direct comparison of sunitinib with pazopanib in first-line treatment showed a similar efficacy for both TKIs with a distinct toxicity profile. Data from two phase II trials showed that sunitinib has also activity in non-clear cell cancer and is an option due to a lack of better alternatives. Currently, after immune checkpoint inhibitors have shown very promising results in the second-line treatment of RCC, they are being tested in a number of phase III trials in the first-line setting. The future will show the position of sunitinib in the first-line treatment of RCC in the era of the immune checkpoint inhibitors.
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Affiliation(s)
- Thomas A. Schmid
- Royal Marsden NHS Foundation Trust, Fulham Road, London, SW3 6JJ, UK
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42
Motzer RJ, Escudier B, Gannon A, Figlin RA. Sunitinib: Ten Years of Successful Clinical Use and Study in Advanced Renal Cell Carcinoma.
Oncologist 2016;
22:41-52. [PMID:
27807302 DOI:
10.1634/theoncologist.2016-0197]
[Citation(s) in RCA: 70] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2016] [Accepted: 08/03/2016] [Indexed: 01/07/2023] Open
Abstract
The oral multikinase inhibitor sunitinib malate was approved by the U.S. Food and Drug Administration in January 2006 for use in patients with advanced renal cell carcinoma (RCC). Since then, it has been approved globally for this indication and for patients with imatinib-resistant or -intolerant gastrointestinal stromal tumors and advanced pancreatic neuroendocrine tumors. As we mark the 10-year anniversary of the beginning of the era of targeted therapy, and specifically the approval of sunitinib, it is worthwhile to highlight the progress that has been made in advanced RCC as it relates to the study of sunitinib. We present the key trials and data for sunitinib that established it as a reference standard of care for first-line advanced RCC therapy and, along with other targeted agents, significantly altered the treatment landscape in RCC. Moreover, we discuss the research with sunitinib that has sought to refine its role via patient selection and prognostic markers, improve dosing and adverse event management, and identify predictive efficacy biomarkers, plus the extent to which this research has contributed to the overall understanding and management of RCC. We also explore the key learnings regarding study design and data interpretation from the sunitinib studies and how these findings and the sunitinib development program, in general, can be a model for successful development of other agents. Finally, ongoing research into the continued and future role of sunitinib in RCC management is discussed.
THE ONCOLOGIST
2017;22:41-52 IMPLICATIONS FOR PRACTICE: Approved globally, sunitinib is established as a standard of care for first-line advanced renal cell carcinoma (RCC) therapy and, along with other targeted agents, has significantly altered the treatment landscape in RCC. Research with sunitinib that has sought to refine its role via patient selection and prognostic markers, improve dosing and adverse event management, and identify predictive efficacy biomarkers has contributed to the overall understanding and management of RCC. Key learnings regarding study design and data interpretation from the sunitinib studies and the sunitinib development program, in general, can be a model for the successful development of other agents.
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Affiliation(s)
- Robert J Motzer
- Memorial Sloan Kettering Cancer Center, New York, New York, USA
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- Robert A Figlin
- Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
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43
Metastatic clear cell renal cell carcinoma: Circulating biomarkers to guide antiangiogenic and immune therapies.
Urol Oncol 2016;
34:510-518. [DOI:
10.1016/j.urolonc.2016.06.020]
[Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2016] [Revised: 05/29/2016] [Accepted: 06/18/2016] [Indexed: 11/23/2022]
44
Effect of a novel oral chemotherapeutic agent containing a combination of trifluridine, tipiracil and the novel triple angiokinase inhibitor nintedanib, on human colorectal cancer xenografts.
Oncol Rep 2016;
36:3123-3130. [PMID:
27805254 PMCID:
PMC5112602 DOI:
10.3892/or.2016.5208]
[Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2016] [Accepted: 09/06/2016] [Indexed: 11/09/2022] Open
Abstract
Trifluridine/tipiracil (TFTD) is a combination drug that is used for the treatment of metastatic colorectal cancer and was formerly known as TAS-102. It is a combination of two active pharmaceutical compounds, trifluridine, an antineoplastic thymidine-based nucleoside analog, and tipiracil, which enhances the bioavailability of trifluridine in vivo. TFTD is used for the treatment of patients with unresectable advanced or recurrent colorectal cancer that is resistant to standard therapies. In the present study, the anticancer effects of trifluridine in combination with nintedanib, an oral triple angiokinase inhibitor, on human colorectal cancer cell lines were investigated. The cytotoxicity against DLD-1, HT-29, and HCT116 cell lines was determined by the crystal violet staining method. The combination of trifluridine and nintedanib exerted an additive effect on the growth inhibition of DLD-1 and HT-29 cells and a sub-additive effect on HCT116 cells, as determined by isobologram analyses. Subsequently, the human colorectal cancer cell lines were implanted subcutaneously into nude mice to allow the evaluation of the in vivo tumor growth inhibitory effects of TFTD and nintedanib combination therapy. TFTD (150 mg/kg/day) and/or nintedanib (40 mg/kg/day) were orally administered to the mice twice daily from day 1 to day 14. The tumor growth inhibition with combination therapy was 61.5, 72.8, 67.6 and 67.5% for the DLD-1, DLD-1/5-FU, HT-29, and HCT116 xenografts, respectively. This was significantly (P<0.05) higher than the effects of monotherapy with either TFTD or nintedanib. These results demonstrated the effectiveness of the combination of TFTD and nintedanib in the treatment of colorectal cancer xenografts. The concentration of trifluridine incorporated into DNA in the HT-29 and HCT116 tumors was determined by liquid chromatography-tandem mass spectrometry. The incorporation levels following treatment with TFTD and nintedanib for 14 consecutive days were higher than those associated with TFTD treatment alone. The preclinical findings indicate that the combination therapy with TFTD and nintedanib is a promising treatment option for colorectal cancer.
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45
Stratigos M, Matikas A, Voutsina A, Mavroudis D, Georgoulias V. Targeting angiogenesis in small cell lung cancer.
Transl Lung Cancer Res 2016;
5:389-400. [PMID:
27652203 DOI:
10.21037/tlcr.2016.08.04]
[Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
Small cell lung cancer (SCLC) is a highly aggressive and lethal malignancy. Despite high initial response rates to systemic chemotherapy, the disease eventually relapses; further treatment only modestly improves outcomes and overall survival (OS) for patients with extensive stage disease is less than one year. Little progress has been made during the past decades, with no new drugs approved. Consequently, the development of novel strategies is an unmet need. The inhibition of angiogenesis, a defining characteristic of cancer, has demonstrated modest efficacy in several human malignancies, including non-small cell lung cancer (NSCLC). However, results from clinical trials in SCLC have been disappointing, and no anti-angiogenic agent has received regulatory approval due to lack of clinical efficacy. The elucidation of underlying mechanisms responsible for tumor resistance to angiogenic therapy and the simultaneous blockade of multiple elements that play a role in angiogenesis need to be further explored.
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Affiliation(s)
- Michalis Stratigos
- Department of Medical Oncology, University General Hospital of Heraklion, Heraklion, Crete, Greece
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- Alexios Matikas
- Department of Medical Oncology, University General Hospital of Heraklion, Heraklion, Crete, Greece;; Hellenic Oncology Research Group (HORG), Athens, Greece
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- Alexandra Voutsina
- Laboratory of Translational Oncology, University of Crete, School of Medicine, Heraklion, Crete, Greece
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- Dimitrios Mavroudis
- Department of Medical Oncology, University General Hospital of Heraklion, Heraklion, Crete, Greece;; Laboratory of Translational Oncology, University of Crete, School of Medicine, Heraklion, Crete, Greece
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- Vassilis Georgoulias
- Hellenic Oncology Research Group (HORG), Athens, Greece;; Laboratory of Translational Oncology, University of Crete, School of Medicine, Heraklion, Crete, Greece
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46
Barbieri CE, Chinnaiyan AM, Lerner SP, Swanton C, Rubin MA. The Emergence of Precision Urologic Oncology: A Collaborative Review on Biomarker-driven Therapeutics.
Eur Urol 2016;
71:237-246. [PMID:
27567210 DOI:
10.1016/j.eururo.2016.08.024]
[Citation(s) in RCA: 48] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2016] [Accepted: 08/09/2016] [Indexed: 12/25/2022]
Abstract
CONTEXT
Biomarker-driven cancer therapy, also referred to as precision oncology, has received increasing attention for its promise of improving patient outcomes by defining subsets of patients more likely to respond to various therapies.
OBJECTIVE
In this collaborative review article, we examine recent literature regarding biomarker-driven therapeutics in urologic oncology, to better define the state of the field, explore the current evidence supporting utility of this approach, and gauge potential for the future.
EVIDENCE ACQUISITION
We reviewed relevant literature, with a particular focus on recent studies about targeted therapy, predictors of response, and biomarker development.
EVIDENCE SYNTHESIS
The recent advances in molecular profiling have led to a rapid expansion of potential biomarkers and predictive information for patients with urologic malignancies. Across disease states, distinct molecular subtypes of cancers have been identified, with the potential to inform choices of management strategy. Biomarkers predicting response to standard therapies (such as platinum-based chemotherapy) are emerging. In several malignancies (particularly renal cell carcinoma and castration-resistant prostate cancer), targeted therapy against commonly altered signaling pathways has emerged as standard of care. Finally, targeted therapy against alterations present in rare patients (less than 2%) across diseases has the potential to drastically alter patterns of care and choices of therapeutic options.
CONCLUSIONS
Precision medicine has the highest potential to impact the care of patients. Prospective studies in the setting of clinical trials and standard of care therapy will help define reliable predictive biomarkers and new therapeutic targets leading to real improvement in patient outcomes.
PATIENT SUMMARY
Precision oncology uses molecular information (DNA and RNA) from the individual and the tumor to match the right patient with the right treatment. Tremendous strides have been made in defining the molecular underpinnings of urologic malignancies and understanding how these predict response to treatment-this represents the future of urologic oncology.
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Affiliation(s)
- Christopher E Barbieri
- Department of Urology, Weill Cornell Medical College, New York, NY, USA; Sandra and Edward Meyer Cancer Center of Weill Cornell Medical College, New York, NY, USA.
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- Arul M Chinnaiyan
- Michigan Center for Translational Pathology, Departments of Pathology and Urology, and Howard Hughes Medical Institute, University of Michigan Medical School, Ann Arbor, MI, USA
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- Seth P Lerner
- Scott Department of Urology, Baylor College of Medicine, Houston, TX, USA
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- Charles Swanton
- University College London Cancer Institute, Cancer Research UK Lung Cancer Centre of Excellence, London, UK
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- Mark A Rubin
- Department of Urology, Weill Cornell Medical College, New York, NY, USA; Sandra and Edward Meyer Cancer Center of Weill Cornell Medical College, New York, NY, USA; Englander Institute for Precision Medicine, Weill Cornell Medical College, New York, NY, USA
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47
Falcon BL, Chintharlapalli S, Uhlik MT, Pytowski B. Antagonist antibodies to vascular endothelial growth factor receptor 2 (VEGFR-2) as anti-angiogenic agents.
Pharmacol Ther 2016;
164:204-25. [PMID:
27288725 DOI:
10.1016/j.pharmthera.2016.06.001]
[Citation(s) in RCA: 96] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Interaction of numerous signaling pathways in endothelial and mesangial cells results in exquisite control of the process of physiological angiogenesis, with a central role played by vascular endothelial growth factor receptor 2 (VEGFR-2) and its cognate ligands. However, deregulated angiogenesis participates in numerous pathological processes. Excessive activation of VEGFR-2 has been found to mediate tissue-damaging vascular changes as well as the induction of blood vessel expansion to support the growth of solid tumors. Consequently, therapeutic intervention aimed at inhibiting the VEGFR-2 pathway has become a mainstay of treatment in cancer and retinal diseases. In this review, we introduce the concepts of physiological and pathological angiogenesis, the crucial role played by the VEGFR-2 pathway in these processes, and the various inhibitors of its activity that have entered the clinical practice. We primarily focus on the development of ramucirumab, the antagonist monoclonal antibody (mAb) that inhibits VEGFR-2 and has recently been approved for use in patients with gastric, colorectal, and lung cancers. We examine in-depth the pre-clinical studies using DC101, the mAb to mouse VEGFR-2, which provided a conceptual foundation for the role of VEGFR-2 in physiological and pathological angiogenesis. Finally, we discuss further clinical development of ramucirumab and the future of targeting the VEGF pathway for the treatment of cancer.
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48
Benson AB, Kiss I, Bridgewater J, Eskens FALM, Sasse C, Vossen S, Chen J, Van Sant C, Ball HA, Keating A, Krivoshik A. BATON-CRC: A Phase II Randomized Trial Comparing Tivozanib Plus mFOLFOX6 with Bevacizumab Plus mFOLFOX6 in Stage IV Metastatic Colorectal Cancer.
Clin Cancer Res 2016;
22:5058-5067. [PMID:
27401244 DOI:
10.1158/1078-0432.ccr-15-3117]
[Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2016] [Accepted: 06/20/2016] [Indexed: 11/16/2022]
Abstract
PURPOSE
Tivozanib, a selective inhibitor of VEGFR-1, -2, and -3, plus mFOLFOX6 in an advanced gastrointestinal cancer phase Ib study had encouraging antineoplastic activity and a tolerable safety profile. This randomized, open-label, phase II trial of tivozanib/mFOLFOX6 versus bevacizumab/mFOLFOX6 in patients with previously untreated metastatic colorectal cancer (mCRC) evaluated tivozanib activity versus bevacizumab.
EXPERIMENTAL DESIGN
Treatment-naïve patients received mFOLFOX6 every 2 weeks of each 28-day cycle plus either tivozanib orally 1.5 mg once daily for 21 days or bevacizumab intravenously 5 mg/kg every 2 weeks. Investigator-assessed progression-free survival (PFS) was the primary endpoint; some secondary endpoints included safety, overall survival, overall response rate (ORR), duration of response, time to treatment failure, and biomarker subgroup analyses.
RESULTS
A prespecified interim futility analysis demonstrated that the futility boundary for superiority of tivozanib/mFOLFOX6 over bevacizumab/mFOLFOX6 for PFS in the intent-to-treat population was crossed; median PFS was 9.4 versus 10.7 months [HR = 1.091; confidence interval (CI), 0.693-1.718; P = 0.706]. Tivozanib/mFOLFOX6 resulted in PFS and ORR comparable with bevacizumab/mFOLFOX6; interim analyses biomarker results revealed no significant PFS association. Post hoc final analyses demonstrated a potential difference in tivozanib-specific PFS in patients with low neuropilin-1 (NRP-1), but not in patients with high NRP-1. Tivozanib/mFOLFOX6 was tolerable and adverse events were comparable with both bevacizumab/mFOLFOX6 and previous tivozanib studies.
CONCLUSIONS
The efficacy of tivozanib/mFOLFOX6 was comparable with but not superior to bevacizumab/mFOLFOX6 in patients with previously untreated mCRC. Since data from the prespecified interim analysis did not demonstrate superiority, this resulted in discontinuation of the study. The safety and tolerability profile of tivozanib/mFOLFOX6 was consistent with other tivozanib trials. NRP-1 is a potential predictive biomarker for tivozanib activity, but these results require further validation. Clin Cancer Res; 22(20); 5058-67. ©2016 AACR.
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Affiliation(s)
- Al B Benson
- Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, Illinois.
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- Igor Kiss
- Masaryk Memorial Cancer Institute, Brno, Czech Republic
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- John Bridgewater
- University College London Cancer Institute, London, United Kingdom
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- Carolyn Sasse
- Astellas Pharma Global Development, Northbrook, Illinois
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- Sandra Vossen
- Astellas Pharma Global Development, Northbrook, Illinois
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- Jihong Chen
- Astellas Pharma Global Development, Northbrook, Illinois
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- Chip Van Sant
- Astellas Pharma Global Development, Northbrook, Illinois
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- Howard A Ball
- Astellas Pharma Global Development, Northbrook, Illinois
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- Anne Keating
- Astellas Pharma Global Development, Northbrook, Illinois
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49
Fibroblast Growth Factor Receptor-Dependent and -Independent Paracrine Signaling by Sunitinib-Resistant Renal Cell Carcinoma.
Mol Cell Biol 2016;
36:1836-55. [PMID:
27141054 DOI:
10.1128/mcb.00189-16]
[Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2016] [Accepted: 04/26/2016] [Indexed: 11/20/2022] Open
Abstract
Antiangiogenic therapies, such as sunitinib, have revolutionized renal cell carcinoma (RCC) treatment. However, a precarious understanding of how resistance emerges and a lack of tractable experimental systems hinder progress. We evaluated the potential of primary RCC cultures (derived from tumors and tumor grafts) to signal to endothelial cells (EC) and fibroblasts in vitro and to stimulate angiogenesis ex vivo in chorioallantoic membrane (CAM) assays. From 65 patients, 27 primary cultures, including several from patients with sunitinib-resistant RCC, were established. RCC cells supported EC survival in coculture assays and induced angiogenesis in CAM assays. RCC-induced EC survival was sensitive to sunitinib in half of the tumors and was refractory in tumors from resistant patients. Sunitinib sensitivity correlated with vascular endothelial growth factor (VEGF) production. RCC induced paracrine extracellular signal-regulated kinase (ERK) activation in EC which was inhibited by sunitinib in sensitive but not in resistant tumors. As determined by fibroblast growth factor receptor substrate 2 (FRS2) phosphorylation in fibroblasts, RCC broadly induced low-level fibroblast growth factor receptor (FGFR) signaling. Whereas ERK activation in EC was uniformly inhibited by combined VEGF/platelet-derived growth factor (PDGF)/FGF receptor inhibitors, paracrine ERK activation in fibroblasts was blocked in only a fraction of tumors. Our data show that RCC activates EC through VEGF-dependent and -independent pathways, that sunitinib sensitivity correlates with VEGF-mediated ERK activation, and that combined inhibition of VEGF/PDGF/FGF receptors is sufficient to inhibit mitogenic signaling in EC but not in fibroblasts.
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50
Association between new-onset hypothyroidism and clinical response in patients treated with tyrosine kinase inhibitor therapy in phase I clinical trials.
Cancer Chemother Pharmacol 2016;
78:167-71. [DOI:
10.1007/s00280-016-3073-z]
[Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2016] [Accepted: 06/02/2016] [Indexed: 10/21/2022]