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Inhibition of Tumor Angiogenesis in GIST Therapy

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Tumor Angiogenesis

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Abstract

Gastrointestinal stromal tumors (GISTs) are rare tumors accounting 10–15 new cases/year per million individuals and only represent 2–3% to all gastrointestinal malignancies. They usually arise from the stomach, less frequently from the small bowel, rectum, and esophagus. The hallmark of GISTs is the presence of activating mutations in KIT or platelet-derived growth factor-alpha (PDGFRA) genes, which are considered key drivers in the molecular pathogenesis and that represent important predictive factors. Before the angiogenic inhibition era, GIST was found to be resistant to cytotoxic chemotherapeutic agents. The introduction of small molecules able to inhibit angiogenesis and tumor growth has utterly changed the clinical history of this rare tumor. GISTs have represented for years a model for anti-angiogenic treatment in solid cancer. Tyrosine kinase inhibitors against pro-angiogenic targets, such as imatinib, sunitinib, and regorafenib, are currently available in GIST treatment. One of the main concerns with this molecular therapy is acquired resistance due to a huge variety of factors, including activation of parallel angiogenic pathways. A second important aspect in learning curve of tyrosine kinase inhibitor mechanism of action is the different toxicity profile compared to cytotoxic chemotherapy.

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References

  • Adenis A, Baly J-Y, Bui-Nguyen B et al (2014) Masitinib in advanced gastrointestinal stromal tumor (GIST) after failure of imatinib: a randomized controlled open-label trial. Ann Oncol 25(9):1762–1769

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Agrawal MD, Pinho DF, Kulkarni NM et al (2014) Oncologic applications of dual-energy CT in the abdomen. Radiogr Rev Publ Radiol Soc N Am Inc 34(3):589–612

    Google Scholar 

  • Antonescu CR, Besmer P, Guo T et al (2005) Acquired resistance to imatinib in gastrointestinal stromal tumor occurs through secondary gene mutation. Clin Cancer Res 11(11):4182–4190

    Article  CAS  PubMed  Google Scholar 

  • Bauer S, Duensing A, Demetri GD et al (2007) KIT oncogenic signaling mechanisms in imatinib-resistant gastrointestinal stromal tumor: PI3-kinase/AKT is a crucial survival pathway. Oncogene 26(54):7560–7568

    Article  CAS  PubMed  Google Scholar 

  • Ben-Ami E, Barysauskas CM, von Mehren M et al (2016) Long-term follow-up results of the multicenter phase II trial of regorafenib in patients with metastatic and/or unresectable GI stromal tumor after failure of standard tyrosine kinase inhibitor therapy. Ann Oncol 27(9):1794–1799

    Article  CAS  PubMed  Google Scholar 

  • Bernard Lyon CI, Blay JY, Shen L et al (2015) Nilotinib versus imatinib as first-line therapy for patients with unresectable or metastatic gastrointestinal stromal tumours (ENESTg1): a randomised phase 3 trial. Lancet Oncol 16(16):550–560

    Google Scholar 

  • Bilen MA, Patel A, Hess K et al (2016) Association between new-onset hypothyroidism and clinical response in patients treated with tyrosine kinase inhibitor therapy in phase I clinical trials. Cancer Chemother Pharmacol 78(1):167–171

    Article  CAS  PubMed  Google Scholar 

  • Blanke CD, Demetri G, von Mehren M et al (2008) Long-term results from a randomized phase II trial of standard- versus higher-dose imatinib mesylate for patients with unresectable or metastatic gastrointestinal stromal tumors expressing KIT. J Clin Oncol 26(4):620–625

    Article  CAS  PubMed  Google Scholar 

  • Blanke CD, Rankin C, Corless C et al (2015) S0502: a SWOG phase III randomized study of imatinib, with or without bevacizumab, in patients with untreated metastatic or unresectable gastrointestinal stromal tumors. Oncologist 20(12):1353–1354

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Botchkareva NV, Khlgatian M, Longley BJ et al (2001) SCF/c-kit signaling is required for cyclic regeneration of the hair pigmentation unit. FASEB J 15:645–658

    Article  CAS  PubMed  Google Scholar 

  • Choi H, Charnsangavej C, Faia S et al (2007) Correlation of computed tomography and positron emission tomography in patients with metastatic gastrointestinal stromal tumor treated at a single institution with imatinib mesylate: proposal of new computed tomography response criteria. J Clin Oncol Off J Am Soc Clin Oncol 25(13):1753–1759

    Article  Google Scholar 

  • Dematteo RP, Lewis J, Leung D et al (2000) Two hundred gastrointestinal stromal tumors recurrence patterns and prognostic factors for survival. Ann Surg 231(1):51–58

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dematteo RP, Ballman K, Antonescu C et al (2009) Adjuvant imatinib mesylate after resection of localised, primary gastrointestinal stromal tumour: a randomised, double-blind, placebo-controlled trial. Lancet 373(9669):1097–1104

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Demetri GD, von Meheren M, Blanke CD et al (2002) Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med 347(7):472–480

    Article  CAS  PubMed  Google Scholar 

  • Demetri GD, van Oosterom AT, Garrett CR et al (2006) Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial. Lancet 368(9544):1329–1338

    Article  CAS  PubMed  Google Scholar 

  • Demetri GD, Garret CR, Shöffsky P et al (2012) Complete longitudinal analyses of the randomized, placebo-controlled, phase III trial of sunitinib in patients with gastrointestinal stromal tumor following imatinib failure. Clin Cancer Res Off J Am Assoc Cancer Res 18(11):170–179

    Article  Google Scholar 

  • Demetri GD, Reichardt P, Kang Y-R et al (2013) Efficacy and safety of regorafenib for advanced gastrointestinal stromal tumours after failure of imatinib and sunitinib (GRID): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet 381(9863):295–302

    Article  CAS  PubMed  Google Scholar 

  • Desai J, Yassa L, Marqusee E et al (2006) Hypothyroidism after sunitinib treatment for patients with gastrointestinal stromal tumors. Ann Intern Med 145(9):660–664

    Article  PubMed  Google Scholar 

  • Druker BJ, Talpaz M, Resta D et al (2001) Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med 344(14):1031–1037

    Article  CAS  PubMed  Google Scholar 

  • Folkman J, Merler E, Abernathy C et al (1971) Isolation of a tumor factor responsible for angiogenesis. J Exp Med 133(2):275–288

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ganjoo KN, Villalobos VM, Kamaya A et al (2014) A multicenter phase II study of pazopanib in patients with advanced gastrointestinal stromal tumors (GIST) following failure of at least imatinib and sunitinib. Ann Oncol 25(1):236–240

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gastrointestinal Stromal Tumor Meta-Analysis Group (MetaGIST) (2010) Comparison of two doses of imatinib for the treatment of unresectable or metastatic gastrointestinal stromal tumors: a meta-analysis of 1,640 patients. J Clin Oncol Off J Am Soc Clin Oncol 28(7):1247–1253

    Article  Google Scholar 

  • Ghatalia P, Morgan CJ, Je Y et al (2015) Congestive heart failure with vascular endothelial growth factor receptor tyrosine kinase inhibitors. Crit Rev Oncol Hematol 94:228–237

    Article  PubMed  Google Scholar 

  • Gotink KJ, Verheul HMW (2010) Anti-angiogenic tyrosine kinase inhibitors: what is their mechanism of action? Angiogenesis 13:1–14

    Article  CAS  PubMed  Google Scholar 

  • Hirota S, Isozak K, Moriyama Y et al (1998) Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. Science 279(5350):577–580

    Article  CAS  PubMed  Google Scholar 

  • Hirota S, Ohashi A, Nishida T et al (2003) Gain-of-function mutations of platelet-derived growth factor receptor α gene in gastrointestinal stromal tumors. Gastroenterology 125(3):660–667

    Article  CAS  PubMed  Google Scholar 

  • Joensuu H, Robert PJ, Sarlomo-Rilkala M et al (2001) Effect of tyrosine kinase inhibitor STI571 in a patient with a metastatic gastrointestinal stromal tumor. N Engl J Med 344(14):1052

    Article  CAS  PubMed  Google Scholar 

  • Joensuu H, De Braud F, Grignani G et al (2011) Vatalanib for metastatic gastrointestinal stromal tumour (GIST) resistant to imatinib: final results of a phase II study. Br J Cancer 104:1686–1690

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lasota J, Miettinen M (2008) Clinical significance of oncogenic KIT and PDGFRA mutations in gastrointestinal stromal tumours. Histopathology 53(3):245–266

    Article  CAS  PubMed  Google Scholar 

  • Le Cesne A, Blay JY, Bui BN et al (2010) Phase II study of oral masitinib mesilate in imatinib-naïve patients with locally advanced or metastatic gastro-intestinal stromal tumour (GIST). Eur J Cancer 46:1344–1351

    Article  PubMed  Google Scholar 

  • León-Mateos L, Mosquera J, Antón Aparicio L (2015) Treatment of sunitinib-induced hypertension in solid tumor by nitric oxide donors. Redox Biol 6:421–425

    Article  PubMed  PubMed Central  Google Scholar 

  • Mannavola D, Coco P, Vannucchi G et al (2007) A novel tyrosine-kinase selective inhibitor, sunitinib, induces transient hypothyroidism by blocking iodine uptake. J Clin Endocrinol Metab 92(9):3531–3534

    Article  CAS  PubMed  Google Scholar 

  • Montemurro M, Gelderblom H, Bitz U et al (2013) Sorafenib as third- or fourth-line treatment of advanced gastrointestinal stromal tumour and pretreatment including both imatinib and sunitinib, and nilotinib: a retrospective analysis. Eur J Cancer 49(5):1027–1031

    Article  CAS  PubMed  Google Scholar 

  • Pollard PJ, Briere JJ, Alam NA et al (2005) Accumulation of Krebs cycle intermediates and over-expression of HIF1α in tumours which result from germline FH and SDH mutations. Hum Mol Genet 14(15):2231–2239

    Article  CAS  PubMed  Google Scholar 

  • Prenen H, Cools J, Mentens N et al (2006) Efficacy of the kinase inhibitor SU11248 against gastrointestinal stromal tumor mutants refractory to imatinib mesylate. Clin Cancer Res 12(8):2622–2627

    Article  CAS  PubMed  Google Scholar 

  • Raica M, Cimpean AM (2010) Platelet-derived growth factor (PDGF)/PDGF receptors (PDGFR) axis as target for antitumor and antiangiogenic therapy. Pharmaceuticals 3(3):572–599

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Raimondi C, Fantin A, Lampropoulou A et al (2014) Imatinib inhibits VEGF-independent angiogenesis by targeting neuropilin 1-dependent ABL1 activation in endothelial cells. J Exp Med 211(6):1167–1183

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Reichardt P, Baly J-Y, Gelderblom H et al (2012) Phase III study of nilotinib versus best supportive care with or without a TKI in patients with gastrointestinal stromal tumors resistant to or intolerant of imatinib and sunitinib. Ann Oncol 23(7):1680–1687

    Article  CAS  PubMed  Google Scholar 

  • Ribatti D, Vacca A, Dammacco F (1999) The role of the vascular phase in solid tumor growth: a historical review. Neoplasia 1(4):293–302.

    Google Scholar 

  • Schöffski P, Reichardt P, Blay J-Y et al (2010) A phase I-II study of everolimus (RAD001) in combination with imatinib in patients with imatinib-resistant gastrointestinal stromal tumors. Ann Oncol 21(10):1990–1998

    Article  PubMed  Google Scholar 

  • Seifert AM, Zeng S, Zhang QJ et al (2017) PD-1/PD-L1 blockade enhances T cell activity and antitumor efficacy of imatinib in gastrointestinal stromal tumors. Clin Cancer Res 23(2):454–465

    Article  CAS  PubMed  Google Scholar 

  • Soria JC, Massard C, Magne N et al (2009) Phase 1 dose-escalation study of oral tyrosine kinase inhibitor masitinib in advanced and/or metastatic solid cancers masitinib is a tyrosine kinase inhibitor with a pre-clinical profile suggesting. Europ Jurn of Cancer 45:2333–2341

    Article  CAS  Google Scholar 

  • Tuveson DA, Willis NA, Jacks T et al (2001) STI571 inactivation of the gastrointestinal stromal tumor c-KIT oncoprotein: biological and clinical implications. Oncogene 20:5054–5058

    Article  CAS  PubMed  Google Scholar 

  • Wada R, Arai H, Kure S et al (2016) “Wild type” GIST: clinicopathological features and clinical practice. Pathol Int 66(8):431–437

    Article  CAS  PubMed  Google Scholar 

  • Zhou Y, Pathak HB, Belinsky M et al (2017) Combination of imatinib mesylate and AKT inhibitor provides synergistic effects in preclinical study of gastrointestinal stromal tumor. Clin Cancer Res 23(1):171–180

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Sarcoma Unit, Royal Marsden Hospital, NHS Foundation, Fulham Road, London, UK

    Charlotte Benson & Michela Libertini

Authors
  1. Charlotte Benson
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  2. Michela Libertini
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Correspondence to Charlotte Benson .

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Editors and Affiliations

  1. Tumor Biology Center, Freiburg, Baden-Württemberg, Germany

    Dieter Marmé

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Benson, C., Libertini, M. (2017). Inhibition of Tumor Angiogenesis in GIST Therapy. In: Marmé, D. (eds) Tumor Angiogenesis. Springer, Cham. https://doi.org/10.1007/978-3-319-31215-6_19-1

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  • DOI: https://doi.org/10.1007/978-3-319-31215-6_19-1

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  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-31215-6

  • Online ISBN: 978-3-319-31215-6

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