Abstract
Blocking angiogenesis represents a fundamental process in Colorectal Cancer (CRC) treatment. VEGF (vascular endothelial growth factor) pathway is implicated in various processes that regulate tumor vascularization and proliferation. In the last years, great efforts have been made thanks to the discovery of targeted drugs that block VEGF and its receptors conferring a benefit in a variety of tumors, including CRC. To date, four drugs have been approved for the treatment of metastatic CRC (mCRC): bevacizumab, aflibercept, ramucirumab and regorafenib. Unfortunately, patients relapse due to the appearance of resistance. The VEGF family, its role in the angiogenesis and complex heterogeneity of mechanisms that escape tumor blockade are not completely understood and there is a lack of biomarkers of response to anti-angiogenic drugs. We describe the principal mechanisms of resistance to anti-VEGF therapy and discuss potential biomarkers to be investigated in the near future.
Keywords: Colorectal cancer, angiogenesis, resistance, VEGF, biomarkers, targeted therapy.
Graphical Abstract
[1]
Siegel RL, Miller KD, Jemal A. Cancer statistics. CA Cancer J Clin 2016; 66: 7-30.Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin 2015; 65: 87-108.
[2]
Tol J, Koopman M, Cats A, et al. Chemotherapy, bevacizumab, and cetuximab in metastatic colorectal cancer. N Engl J Med 2009; 360: 563-72.
[3]
Burrell RA, Swanton C. Tumour heterogeneity and the evolution of polyclonal drug resistance. Mol Oncol 2014; 8: 1095-111.
[4]
Hicklin DJ, Ellis LM. Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis. J Clin Oncol 2005; 23: 1011-27.
[5]
Sforza V, Martinelli E, Ciardiello F, et al. Mechanisms of resistance to antiepidermal growth factor receptor inhibitors in metastatic colorectal cancer. World J Gastroenterol 2016; 22: 6345-61.
[6]
Oh HH, Park KJ, Kim N, et al. Impact of KITENIN on tumor angiogenesis and lymphangiogenesis in colorectal cancer. Oncol Rep 2016; 35: 253-60.
[7]
Fan F, Wey JS, McCarty MF, et al. Expression and function of vascular endothelial growth factor receptor-1 on human colorectal cancer cells. Oncogene 2005; 24: 2647-53.
[8]
Dvorak HF. Vascular permeability factor/vascular endothelial growth factor: A critical cytokine in tumor angiogenesis and a potential target for diagnosis and therapy. J Clin Oncol 2002; 20: 4368-80.
[9]
Ellis LM1, Hicklin DJ. VEGF-targeted therapy: Mechanisms of anti-tumour activity. Nat Rev Cancer 2008; 8(8): 579-91.
[10]
Heath VL, Bicknell R. Anticancer strategies involving the vasculature. Nat Rev Clin Oncol 2009; 6: 395-404.
[11]
Carmeliet P, Jain RK. Principles and mechanisms of vessel normalization for cancer and other angiogenic diseases. Nat Rev Drug Discov 2011; 10(6): 417-27.
[12]
Arjaans M, Schroder CP, Oosting SF, et al. VEGF pathway targeting agents, vessel normalization and tumor drug uptake: From bench to bedside. Oncotarget 2016; 7(16): 21247-58.
[13]
Kubota Y, Takubo K, Shimizu T, et al. M-CSF inhibition selectively targets pathological angiogenesis and lymphangiogenesis. J Exp Med 2009; 206(5): 1089-102.
[14]
Fantin A, Vieira JM, Gestri G, et al. Tissuemacrophages act as cellular chaperones for vascular anastomosis downstream of VEGF-mediated endothelial tip cell induction. Blood 2010; 116(5): 829-40.
[16]
Al-Husein B, Abdalla M, Trepte M, Deremer DL, Somanath PR. Anti-angiogenic therapy for cancer: An update. Pharmacotherapy 2012; 32(12): 1095-1.
[17]
Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 2004; 350: 2335-42.
[18]
Hurwitz HI1, Tebbutt NC, Kabbinavar F, et al. Efficacy and safety of bevacizumab in metastatic colorectal cancer: Pooled analysis from seven randomized controlled trials. Oncologist 2013; 18(9): 1004-12.
[19]
Lenz HJ, Lee F, Yau L, et al. MAVERICC, a phase 2 study of mFOLFOX6-bevacizumab (BV) vs. FOLFIRI-BV with biomarker stratification as first-line (1L) chemotherapy (CT) in patients (pts) with metastatic colorectal cancer (mCRC). J Clin Oncol 2016; 34(Suppl. 4S): 493.
[20]
Cremolini C, Loupakis F, Antoniotti C, et al. FOLFOXIRI/bevacizumab versus FOLFIRI/ bevacizumab as first-line treatment in unresectable metastatic colorectal cancer: Results of phase III TRIBE trial by GONO Group. Ann Oncol 2013; 24(Suppl. 4): iv21.
[21]
Giantonio BJ, Catalano PJ, Meropol NJ, et al. Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: Results from the Eastern Cooperative Oncology Group Study. E3200. J Clin Oncol 2007; 25: 1539-44.
[22]
Bennouna J, Sastre J, Arnold D, et al. Continuation of bevacizumab after first progression in metastatic colorectal cancer (ML18147): A randomised phase 3 trial. Lancet Oncol 2013; 14(1): 29-37.
[23]
Simkens LH, van Tinteren H, May A, et al. Maintenance treatment with capecitabine and bevacizumab in metastatic colorectal cancer (CAIRO3): A phase 3 randomised controlled trial of the Dutch Colorectal Cancer Group. Lancet 2015; 385: 1843-52.
[24]
Diaz-Rubio E, Gomez A, Massuti B, et al. First-line XELOX plus bevacizumab followed by XELOX plus bevacizumab or single-agent bevacizumab as maintenance therapy in patients with metastatic colorectal cancer: The phase III MACRO TTD study. Oncologist 2012; 17: 15-25.
[25]
Cunningham D, Lang I, Marcuello E, et al. Bevacizumab plus capecitabine versus capecitabine alone in elderly patients with previously untreated metastatic colorectal cancer (AVEX): An open-label, randomised phase 3 trial. Lancet Oncol 2013; 14(11): 1077-85.
[26]
Allegra CJ, Lakomy R, Tabernero J, et al. Effects of prior bevacizumab (B) use on outcomes from the VELOUR study: A phase III study of aflibercept (Afl) and FOLFIRI in patients (pts) with metastatic colorectal cancer (mCRC) after failure of anoxaliplatin regimen. J Clin Oncol 2012; 30(Suppl.): 3505.
[27]
Tabernero J, Hozak RR, Yoshino T, et al. Analysis of angiogenesis biomarkers for ramucirumab efficacy in patients with metastatic colorectal cancer from RAISE, a global, randomized, double-blind, phase iii study. Ann Oncol 2017; 29(3): 602-9.
[28]
Martinelli E, Sforza V, Cardone C, et al. Clinical outcome and molecular characterisation of chemorefractory metastatic colorectal cancer patients with long-term efficacy of regorafenib treatment. ESMO Open 2017; 2(3)e000177
[29]
Grothey A, Van Cutsem E, Sobrero A, et al. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): An international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet 2013; 381: 303-12.
[30]
Li J, Qin S, Xu R, et al. Regorafenib plus best supportive care versus placebo plus best supportive care in Asian patients with previously treated metastatic colorectal cancer (CONCUR): A randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 2015; 16: 619-29.
[31]
Van Cutsem E, Ciardiello F, Seitz JF, et al. Results from the large, open-label phase 3b CONSIGN study of regorafenib in patients with previously treated metastatic colorectal cancer. Ann Oncol 2015; 26(Suppl. 9): 42-70.
[32]
Adenis A, de la Fouchardiere C, Paule B, et al. Survival, safety, and prognostic factors for outcome with Regorafenib in patients with metastatic colorectal cancer refractory to standard therapies: Results from a multicenter study (REBACCA) nested within a compassionate use program. BMC Cancer 2016; 16: 412.
[33]
Van Cutsem E, Yoshino T, Lenz HJ, et al. Nintedanib for the treatment of patients with refractory metastatic colorectal cancer (LUME-Colon1): A phase III, international, randomized, placebo-controlled study. Ann Oncol 2018; 29(9): 1955-63.
[34]
Rui-Hia X, Lin S, Wang KM, et al. Famitinib versus placebo in the treatment of refractory metastatic colorectal cancer: A multicenter, randomized, double-blinded, placebo-controlled, phase II clinical trial. Chin J Cancer 2017; 36: 97.
[35]
Li J, Qin S, Bai Y, et al. A randomized, double-blind, placebo-controlled, multi-centered phase 3 trial comparing fruquintinib versus placebo plus best supportive care in Chinese patients with metastatic colorectal cancer (FRESCO). J Clin Oncol 2017; 35: 3508.
[36]
Li Y, Hickson JA, Ambrosi DJ, et al. ABT-165, a Dual Variable Domain Immunoglobulin (DVD-Ig) Targeting DLL4 and VEGF, demonstrates superior efficacy and favorable safety profiles in preclinical models. Mol Cancer Ther 2018; 17(5): 1039-50.
[37]
Azam F, Mehta S, Harris AL. Mechanisms of resistance to antiangiogenesis therapy. Eur J Cancer 2010; 46: 1323-32.
[38]
Hanrahan EO, Lin HY, Kim ES, et al. Distinct patterns of cytokine and angiogenic factor modulation and markers of benefit for vandetanib and/or chemotherapy in patients with non- small-cell lung cancer. J Clin Oncol 2009; 28: 193-201.
[39]
Tabernero J, Van Cutsem E, Lakomý R, et al. Aflibercept versus placebo in combination with fluorouracil, leucovorin and irinotecan in the treatment of previously treated metastatic colorectal cancer: Prespecified subgroup analyses from the VELOUR trial. Eur J Cancer 2014; 50: 320-31.
[40]
Allegra CJ, Lakomy R, Tabernero J, et al. Effects of prior bevacizumab (B) use on outcomes from the VELOUR study: A phase III study of aflibercept (Afl) and FOLFIRI in patients (pts) with metastatic colorectal cancer (mCRC) after failure of an oxaliplatin regimen. J Clin Oncol 2012; 30: 3505.
[41]
Weickhardt AJ, Williams DS, Lee CK, et al. Vascular endothelial growth factor D expression is a potential biomarker of bevacizumab bene t in colorectal cancer. Br J Cancer 2015; 113: 37-45.
[42]
Prager GW, Poettler M, Unseld M, et al. Angiogenesis in cancer: Anti-VEGF escape mechanisms. Transl Lung Cancer Res 2012; 1: 14-25.
[43]
Soker S, Takashima S, Miao HQ, et al. Neuropilin1 is expressed by endothelial and tumor cells as an isoformspecific receptor for vascular endothelial growth factor. Cell 1998; 92: 735-45.
[44]
Weekes CD, Beeram M, Tolcher AW, et al. A phase I study of the human monoclonal anti-NRP1 antibody MNRP1685A in patients with advanced solid tumors. Invest New Drugs 2014; 32: 653-60.
[45]
Guarino M. Epithelial-mesenchymal transition and tumour invasion. Int J Biochem Cell Biol 2007; 39: 2153-60.
[46]
Tomida C, Yamagishi N, Nagano H, et al. VEGF pathwaytargeting drugs induce evasive adaptation by activation od neuropilin- 1/cMET in colon cancer cells. Int J Oncol 218 52(4): 1350-62.
[47]
Patnaik A, LoRusso PM, Messersmith WA, et al. A Phase Ib study evaluating MNRP1685A, a fully human anti-NRP1 monoclonal antibody, in combination with bevacizumab and paclitaxel in patients with advanced solid tumors. Cancer Chemother Pharmacol 2014; 73: 951-60.
[48]
Fraisl P, Mazzone M, Schmidt T, et al. Regulation of angiogenesis by oxygen and metabolism. Dev Cell 2009; 16: 167-79.
[49]
Hashimoto T, Shibasaki F. Hypoxia-inducible factor as an angiogenic master switch. Front Pediatr 2015; 3: 33.
[50]
Eichten A, Su J, Adler AP, et al. Resistance to anti-VEGF therapy mediated by autocrine IL6/STAT3 signaling and overcome by IL6 blockade. Cancer Res 2016; 76: 2327-39.
[51]
Bos R, Van Diest PJ, De Jong JS, et al. Hypoxia- inducible factor-1alpha is associated with angiogenesis, and expression of bFGF, PDGF-BB, and EGFR in invasive breast cancer. Histopathology 2005; 46: 31-6.
[52]
Wang J, Xu K, Wu J, et al. The changes of Th17 cells and the related cytokines in the progression of human colorectal cancers. BMC Cancer 2012; 12: 418.
[53]
Lereclus E, Tout M, Girault A, et al. A possible association of baseline serum IL-17A concentrations with progression-free survival of metastatic colorectal cancer patients treated with a bevacizumab-based regimen. BMC Cancer 2017; 17(1): 220.
[54]
Numasaki M, Fukushi J, Ono M, et al. Interleukin-17 promotes angiogenesis and tumor growth. Blood 2003; 101(7): 2620-7.
[55]
Pezzella F, Gatter K, Qian CN. Twenty years after: The beautiful hypothesis and the ugly facts. Chin J Cancer 2016; 35: 22.
[56]
Norden AD, Young GS, Setayesh K, et al. Bevacizumab for recurrent malignant gliomas: Efficacy, toxicity, and patterns of recurrence. Neurology 2008; 70: 779-87.
[57]
Djonov V, Schmid M, Tschanz SA, et al. Intussusceptive angiogenesis: Its role in embryonic vascular network formation. Circ Res 2000; 86: 286-92.
[58]
Maniotis AJ, Folberg R, Hess A, et al. Vascular channel formation by human melanoma cells in vivo and in vitro: Vasculogenic mimicry. Am J Pathol 1999; 155: 739-52.
[59]
Martinelli E, Troiani T, Morgillo F, et al. Emerging VEGF-receptor inhibitors for colorectal cancer. Expert Opin Emerg Drugs 2013; 18(1): 25-37.
[60]
Petrovic N. Targeting angiogenesis in cancer treatments: Where do we Stand? J Pharm Pharm Sci 2016; 19: 226-38.
[61]
Osterlund P, Soveri L-M, Isoniemi H, et al. Hypertension and overall survival in metastatic colorectal cancer patients treated with bevaci- zumab-containing chemotherapy. Br J Cancer 2011; 104: 599-604.
[62]
Poon RT, Fan ST, Wong J. Clinical implications of circulating angiogenic factors in cancer patients. J Clin Oncol 2001; 19: 1207-25.
[63]
Jubb AM, Hurwitz HI, Bai W, et al. Impact of vascular endothelial growth factor-A expression, thrombospondin-2 expression, and microvessel density on the treatment effect of bevacizumab in metastatic colorectal cancer. J Clin Oncol 2006; 24: 217-27.
[64]
Kopetz S, Hoff PM, Morris JS, et al. Phase II trial of infusional fluorouracil, irinotecan, and bevacizumab for metastatic colorectal cancer: Efficacy and circulating angiogenic biomarkers associated with therapeutic resistance. J Clin Oncol 2010; 28: 453-9.
[65]
Tabernero J, Lenz HJ, Siena S, et al. Analysis of circulating DNA and protein biomarkers to predict the clinical activity of regorafenib and assess prognosis in patients with metastatic colorectal cancer: A retrospective, exploratory analysis of the CORRECT trial. Lancet Oncol 2015; 16: 937-48.
[66]
Kiessling F, Farhan N, Lichy MP, et al. Dynamic contrast-enhanced magnetic resonance imaging rapidly indicates vessel regression in human squamous cell carcinomas grown in nude mice caused by VEGF receptor 2 blockade with DC101. Neoplasia 2004; 6: 213-23.
[67]
Ehling J, Lammers T, Kiessling F. Non-invasive imaging for studying anti-angiogenic therapy effects. Thromb Haemost 2013; 109(3): 375-90.
[68]
Khan K, Rata M, Cunningham D, et al. Functional imaging and circulating biomarkers of response to regorafenib in treatment-refractory metastatic colorectal cancer patients in a prospective phase II study. Gut 2017; 67(8): 1484-92.
[69]
Koutras AK, Antonacopoulou AG, Eleftheraki AG, et al. Vascular endothelial growth factor polymorphisms and clinical outcome in colorectal cancer patients treated with irinotecan-based chemotherapy and bevacizumab. Pharmacogenomics J 2012; 12(6): 468-75.
[70]
Loupakis F, Ruzzo A, Salvatore L, et al. Retrospective exploratory analysis of VEGF polymorphisms in the prediction of benefit from first-line FOLFIRI plus bevacizumab in metastatic colorectal cancer. BMC Cancer 2011; 11: 247.
[71]
Loupakis F, Cremolini C, Yang D, et al. Prospective validation of candidate SNPs of VEGF/VEGFR pathway in metastatic colorectal cancer patients treated with first-line FOLFIRI plus bevacizumab. PLoS One 2013; 8(7)e66774
[72]
Cabebe EC, Fisher GA, Sikic BI, et al. A phase I trial of vandetanib combined with capecitabine, oxaliplatin and bevacizumab for the first-line treatment of metastatic colorectal cancer. Invest New Drugs 2012; 30: 1082-7.
[73]
Wilson PM, El-Khoueiry A, Iqbal S, et al. A phase I/II trial of vorinostat in combination with 5-fluorouracil in patients with metastatic colorectal cancer who previously failed 5-FU-based chemotherapy. Cancer Chemother Pharmacol 2010; 65: 979-88.
[74]
Bendell JC, Sauri T, Cubillo A, et al. Final results of the McCAVE trial: A double-blind, randomized phase 2 study of vanucizumab (VAN) plus FOLFOX vs. bevacizumab (BEV) plus FOLFOX in patients (pts) with previously untreated metastatic colorectal carcinoma (mCRC). J Clin Oncol 2017; 25: 3539.
[75]
Tabernero J, Garcia-Carbonero R, Cassidy J, et al. Sorafenib in combination with oxaliplatin, leucovorin, and fluorouracil (modified FOLFOX6) as first-line treatment of metastatic colorectal cancer: The RESPECT trial. Clin Cancer Res 2013; 19: 2541-50.
[76]
Van Cutsem E, Bajetta E, Valle J, et al. Randomized, placebo-controlled, phase III study of oxaliplatin, fluorouracil, and leucovorin with or without PTK787/ZK 222584 in patients with previously treated metastatic colorectal adenocarcinoma. J Clin Oncol 2011; 29: 2004-10.
[77]
Hoff P, Hochhaus A, Pestalozzi B, et al. Cediranib plus FOLFOX/CAPOX versus placebo plus FOLFOX/CAPOX in patients with previously untreated metastatic colorectal cancer: A randomized, double-blind, phase III study (HORIZON II). J Clin Oncol 2012; 30: 3596-603.
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