Antiangiogenes Wirkprinzip – Konzepte der Therapieoptimierung des nicht-squamösen nicht-kleinzelligen Lungenkarzinoms

Zusammenfassung

Antiangiogene Therapieansätze, wie z. B. die Anti-VEGF-Therapie, haben eine nachgewiesene Wirksamkeit bei der Therapie des nicht-kleinzelligen Lungenkarzinoms (NSCLC). Der bisherige klinische Einsatz der therapeutisch verfügbaren Substanzen zeigt jedoch Grenzen der Wirksamkeit in nicht selektionierten Patientenkohorten. Es fehlen relevante Biomarker, die eine therapierelevante Selektion ermöglichen. Der vorliegende Artikel beschäftigt sich mit den therapeutisch relevanten Wirkprinzipien der Antiangiogenese und neuen medikamentösen Ansätzen, die zu einer Optimierung der klinischen Prognose für Patienten führen können.

Abstract

Anti-angiogenic treatment with anti-VEGF compounds plays a central role in the therapy of non-squamous non-small cell lung cancer (NSCLC). However, biometric analysis of overall survival of the established treatment options reveals several limitations of efficacy in unselected patient cohorts. Furthermore, there are no established predictive biomarkers to help select patients who might benefit from this treatment option. This review focuses on underlying principles of action of tumor-related angiogenesis and presents new treatment options that may contribute to improved overall survival.

• Literatur

• 1 Folkman J, Merler E, Abernathy C et al. Isolation of a tumor factor responsible for angiogenesis. J Exp Med 1971; 133: 275-288
• 2 Sandler A, Gray R, Perry MC et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 2006; 355: 2542-2550
• 3 Reck M, von Pawel J, Zatloukal P et al. Phase III trial of cisplatin plus gemcitabine with either placebo or bevacizumab as first-line therapy for nonsquamous non-small-cell lung cancer: AVAil. J Clin Oncol 2009; 27: 1227-1234
• 4 Ebos JM, Lee CR, Cruz-Munoz W et al. Accelerated metastasis after short-term treatment with a potent inhibitor of tumor angiogenesis. Cancer Cell 2009; 15: 232-239
• 5 Paez-Ribes M, Allen E, Hudock J et al. Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. Cancer Cell 2009; 15: 220-231
• 6 Schneider BP, Shen F, Miller KD. Pharmacogenetic biomarkers for the prediction of response to antiangiogenic treatment. Lancet Oncol 2012; 13: e427-436
• 7 Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell 2011; 144: 646-674
• 8 Kim KJ, Li B, Winer J et al. Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo. Nature 1993; 362: 841-844
• 9 Tugues S, Koch S, Gualandi L et al. Vascular endothelial growth factors and receptors: anti-angiogenic therapy in the treatment of cancer. Mol Aspects Med 2011; 32: 88-111
• 10 Prewett M, Huber J, Li Y et al. Antivascular endothelial growth factor receptor (fetal liver kinase 1) monoclonal antibody inhibits tumor angiogenesis and growth of several mouse and human tumors. Cancer Res 1999; 59: 5209-5218
• 11 Jin K, Lan H, Cao F et al. Differential response to EGFR- and VEGF-targeted therapies in patient-derived tumor tissue xenograft models of colon carcinoma and related metastases. Int J Oncol 1983; 41: 583-588
• 12 Casanovas O, Hicklin DJ, Bergers G et al. Drug resistance by evasion of antiangiogenic targeting of VEGF signaling in late-stage pancreatic islet tumors. Cancer Cell 2005; 8: 299-309
• 13 Bergers G, Song S, Meyer-Morse N et al. Benefits of targeting both pericytes and endothelial cells in the tumor vasculature with kinase inhibitors. J Clin Invest 2003; 111: 1287-1295
• 14 Claesson-Welsh L. Blood vessels as targets in tumor therapy. Ups J Med Sci 2012; 117: 178-186
• 15 Sitohy B, Nagy JA, Jaminet SC et al. Tumor-surrogate blood vessel subtypes exhibit differential susceptibility to anti-VEGF therapy. Cancer Res 2011; 71: 7021-7028
• 16 Hashizume M, Akahoshi T, Tomikawa M. Management of gastric varices. J Gastroenterol Hepatol 2011; 26 (Suppl. 01) 102-108
• 17 Fukumura D, Jain RK. Tumor microenvironment abnormalities: causes, consequences, and strategies to normalize. J Cell Biochem 2007; 101: 937-949
• 18 Senger DR, Galli SJ, Dvorak AM et al. Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science 1983; 219: 983-985
• 19 Jain RK. Normalizing tumor microenvironment to treat cancer: bench to bedside to biomarkers. J Clin Oncol 2013; 31: 2205-2218
• 20 di Tomaso E, Snuderl M, Kamoun WS et al. Glioblastoma recurrence after cediranib therapy in patients: lack of “rebound” revascularization as mode of escape. Cancer Res 2011; 71: 19-28
• 21 Chauhan VP, Stylianopoulos T, Martin JD et al. Normalization of tumour blood vessels improves the delivery of nanomedicines in a size-dependent manner. Nat Nanotechnol 2012; 7: 383-388
• 22 Sorensen AG, Emblem KE, Polaskova P et al. Increased survival of glioblastoma patients who respond to antiangiogenic therapy with elevated blood perfusion. Cancer Res 2011; 72: 402-407
• 23 Van der Veldt AA, Lubberink M, Bahce I et al. Rapid decrease in delivery of chemotherapy to tumors after anti-VEGF therapy: implications for scheduling of anti-angiogenic drugs. Cancer Cell 2012; 21: 82-91
• 24 Bottsford-Miller JN, Coleman RL, Sood AK. Resistance and escape from antiangiogenesis therapy: clinical implications and future strategies. J Clin Oncol 2012; 30: 4026-4034
• 25 Korc M, Friesel RE. The role of fibroblast growth factors in tumor growth. Curr Cancer Drug Targets 2009; 9: 639-651
• 26 Socinski MA. Multitargeted receptor tyrosine kinase inhibition: an antiangiogenic strategy in non-small cell lung cancer. Cancer Treat Rev 2011; 37: 611-617
• 27 Ebos JM, Lee CR, Christensen JG et al. Multiple circulating proangiogenic factors induced by sunitinib malate are tumor-independent and correlate with antitumor efficacy. Proc Natl Acad Sci U S A 2007; 104: 17069-17074
• 28 Reinmuth N, Liu W, Jung YD et al. Induction of VEGF in perivascular cells defines a potential paracrine mechanism for endothelial cell survival. FASEB J 2001; 15: 1239-1241
• 29 Erber R, Thurnher A, Katsen AD et al. Combined inhibition of VEGF and PDGF signaling enforces tumor vessel regression by interfering with pericyte-mediated endothelial cell survival mechanisms. FASEB J 2004; 18: 338-340
• 30 Benjamin LE, Hemo I, Keshet E. A plasticity window for blood vessel remodelling is defined by pericyte coverage of the preformed endothelial network and is regulated by PDGF-B and VEGF. Development 1998; 125: 1591-1598
• 31 Crawford Y, Kasman I, Yu L et al. PDGF-C mediates the angiogenic and tumorigenic properties of fibroblasts associated with tumors refractory to anti-VEGF treatment. Cancer Cell 2009; 15: 21-34
• 32 Bellou S, Pentheroudakis G, Murphy C et al. Anti-angiogenesis in cancer therapy: Hercules and hydra. Cancer Lett 2013; 338: 219-228
• 33 Amit L, Ben-Aharon I, Vidal L et al. The impact of Bevacizumab (Avastin) on survival in metastatic solid tumors--a meta-analysis and systematic review. PLoS One 2013; 8: e51780
• 34 Ellis LM, Hicklin DJ. VEGF-targeted therapy: mechanisms of anti-tumour activity. Nat Rev Cancer 2008; 8: 579-591
• 35 Liang W, Zhang L. Multitargeted antiangiogenic tyrosine kinase inhibitors in advanced non-small cell lung cancer: A meta-analysis of randomized controlled trials. J Clin Oncol 2013; 31: A8089
• 36 Soria JC, Mauguen A, Reck M et al. Systematic review and meta-analysis of randomised, phase II/III trials adding bevacizumab to platinum-based chemotherapy as first-line treatment in patients with advanced non-small-cell lung cancer. Ann Oncol 2012; 24: 20-30
• 37 Reck M, Kaiser R, Mellemgaard A et al. Docetaxel plus nintedanib versus docetaxel plus placebo in patients with previously treated non-small-cell lung cancer (LUME-Lung 1): a phase 3, double-blind, randomised controlled trial. Lancet Oncol 2014; 15: 143-155
• 38 Hanna NH, Kaiser R, Sullivan RN et al. Lume-lung 2: A multicenter, randomized, double-blind, phase III study of nintedanib plus pemetrexed versus placebo plus pemetrexed in patients with advanced nonsquamous non-small cell lung cancer (NSCLC) after failure of first-line chemotherapy. J Clin Oncol 2013; 31 abstr 8034
• 39 Perol M, Ciuleanu T-E, Arrieta O et al. REVEL: A randomized, double-blind, phase III study of docetaxel (DOC) and ramucirumab (RAM; IMC-1121B) versus DOC and placebo (PL) in the second-line treatment of stage IV non-small cell lung cancer (NSCLC) following disease progression after one prior platinum-based therapy. J Clin Oncol 2014; 32 abstr LBA8006
• 40 Hicklin DJ, Ellis LM. Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis. J Clin Oncol 2005; 23: 1011-1027
• 41 Ferrara N, Kerbel RS. Angiogenesis as a therapeutic target. Nature 2005; 438: 967-974
• 42 Seto T, Kato T, Nishio M et al. Erlotinib alone or with bevacizumab as first-line therapy in patients with advanced non-squamous non-small-cell lung cancer harbouring EGFR mutations (JO25567): an open-label, randomised, multicentre, phase 2 study. Lancet Oncol 2014; 11: 1236-1244