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Published in: Drugs 4/2014

01-03-2014 | Leading Article

Targeting Angiogenesis in Squamous Non-Small Cell Lung Cancer

Authors: Bilal Piperdi, Amartej Merla, Roman Perez-Soler

Published in: Drugs | Issue 4/2014

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Abstract

Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, and can be further classified as nonsquamous carcinoma (including adenocarcinoma, which accounts for 40 % of NSCLCs) and squamous NSCLC, which makes up 30 % of NSCLC cases. The emergence of inhibitors of epidermal growth factor receptors, anaplastic lymphoma kinase, and vascular endothelial growth factors (VEGF) in the last decade has resulted in steady improvement in clinical outcomes for patients with advanced lung adenocarcinoma. However, improvements in the survival of patients with squamous NSCLC have remained elusive, presenting an urgent need for understanding and investigating therapeutically relevant molecular targets, specifically in squamous NSCLC. Although anti-VEGF therapy has been studied in squamous NSCLC, progress has been slow, in part due to issues related to pulmonary hemorrhage. In addition to these safety concerns, several phase III trials that initially included patients with squamous NSCLC failed to demonstrate improved overall survival (primary endpoint) with the addition of antiangiogenic therapy to chemotherapy compared with chemotherapy alone. Angiogenesis is an established hallmark of tumor progression and metastasis, and the role of VEGF signaling in angiogenesis is well established. However, some studies suggest that, while inhibiting VEGF signaling may be beneficial, prolonged exposure to VEGF/VEGF receptor (VEGFR) inhibitors may allow tumor cells to utilize alternative angiogenic mechanisms and become resistant. As a result, agents that target multiple angiogenic pathways simultaneously are also under evaluation. This review focuses on current and investigational antiangiogenic targets in squamous NSCLC, including VEGF/VEGFRs, fibroblast growth factor receptors, platelet-derived growth factor receptors, and angiopoietin. Additionally, clinical trials investigating VEGF- and multi-targeted antiangiogenic therapies are discussed.
Literature
1.
American Cancer Society. Cancer facts & figures, 2013. Atlanta: American Cancer Society; 2013.
2.
3.
4.
American Cancer Society. Detailed guide: lung cancer—non-small cell. What is non-small cell lung cancer?. http://​www.​cancer.​org/​Cancer/​LungCancer-Non-SmallCell/​DetailedGuide/​lung-cancer–non-small-cell–non-small-cell-lung-cancer. Accessed 8 Jul 2010.
5.
Morgensztern D, Waqar S, Subramanian J, et al. Improving survival for stage IV non-small cell lung cancer: a surveillance, epidemiology, and end results survey from 1990 to 2005. J Thorac Oncol. 2009;4:1524–9.PubMedCrossRef
6.
Gold KA, Wistuba II, Kim ES. New strategies in squamous cell carcinoma of the lung: identification of tumor drivers to personalize therapy. Clin Cancer Res. 2012;18:3002–7.PubMedCentralPubMedCrossRef
7.
8.
Dvorak HF, Sioussat TM, Brown LF, et al. Distribution of vascular permeability factor (vascular endothelial growth factor) in tumors: concentration in tumor blood vessels. J Exp Med. 1991;174:1275–8.PubMedCrossRef
9.
Kim KJ, Li B, Winer J, et al. Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo. Nature. 1993;362:841–4.PubMedCrossRef
10.
Toi M, Matsumoto T, Bando H. Vascular endothelial growth factor: its prognostic, predictive, and therapeutic implications. Lancet Oncol. 2001;2:667–73.PubMedCrossRef
11.
Folkman J, Klagsbrun M. Vascular physiology. A family of angiogenic peptides. Nature. 1987;329:671–2.PubMedCrossRef
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.PubMedCrossRef
13.
Lohela M, Bry M, Tammela T, et al. VEGFs and receptors involved in angiogenesis versus lymphangiogenesis. Curr Opin Cell Biol. 2009;21:154–65.PubMedCrossRef
14.
15.
Blakely C, Jahan T. Emerging antiangiogenic therapies for non-small-cell lung cancer. Expert Rev Anticancer Ther. 2011;11:1607–18.PubMedCrossRef
16.
17.
Bonnesen B, Pappot H, Holmstav J, et al. Vascular endothelial growth factor A and vascular endothelial growth factor receptor 2 expression in non-small cell lung cancer patients: relation to prognosis. Lung Cancer. 2009;66:314–8.PubMedCrossRef
18.
Donnem T, Al-Saad S, Al-Shibli K, et al. Co-expression of PDGF-B and VEGFR-3 strongly correlates with lymph node metastasis and poor survival in non-small-cell lung cancer. Ann Oncol. 2010;21:223–31.PubMedCrossRef
19.
Ohta Y, Endo Y, Tanaka M, et al. Significance of vascular endothelial growth factor messenger RNA expression in primary lung cancer. Clin Cancer Res. 1996;2:1411–6.PubMed
20.
Fontanini G, Vignati S, Boldrini L, et al. Vascular endothelial growth factor is associated with neovascularization and influences progression of non-small cell lung carcinoma. Clin Cancer Res. 1997;3:861–5.PubMed
21.
Imoto H, Osaki T, Taga S, et al. Vascular endothelial growth factor expression in non-small-cell lung cancer: prognostic significance in squamous cell carcinoma. J Thorac Cardiovasc Surg. 1998;115:1007–14.PubMedCrossRef
22.
23.
Shikada Y, Yonemitsu Y, Koga T, et al. Platelet-derived growth factor-AA is an essential and autocrine regulator of vascular endothelial growth factor expression in non-small cell lung carcinomas. Cancer Res. 2005;65:7241–8.PubMedCrossRef
24.
McDermott U, Ames RY, Iafrate AJ, et al. Ligand-dependent platelet-derived growth factor receptor (PDGFR)-alpha activation sensitizes rare lung cancer and sarcoma cells to PDGFR kinase inhibitors. Cancer Res. 2009;69:3937–46.PubMedCentralPubMedCrossRef
25.
Kawai T, Hiroi S, Torikata C. Expression in lung carcinomas of platelet-derived growth factor and its receptors. Lab Invest. 1997;77:431–6.PubMed
26.
Donnem T, Al-Saad S, Al-Shibli K, et al. Prognostic impact of platelet-derived growth factors in non-small cell lung cancer tumor and stromal cells. J Thorac Oncol. 2008;3:963–70.PubMedCrossRef
27.
Andersen S, Donnem T, Al-Saad S, et al. Angiogenic markers show high prognostic impact on survival in marginally operable non-small cell lung cancer patients treated with adjuvant radiotherapy. J Thorac Oncol. 2009;4:463–71.PubMedCrossRef
28.
Cao Y. Opinion: emerging mechanisms of tumour lymphangiogenesis and lymphatic metastasis. Nat Rev Cancer. 2005;5:735–43.PubMedCrossRef
29.
Cao R, Bjorndahl MA, Religa P, et al. PDGF-BB induces intratumoral lymphangiogenesis and promotes lymphatic metastasis. Cancer Cell. 2004;6:333–45.PubMedCrossRef
30.
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;111:1287–95.PubMedCentralPubMedCrossRef
31.
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;18:338–40.PubMed
32.
Saharinen P, Eklund L, Miettinen J, et al. Angiopoietins assemble distinct Tie2 signalling complexes in endothelial cell-cell and cell-matrix contacts. Nat Cell Biol. 2008;10:527–37.PubMedCrossRef
33.
Holopainen T, Huang H, Chen C, et al. Angiopoietin-1 overexpression modulates vascular endothelium to facilitate tumor cell dissemination and metastasis establishment. Cancer Res. 2009;69:4656–64.PubMedCrossRef
34.
Takanami I. Overexpression of Ang-2 mRNA in non-small cell lung cancer: association with angiogenesis and poor prognosis. Oncol Rep. 2004;12:849–53.PubMed
35.
Tanaka F, Ishikawa S, Yanagihara K, et al. Expression of angiopoietins and its clinical significance in non-small cell lung cancer. Cancer Res. 2002;62:7124–9.PubMed
36.
Andersen S, Donnem T, Al-Shibli K, et al. Prognostic impacts of angiopoietins in NSCLC tumor cells and stroma: VEGF-A impact is strongly associated with Ang-2. PLoS One. 2011;6:e19773.PubMedCentralPubMedCrossRef
37.
Presta M, Dell’Era P, Mitola S, et al. Fibroblast growth factor/fibroblast growth factor receptor system in angiogenesis. Cytokine Growth Factor Rev. 2005;16:159–78.PubMedCrossRef
38.
Wesche J, Haglund K, Haugsten EM. Fibroblast growth factors and their receptors in cancer. Biochem J. 2011;437:199–213.PubMedCrossRef
39.
Marek L, Ware KE, Fritzsche A, et al. Fibroblast growth factor (FGF) and FGF receptor-mediated autocrine signaling in non-small-cell lung cancer cells. Mol Pharmacol. 2009;75:196–207.PubMedCentralPubMedCrossRef
40.
Dudek AZ, Mahaseth H. Circulating angiogenic cytokines in patients with advanced non-small cell lung cancer: correlation with treatment response and survival. Cancer Invest. 2005;23:193–200.PubMedCrossRef
41.
42.
Weiss J, Sos ML, Seidel D, et al. Frequent and focal FGFR1 amplification associates with therapeutically tractable FGFR1 dependency in squamous cell lung cancer. Sci Transl Med. 2010;2:62ra93.PubMedCrossRef
43.
Sasaki H, Shitara M, Yokota K, et al. Increased FGFR1 copy number in lung squamous cell carcinomas. Mol Med Report. 2012;5:725–8.
44.
Slodkowska J, Sikora J, Roszkowski-Sliz K, et al. Expression of vascular endothelial growth factor and basic fibroblast growth factor receptors in lung cancer. Anal Quant Cytol Histol. 2000;22:398–402.PubMed
45.
Brattstrom D, Bergqvist M, Hesselius P, et al. Elevated preoperative serum levels of angiogenic cytokines correlate to larger primary tumours and poorer survival in non-small cell lung cancer patients. Lung Cancer. 2002;37:57–63.PubMedCrossRef
46.
Iwasaki A, Kuwahara M, Yoshinaga Y, et al. Basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) levels, as prognostic indicators in NSCLC. Eur J Cardiothorac Surg. 2004;25:443–8.PubMedCrossRef
47.
Kuhn H, Kopff C, Konrad J, et al. Influence of basic fibroblast growth factor on the proliferation of non-small cell lung cancer cell lines. Lung Cancer. 2004;44:167–74.PubMedCrossRef
48.
Fischer H, Taylor N, Allerstorfer S, et al. Fibroblast growth factor receptor-mediated signals contribute to the malignant phenotype of non-small cell lung cancer cells: therapeutic implications and synergism with epidermal growth factor receptor inhibition. Mol Cancer Ther. 2008;7:3408–19.PubMedCentralPubMedCrossRef
49.
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;355:2542–50.PubMedCrossRef
50.
Johnson DH, Fehrenbacher L, Novotny WF, et al. Randomized phase II trial comparing bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in previously untreated locally advanced or metastatic non-small-cell lung cancer. J Clin Oncol. 2004;22:2184–91.PubMedCrossRef
51.
Avastin. AVASTIN® (bevacizumab) solution for intravenous infusion [package insert]. South San Francisco: Genentech, Inc.; 2012.
52.
Schmidinger M, Bellmunt J. Plethora of agents, plethora of targets, plethora of side effects in metastatic renal cell carcinoma. Cancer Treat Rev. 2010;36:416–24.PubMedCrossRef
53.
54.
Reck M, Barlesi F, Crino L, et al. Predicting and managing the risk of pulmonary haemorrhage in patients with NSCLC treated with bevacizumab: a consensus report from a panel of experts. Ann Oncol. 2012;23:1111–20.PubMedCentralPubMedCrossRef
55.
Hainsworth JD, Fang L, Huang JE, et al. BRIDGE: an open-label phase II trial evaluating the safety of bevacizumab + carboplatin/paclitaxel as first-line treatment for patients with advanced, previously untreated, squamous non-small cell lung cancer. J Thorac Oncol. 2011;6:109–14.PubMedCrossRef
56.
Wozniak AJ, Moon J, Thomas CR, et al. SWOG S0533: a pilot trial of cisplatin (C)/etoposide (E)/radiotherapy (RT) followed by consolidation docetaxel (D) and bevacizumab (B) (NSC-704865) in three cohorts of patients (pts) with inoperable locally advanced stage III non-small cell lung cancer (NSCLC). J Clin Oncol. 2012;30(suppl): Abstract 7018.
57.
Socinski MA, Stinchcombe TE, Moore DT, et al. Incorporating bevacizumab and erlotinib in the combined-modality treatment of stage III non-small-cell lung cancer: results of a phase I/II trial. J Clin Oncol. 2012;30:3953–9.PubMedCrossRef
58.
Scagliotti GV, Vynnychenko I, Park K, et al. International, randomized, placebo-controlled, double-blind phase III study of motesanib plus carboplatin/paclitaxel in patients with advanced nonsquamous non-small-cell lung cancer: MONET1. J Clin Oncol. 2012;30:2829–36.PubMedCrossRef
59.
60.
Socinski MA, Novello S, Brahmer JR, et al. Multicenter, phase II trial of sunitinib in previously treated, advanced non-small-cell lung cancer. J Clin Oncol. 2008;26:650–6.PubMedCentralPubMedCrossRef
61.
Scagliotti G, Novello S, von Pawel J, et al. Phase III study of carboplatin and paclitaxel alone or with sorafenib in advanced non-small-cell lung cancer. J Clin Oncol. 2010;28:1835–42.PubMedCrossRef
62.
Gatzemeier U, Eisen T, Santoro A, et al. Sorafenib (S) + gemcitabine/cisplatin (GC) vs GC alone in the first-line treatment of advanced non-small cell lung cancer (NSCLC): phase III NSCLC research experience utilizing sorafenib (NEXUS) trial. Ann Oncol. 2010;21(Suppl 8):viii7.
63.
Heist RS, Wang XF, Hodgson L, et al. CALGB 30704: a randomized phase II study to assess the efficacy of pemetrexed or sunitinib or pemetrexed plus sunitinib in the second-line treatment of advanced non-small cell lung cancer (NSCLC). J Clin Oncol. 2012;30(suppl): Abstract 7513.
64.
Horn L, Sandler AB. Emerging data with antiangiogenic therapies in early and advanced non-small-cell lung cancer. Clin Lung Cancer. 2009;10(Suppl 1):S7–16.PubMedCentralPubMedCrossRef
65.
Scagliotti GV, Krzakowski M, Szczesna A, et al. Sunitinib plus erlotinib versus placebo plus erlotinib in patients with previously treated advanced non-small-cell lung cancer: a phase III trial. J Clin Oncol. 2012;30:2070–8.PubMedCrossRef
66.
Lara PN Jr, Douillard JY, Nakagawa K, et al. Randomized phase III placebo-controlled trial of carboplatin and paclitaxel with or without the vascular disrupting agent vadimezan (ASA404) in advanced non-small-cell lung cancer. J Clin Oncol. 2011;29:2965–71.PubMedCrossRef
67.
Schiller JH, Larson T, Ou SH, et al. Efficacy and safety of axitinib in patients with advanced non-small-cell lung cancer: results from a phase II study. J Clin Oncol. 2009;27:3836–41.PubMedCrossRef
68.
Giles FJ, Bellamy WT, Estrov Z, et al. The anti-angiogenesis agent, AG-013736, has minimal activity in elderly patients with poor prognosis acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). Leuk Res. 2006;30:801–11.PubMedCrossRef
69.
Hilberg F, Roth GJ, Krssak M, et al. BIBF 1120: triple angiokinase inhibitor with sustained receptor blockade and good antitumor efficacy. Cancer Res. 2008;68:4774–82.PubMedCrossRef
70.
Wedge SR, Kendrew J, Hennequin LF, et al. AZD2171: a highly potent, orally bioavailable, vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor for the treatment of cancer. Cancer Res. 2005;65:4389–400.PubMedCrossRef
71.
Sternberg CN, Davis ID, Mardiak J, et al. Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trial. J Clin Oncol. 2010;28:1061–8.PubMedCrossRef
72.
Sloan B, Scheinfeld NS. Pazopanib, a VEGF receptor tyrosine kinase inhibitor for cancer therapy. Curr Opin Investig Drugs. 2008;9:1324–35.PubMed
73.
Spratlin JL, Cohen RB, Eadens M, et al. Phase I pharmacologic and biologic study of ramucirumab (IMC-1121B), a fully human immunoglobulin G1 monoclonal antibody targeting the vascular endothelial growth factor receptor-2. J Clin Oncol. 2010;28:780–7.PubMedCentralPubMedCrossRef
74.
Doebele RC, Conkling P, Traynor AM, et al. A phase I, open-label dose-escalation study of continuous treatment with BIBF 1120 in combination with paclitaxel and carboplatin as first-line treatment in patients with advanced non-small-cell lung cancer. Ann Oncol. 2012;23:2094–102.PubMedCrossRef
75.
Reck M, Kaiser R, Mellemgaard A, et al. Nintendanib (BIBF 1120) + docetaxel in NSCLC patients progressing after one prior chemotherapy regimen: LUME-Lung 1, a randomized, double-blind, phase III trial. Presented at: the 49th Annual Meeting of the American Society for Clinical Oncology, May 31–June 4, 2013, Chicago, IL; 2013.
76.
Hammerman PS, Sos ML, Ramos AH, et al. Mutations in the DDR2 kinase gene identify a novel therapeutic target in squamous cell lung cancer. Cancer Discov. 2011;1:78–89.PubMedCentralPubMedCrossRef
77.
Kawano O, Sasaki H, Endo K, et al. PIK3CA mutation status in Japanese lung cancer patients. Lung Cancer. 2006;54:209–15.PubMedCrossRef
78.
79.
Engelman JA, Chen L, Tan X, et al. Effective use of PI3K and MEK inhibitors to treat mutant Kras G12D and PIK3CA H1047R murine lung cancers. Nat Med. 2008;14:1351–6.PubMedCentralPubMedCrossRef
80.
The Cancer Genome Atlas Research Network. Comprehensive genomic characterization of squamous cell lung cancers. Nature. 2012;489:519–25.PubMedCentralCrossRef
81.
D’Arcangelo M, D’Incecco A, Cappuzzo F. Rare mutations in non-small-cell lung cancer. Future Oncol. 2013;9:699–711.PubMedCrossRef
82.
Minuti G, D’Incecco A, Cappuzzo F. Targeted therapy for NSCLC with driver mutations. Expert Opin Biol Ther. 2013;13:1401–12.PubMedCrossRef
83.
Metadata
Title
Targeting Angiogenesis in Squamous Non-Small Cell Lung Cancer
Authors
Bilal Piperdi
Amartej Merla
Roman Perez-Soler
Publication date
01-03-2014
Publisher
Springer International Publishing
Published in
Drugs / Issue 4/2014
Print ISSN: 0012-6667
Electronic ISSN: 1179-1950
DOI
https://doi.org/10.1007/s40265-014-0182-z

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