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Targeting Angiogenesis in Squamous Non-Small Cell Lung Cancer

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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.

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Acknowledgments

This work was supported by Boehringer Ingelheim Pharmaceuticals, Inc (BIPI). Writing and editorial assistance was provided by Janetricks Chebukati, PhD, of MedErgy, which was contracted by BIPI for these services. The authors meet criteria for authorship as recommended by the International Committee of Medical Journal Editors (ICMJE), were fully responsible for all content and editorial decisions, and were involved at all stages of manuscript development. The authors received no compensation related to the development of the manuscript.

Conflict of interest statement

Dr. Perez-Soler has served as a consultant/speaker for Genetech/Roche, Lilly, Pfizer, and Boehringer Ingelheim. Dr. Piperdi has served on speaker bureaus for Pfizer and Genentech/Roche, and as an advisor/consultant for Genentech/Roche and Amgen. Dr. Merla has no potential conflicts of interest to disclose.

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Piperdi, B., Merla, A. & Perez-Soler, R. Targeting Angiogenesis in Squamous Non-Small Cell Lung Cancer. Drugs 74, 403–413 (2014). https://doi.org/10.1007/s40265-014-0182-z

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