Angiogenesis inhibitors in early development for gastric cancer

ABSTRACT

Introduction: Angiogenesis, or the generation of new blood vessels from pre-existent ones is a critical process for tumor growth and progression. Hence, the development of angiogenesis inhibitors with therapeutic potential has been a central focus for researchers. Most angiogenesis inhibitors target the Vascular Endothelial Growth Factor (VEGF) pathway, however a number of tyrosine kinase inhibitors (TKIs), immunomodulatory drugs (IMiDs) and inhibitors of the mammalian Target-Of-Rapamycin (mTOR) pathway also display antiangiogenic activity.

Areas covered: Here we review the effectiveness of a variety of compounds with antiangiogenic properties in preclinical and clinical settings in gastric cancer (GC).

Expert opinion: In coming years angiogenesis will remain as a therapeutic target in GC. To date, ramucirumab a monoclonal antibody that targets VEGFR2 is the most successful antiangiogenic tested in clinical studies, and it is now well established as a second-line therapy in GC. The arrival of precision medicine and the success of immune checkpoint inhibitors will increase the number of clinical trials using targeted agents like ramucirumab in combination with immune checkpoint inhibitors. A hypothetical working model that combines ramucirumab with immunotherapy is presented. Also, the impact of nanotechnology and a molecular subtype classification of GC are discussed

KEYWORDS:

• Angiogenesis
• antiangiogenesis
• checkpoint inhibitors
• gastric cancer
• ramucirumab
• pembrolizumab
• nivolumab

Article highlights

• Angiogenesis is a key physiological process and cancer cells have the ability to stimulate angiogenesis to enhance tumor growth

• Angiogenesis is a therapeutic target in many types of cancer, including gastric

• Currently, the majority of antiangiogenic drugs target the VEGF pathway

• To date the most successful antiangiogenic in gastric cancer is ramucirumab, a humanized monoclonal VEGFR antibody

• In addition to VEGF-targeted treatments, Tyrosine Kinase Inhibitors, Inhibitors of the mTOR pathway and immunomodulator drugs also display antiangiogenic activity

• Given its key role, angiogenesis will remain a therapeutic target in gastric cancer and future studies will determine efficacy of combinatorial treatment regimes with antiangiogenics

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Declaration of interest

M Garrido is a consultant for, or a board member with Abbot-Recalcine, Merck Sharp & Dohme LLC, Bayer, Bristol-Myers Squibb, Lilly. MG has received a research grant from Novartis. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

CONICYT-FONDAP 15130011, Millenium Institute on Immunology & Immunotherapy IMII P09/016-F, BMRC 13CTI-21526-P6, CORFO 13IDL2-18608, and FONDECYT grant #1140970.