Circulating Biomarkers of Response to Sunitinib in Gastroenteropancreatic Neuroendocrine Tumors
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After years of limited progress in the treatment of patients with advanced-stage gastroenteropancreatic neuroendocrine tumors (GEP-NETs), strategies using targeted agents have been developed on the basis of increased knowledge of the biology of these tumors. Some of these agents, targeting vascular endothelial growth factor (VEGF) and the mammalian target of rapamycin (mTOR) pathway, have shown efficacy in randomized clinical trials. The tyrosine kinase inhibitor sunitinib and the mTOR inhibitor everolimus have received international approval for the treatment of advanced well differentiated pancreatic NETs after showing survival benefit in randomized phase III trials. There is now an imperative need to identify biomarkers of the biologic activity of such targeted therapies in specific disease contexts, as well as new markers of response and prognosis. This approach may allow rational development of drugs and early identification of patients who may obtain benefit from treatments. In this article, we review recent developments in circulating biomarkers of the clinical benefit of targeted therapies for GEP-NET, including soluble proteins and circulating cells, with an emphasis on sunitinib. No validated molecular biomarkers are yet integrated into clinical practice for sunitinib in NET, although some markers have shown correlation with clinical outcomes and may be implicated in resistance. The VEGF-pathway proteins and interleukin-8 (IL-8) are possibly prognostic in GEP-NET; other possible soluble markers of the activity of sunitinib and everolimus include stromal cell-derived factor 1α, chromogranin A, and neuron-specific enolase. We additionally discuss treatment-induced modulation of circulating endothelial cells and progenitors and subpopulations of cells of the myeloid lineage. These candidate markers should be considered in the development of future combination or sequential therapies.
KeywordsVascular Endothelial Growth Factor Sunitinib Everolimus Carcinoid Tumor Vascular Endothelial Growth Factor Concentration
This research was supported in part by the National Institutes of Health through MD Anderson Cancer Center Support Grant Number CA016672. John Heymach has received a research grant from the LUNGevity Foundation and research funding and advisory board honoraria from Pfizer, AstraZeneca, and GlaxoSmithKline. Amado Zurita has received a research grant from the MD Anderson–AstraZeneca alliance.
Joaquin Mateo now works in the Drug Development Unit at the Royal Marsden Hospital – Institute of Cancer Research, Sutton, Surrey, UK.
The authors would like to thank Karen F. Phillips for editorial assistance.
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