Grant Recipient: Dr. John V. Heymach
Title of Project: Predictive blood-based markers of response to VEGF inhibitors in NSCLC
Sponsoring Institution: University of Texas M.D. Anderson Cancer Center
Drugs that target tumor blood vessels, such as bevacizumab and other inhibitors of the VEGF pathway, have improved survival in patients with advanced NSCLC, but only a subset of patients benefit significantly from the drugs while others experience no benefit or even life-threatening toxicities. Furthermore, almost all NSCLC tumors eventually become resistant to these treatments. There is therefore a critical unmet need for biomarkers to identify which patients will benefit from a VEGF inhibitor (predictive markers) and to understand how tumors become resistant to these agents. A major challenge for developing these markers is that tumor angiogenesis is promoted by circulating cytokines and angiogenic factors (CAFs) that may be produced by the tumor as well as the host. Therefore, it is likely that predictive markers for VEGF inhibitors may reflect both influences. For this reason, we hypothesize that by comprehensively profiling angiogenesis-related CAFs and other peptides in the blood, as well as germline variations in angiogenesis-related genes, predictive markers for identifying which patients benefit from VEGF inhibitors (alone or with chemotherapy) can be developed and validated. The PIs of this proposal have already conducted studies establishing three promising and potentially complementary approaches to identify predictive markers using blood samples: 1) multiplex CAF profiling; 2) proteomic analysis using mass spectroscopy (MALDI-TOF); and 3) a signature of single nucleotide polymorphisms (SNPs) in three angiogenesis genes. In this proposal, these three approaches will be tested using samples from completed clinical trials of VEGF inhibitors in NSCLC patients; the most promising markers will then be validated using samples from two independent randomized trials. These studies have the potential to significantly advance the treatment of NSCLC patients by identifying which patients are most likely to benefit from a VEGF inhibitor, and by sparing patients who are unlikely to benefit from these drugs. They can also provide critical insights into mechanisms of resistance that can guide future combination regimens.