Molecular profiling of melanoma tumor biopsies to identify a response signature to the multi-RTK inhibitor, E7080.

Abstract

8595 Background: E7080 is an oral TKI targeting VEGFR1-3, FGFR1-4, PDGFRβ, RET and KIT, which affects tumor cell proliferation and tumor vascularization in laboratory models. Tumor response (RECIST) and prolonged disease stabilization (> 6 months) were observed in melanoma patients treated in phase I. The present study sought to identify predictive genomic/proteomic signatures. Methods: 25 patients with metastatic melanoma received E7080 10mg twice daily continuously. Biopsy of accessible lesions was performed pre-treatment D1 and on D22 post-treatment. The patient responses were: 2 PR, 14 SD > 3 months, 1 SD > 2 months and 5 PD (3 patients non evaluable). Tumor biopsies (D1 and D22) were frozen and preserved for sectioning. Melanoma cells and tumor infiltrating vasculature (IHC CD31+) were separately collected by laser capture micro-dissection for profiling from ~ 5,000 cells on Affymetrix U133+2 microarrays and from ~30,000 cells via a gel electrophoretic-tryptic digest-LC/MS/ MS method. Results: From 25 patient samples, 22 D1 samples yielded quality melanoma mRNA samples for hybridization and analyses used data from ~24,000 RMA-normalized probes. The genomic data was analyzed using Student's T-test based on clinical benefit (=PR or SD ≥ 6 months); regression analysis for the continuous measure of tumor shrinkage and by Cox proportional regression based on PFS. The analysis identified genes encoding elements of the target RTK signaling pathways. At the intersection of the regression analyses was a set of 46 genes correlating with the observed clinical response. Conclusions: A small set of genes in melanoma cells may potentially be used to predict clinical response in melanoma patients to E7080. The list will be refined based on on-going proteomic analysis of melanoma cells, gene expression data from the tumor vasculature and genotyping for melanoma-associated mutations from these same tumors. These will be tested for their predictive value in an ongoing Ph2 trial.