Genomic and molecular profiling predicts response to temozolomide in melanoma.

Journal Article

PURPOSE: Despite objective response rates of only approximately 13%, temozolomide remains one of the most effective single chemotherapy agents against metastatic melanoma, second only to dacarbazine, the current standard of care for systemic treatment of melanoma. The goal of this study was to identify molecular and/or genetic markers that correlate with, and could be used to predict, response to temozolomide-based treatment regimens and that reflect the intrinsic properties of a patient's tumor. EXPERIMENTAL DESIGN: Using a panel of 26 human melanoma-derived cell lines, we determined in vitro temozolomide sensitivity, O(6)-methylguanine-DNA methyltransferase (MGMT) activity, MGMT protein expression and promoter methylation status, and mismatch repair proficiency, as well as the expression profile of 38,000 genes using an oligonucleotide-based microarray platform. RESULTS: The results showed a broad spectrum of temozolomide sensitivity across the panel of cell lines, with IC(50) values ranging from 100 micromol/L to 1 mmol/L. There was a significant correlation between measured temozolomide sensitivity and a gene expression signature-derived prediction of temozolomide sensitivity (P < 0.005). Notably, MGMT alone showed a significant correlation with temozolomide sensitivity (MGMT activity, P < 0.0001; MGMT expression, P

Full Text

Duke Authors

Cited Authors

  • Augustine, CK; Yoo, JS; Potti, A; Yoshimoto, Y; Zipfel, PA; Friedman, HS; Nevins, JR; Ali-Osman, F; Tyler, DS

Published Date

  • January 15, 2009

Published In

Volume / Issue

  • 15 / 2

Start / End Page

  • 502 - 510

PubMed ID

  • 19147755

International Standard Serial Number (ISSN)

  • 1078-0432

Digital Object Identifier (DOI)

  • 10.1158/1078-0432.CCR-08-1916

Language

  • eng

Conference Location

  • United States