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Revealing Targeted Therapy for Human Cancer by Gene Module Maps

¹ Programs in Epithelial Biology and ² Cancer Biology, Stanford University, Stanford, California; Departments of ³ Radiation Oncology and ⁴ Diagnostic Oncology, The Netherlands Cancer Institute, Amsterdam, the Netherlands; ⁵ MIT Department of Biology and Broad Institute of MIT and Harvard, Cambridge, Massachusetts; and ⁶ Department of Computer Science and Applied Mathematics, Weizmann Institute, Rehovot, Israel

Requests for reprints: Howard Y. Chang, Program in Epithelial Biology, Stanford University, CCSR 2155, 269 Campus Drive, Stanford, CA 94305. E-mail: howchang{at}stanford.edu or Marc van de Vijver, Department of Diagnostic Oncology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands. E-mail: m.vd.vijver{at}nki.nl.

A major goal of cancer research is to match specific therapies to molecular targets in cancer. Genome-scale expression profiling has identified new subtypes of cancer based on consistent patterns of variation in gene expression, leading to improved prognostic predictions. However, how these new genetic subtypes of cancers should be treated is unknown. Here, we show that a gene module map can guide the prospective identification of targeted therapies for genetic subtypes of cancer. By visualizing genome-scale gene expression in cancer as combinations of activated and deactivated functional modules, gene module maps can reveal specific functional pathways associated with each subtype that might be susceptible to targeted therapies. We show that in human breast cancers, activation of a poor-prognosis "wound signature" is strongly associated with induction of both a mitochondria gene module and a proteasome gene module. We found that 3-bromopyruvic acid, which inhibits glycolysis, selectively killed breast cells expressing the mitochondria and wound signatures. In addition, inhibition of proteasome activity by bortezomib, a drug approved for human use in multiple myeloma, abrogated wound signature expression and selectively killed breast cells expressing the wound signature. Thus, gene module maps may enable rapid translation of complex genomic signatures in human disease to targeted therapeutic strategies. [Cancer Res 2008;68(2):369–78]