The COXEN principle: translating signatures of in vitro chemosensitivity into tools for clinical outcome prediction and drug discovery in cancer.

摘要

Substantial effort has been devoted to in vitro testing of candidate chemotherapeutic agents. In particular, the United States National Cancer Institute Developmental Therapeutics Program (NCI-DTP) Human Tumor Cell Line Screen has screened hundreds of thousands of compounds and extracts, for which data on more than 40,000 compounds tested on a panel of 60 cancer cell lines (NCI-60) are publically available. In tandem, gene expression profiling has brought about a sea change in our understanding of cancer biology, allowing discovery of biomarkers or signatures able to characterize, classify, and prognosticate clinical behavior of human tumors. Recent studies have used tumor profiling matched to clinical trial outcome data to derive gene expression models predicting therapeutic outcomes, though such efforts are costly, time-consuming, tumor type-specific, and not amenable to rare diseases. Furthermore, addition of new or established drugs to multidrug combinations in which such models are already available requires the entire model to be re-derived. Can the aforementioned in vitro testing platform, coupled to the universal language of genomics, be used to develop, a priori, gene expression models predictive of clinical outcomes? Recent advances, including the CO-eXpression ExtrapolatioN (COXEN) algorithm, suggest that development of these models may be possible and raise important implications for future trial design and drug discovery.