Drugs that target oncogene- or non-oncogene-based dependencies acquired by cancers as a result of specific genomic alterations can yield high clinical response rates, although current drugs in this category benefit only a small fraction of cancer patients and the beneficial responses are not always durable. This project aims to discover drug-targetable dependencies for a wide range of cancer genomic alterations and identify the combinations of drugs that can avoid or overcome resistance. As part of the five-center and now nine-center CTD2 Network, we applied quantitative genomic cancer cell-line profiling to build an interactive resource for identifying cancer genetic dependencies targeted by small molecules. We made all aspects of this resource available to the cancer community through a public database, interactive data-analysis tools, code, and instructions that guide users through potentially confounding data- analysis issues. We now propose to advance the resource substantially in ways that enhance other Network research and impact the health of cancer patients. The project will integrate small-molecule and RNAi data from genomic cancer cell-line profiling within the interactive resource and discover dependencies targeted by single agents. It will also identify and test hypotheses suggested by the interactive resource about cancer genetic dependencies targeted by small molecules. Finally, the project will identify combinations of small- molecule agents that target oncogene or non-oncogene dependencies in cancer cells and that avoid or overcome drug resistance seen with single agents.

Public Health Relevance

The ability to understand cancer genomes combined with advances in small-molecule science provide a radically new foundation for creating medicines we've only imagined since declaring war on cancer decades earlier - the ones needed to take out this disease. This project, which begins and ends with cancer patients, aims to exploit our new foundation and insights by discovering cancer dependencies associated with specific genomic alterations and targeted by small molecules. These advances will point to new medicines that are tailored to the specific genetic features of individual cancer patients'tumors genetically informed medicines.

National Institute of Health (NIH)
Research Project--Cooperative Agreements (U01)
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Special Emphasis Panel (ZCA1)
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Gerhard, Daniela
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Broad Institute, Inc.
United States
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Adams, Drew J; Ito, Daisuke; Rees, Matthew G et al. (2014) NAMPT is the cellular target of STF-31-like small-molecule probes. ACS Chem Biol 9:2247-54