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.

Agency
National Institute of Health (NIH)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01CA176152-02
Application #
8657018
Study Section
Special Emphasis Panel (ZCA1)
Program Officer
Gerhard, Daniela
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Broad Institute, Inc.
Department
Type
DUNS #
City
Cambridge
State
MA
Country
United States
Zip Code
02142
Hong, Andrew L; Tseng, Yuen-Yi; Cowley, Glenn S et al. (2016) Integrated genetic and pharmacologic interrogation of rare cancers. Nat Commun 7:11987
Rees, Matthew G; Seashore-Ludlow, Brinton; Cheah, Jaime H et al. (2016) Correlating chemical sensitivity and basal gene expression reveals mechanism of action. Nat Chem Biol 12:109-16
Yard, Brian D; Adams, Drew J; Chie, Eui Kyu et al. (2016) A genetic basis for the variation in the vulnerability of cancer to DNA damage. Nat Commun 7:11428
de Waal, Luc; Lewis, Timothy A; Rees, Matthew G et al. (2016) Identification of cancer-cytotoxic modulators of PDE3A by predictive chemogenomics. Nat Chem Biol 12:102-8
Cancer Target Discovery and Development Network (2016) Transforming Big Data into Cancer-Relevant Insight: An Initial, Multi-Tier Approach to Assess Reproducibility and Relevance. Mol Cancer Res 14:675-82
Hanaford, Allison R; Archer, Tenley C; Price, Antoinette et al. (2016) DiSCoVERing Innovative Therapies for Rare Tumors: Combining Genetically Accurate Disease Models with In Silico Analysis to Identify Novel Therapeutic Targets. Clin Cancer Res 22:3903-14
Kuo, Szu-Yu; Castoreno, Adam B; Aldrich, Leslie N et al. (2015) Small-molecule enhancers of autophagy modulate cellular disease phenotypes suggested by human genetics. Proc Natl Acad Sci U S A 112:E4281-7
Stewart, Michelle L; Tamayo, Pablo; Wilson, Andrew J et al. (2015) KRAS Genomic Status Predicts the Sensitivity of Ovarian Cancer Cells to Decitabine. Cancer Res 75:2897-906
Aldrich, Leslie N; Kuo, Szu-Yu; Castoreno, Adam B et al. (2015) Discovery of a Small-Molecule Probe for V-ATPase Function. J Am Chem Soc 137:5563-8
Martins, Maria M; Zhou, Alicia Y; Corella, Alexandra et al. (2015) Linking tumor mutations to drug responses via a quantitative chemical-genetic interaction map. Cancer Discov 5:154-67

Showing the most recent 10 out of 12 publications