Targeted therapies and immunotherapies are two of the most transformative and promising advances in cancer treatment over the last two decades. Yet they, like conventional chemotherapies, frequently succumb to the ability of cancers eventually to resist therapeutic attacks on their vulnerabilities, reversing the initially impressive clinical responses to these treatments. This project focuses on conserved non-mutational mechanisms of resistance that are frequently encountered in resistance arising in multiple therapeutic regimens across multiple cancer types. In the current phase of the CTD2 Network, we developed powerful new tools and capabilities that enable the community to identify novel cancer vulnerabilities. The method relies on the Cancer Therapeutics Response Portal (CTRP), which houses a large dataset of quantitative compound sensitivity data and has been made available without restriction. Using CTRP, we found evidence for the existence of at least one such common therapy-resistant state, associated with mesenchymal characteristics of cancer cells. Importantly, this state emerges from treatment with either chemotherapy or targeted therapeutics across several cancer types. This project aims to fully dissect this pathway, and to discover other such pathways, to understand the bases of resistant-state vulnerabilities, and to learn how to exploit them therapeutically in a safe and effective way.

Public Health Relevance

Overcoming resistance to cancer therapy has emerged as one of the most pressing and universal issues in oncology. We have developed powerful new tools and capabilities that enable the community to identify novel cancer vulnerabilities, including those that arise in cancer resistance. This project aims to 1) discover common drug-resistant cancer cell states, 2) define vulnerabilities of these cancer cell states, and 3) identify small molecules that can attack those vulnerabilities, providing a path forward for combination therapies aimed at curing cancers.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01CA217848-03
Application #
9742438
Study Section
Special Emphasis Panel (ZCA1)
Program Officer
Gerhard, Daniela
Project Start
2017-08-01
Project End
2022-07-31
Budget Start
2019-08-01
Budget End
2020-07-31
Support Year
3
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Broad Institute, Inc.
Department
Type
DUNS #
623544785
City
Cambridge
State
MA
Country
United States
Zip Code
02142
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