The overall goal of this proposal is to understand and target cancer cell addictions to stress- tolerance pathways. We have discovered that cancer cells maintain proliferation by engaging in a pathway known as translesion synthesis (TLS). By employing TLS, cancer cells are able to replicate in a continuous manner and subvert the replication stress response. Here, we propose to implement state-of-the-art assays to analyze how cancer cells alter DNA replication fork dynamics and replisome components to promote TLS. By defining the core TLS machinery, we will seek to identify biomarkers and novel targets of TLS. Importantly, we have developed a small molecule inhibitor of TLS that selectively halts DNA replication in several cancer cell lines that are dependent on TLS. Moreover, we found that the colony forming potential of TLS-dependent cancer cells is dramatically reduced upon inhibition of TLS. Thus, we propose to identify the scope of TLS dependent cancers using cell screening and data base analysis. In addition, to fully further develop the therapeutic potential of TLS inhibition, we propose to measure and improve the anti- cancer potential of our lead small molecules. Collectively, these proposed studies will identify how cancer cells engage TLS and how best to block TLS to selectively target cancer.

Public Health Relevance

The overall goal of this proposal is to understand and target cancer cell addictions to stress- tolerance pathways. We have identified that many different cancer cells employ translesion synthesis (TLS) to replicate in a continuous manner and subvert the replication stress response. Here, we will implement state-of-the-art assays to analyze how TLS alters DNA replication fork dynamics, replisome components, and identify cancers dependent on TLS in order to fully develop the anti-cancer potential of our lead small molecule inhibitors of TLS.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA247232-02
Application #
10116341
Study Section
Radiation Therapeutics and Biology Study Section (RTB)
Program Officer
Oberdoerffer, Philipp
Project Start
2020-03-01
Project End
2025-02-28
Budget Start
2021-03-01
Budget End
2022-02-28
Support Year
2
Fiscal Year
2021
Total Cost
Indirect Cost
Name
University of Massachusetts Medical School Worcester
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
603847393
City
Worcester
State
MA
Country
United States
Zip Code
01655