Camptothecin (CPT) is a potent inhibitor of cell proliferation, and camptothecin derivatives, such as irinotecan and topotecan, have proven valuable in treatment of solid tumors. The goal of this project to develop a clearer mechanistic and molecular understanding of repair of CPT-induced DNA damage, and to apply this knowledge to developing a rapid assay for CPT-sensitivity based on repair capability. We propose three specific aims to that end. (1) We will determine the molecular mechanism by which MRE11 contributes to repair of CPT-induced DNA damage. (2) We will elucidate the roles of RecQ family helicases and G4 DNA in CPT sensitivity. (3) We will test the utility of y-sH2AX as a biomarker for chemotherapeutic sensitivity and DNA repair. The results of the proposed research will provide an important step toward improved treatment of cancer based on stratification of tumor response to CPT.

Public Health Relevance

By applying basic understanding of DNA repair mechanisms to cancer therapy, the proposed research will define an opportunity for personalized medicine which has not heretofore been exploited, and provide a guide for stratification of tumors based on response to chemotherapy.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA077852-15
Application #
8494584
Study Section
Special Emphasis Panel (ZCA1-GRB-S)
Project Start
Project End
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
15
Fiscal Year
2013
Total Cost
$253,608
Indirect Cost
$71,026
Name
University of Washington
Department
Type
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
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