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 #
5P01CA077852-12
Application #
8079584
Study Section
Special Emphasis Panel (ZCA1)
Project Start
Project End
Budget Start
2010-07-01
Budget End
2011-06-30
Support Year
12
Fiscal Year
2010
Total Cost
$278,537
Indirect Cost
Name
University of Washington
Department
Type
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Orozco, Javier I J; Knijnenburg, Theo A; Manughian-Peter, Ayla O et al. (2018) Epigenetic profiling for the molecular classification of metastatic brain tumors. Nat Commun 9:4627
Schmitt, Michael W; Pritchard, Justin R; Leighow, Scott M et al. (2018) Single-Molecule Sequencing Reveals Patterns of Preexisting Drug Resistance That Suggest Treatment Strategies in Philadelphia-Positive Leukemias. Clin Cancer Res 24:5321-5334
Mikheev, Andrei M; Mikheeva, Svetlana A; Severs, Liza J et al. (2018) Targeting TWIST1 through loss of function inhibits tumorigenicity of human glioblastoma. Mol Oncol 12:1188-1202
Lee, Su-In; Celik, Safiye; Logsdon, Benjamin A et al. (2018) A machine learning approach to integrate big data for precision medicine in acute myeloid leukemia. Nat Commun 9:42
Salk, Jesse J; Schmitt, Michael W; Loeb, Lawrence A (2018) Enhancing the accuracy of next-generation sequencing for detecting rare and subclonal mutations. Nat Rev Genet 19:269-285
Davis, Luther; Zhang, Yinbo; Maizels, Nancy (2018) Assaying Repair at DNA Nicks. Methods Enzymol 601:71-89
Yu, Ming; Heinzerling, Tai J; Grady, William M (2018) DNA Methylation Analysis Using Droplet Digital PCR. Methods Mol Biol 1768:363-383
Knijnenburg, Theo A; Wang, Linghua; Zimmermann, Michael T et al. (2018) Genomic and Molecular Landscape of DNA Damage Repair Deficiency across The Cancer Genome Atlas. Cell Rep 23:239-254.e6
Poston, Jacqueline N; Becker, Pamela S (2017) Controversies Regarding Use of Myeloid Growth Factors in Leukemia. J Natl Compr Canc Netw 15:1551-1557
Kamath-Loeb, Ashwini S; Zavala-van Rankin, Diego G; Flores-Morales, Jeny et al. (2017) Homozygosity for the WRN Helicase-Inactivating Variant, R834C, does not confer a Werner syndrome clinical phenotype. Sci Rep 7:44081

Showing the most recent 10 out of 137 publications