Poly (ADP-ribose) polymerase inhibitors (PARPis) have clinical promise, but their potential has yet to be fully realized. These drugs have shown efficacy in hereditary breast cancers with defects in BRCA1/2 that participate in a particular form of DNA double strand break (DSB) repair, homologous recombination (HR). However, PARPi studies in sporadic triple negative breast cancers and other tumor types have been disappointing. We have recently shown that an alternative and highly error-prone pathway that involves PARP- 1 is significantly increased in multiple sporadic cancers, including triple negative breast cancer and leukemia (chronic and acute myeloid leukemia [CML and AML]). The central goal of this application is to test the novel hypothesis that sensitivity to PARP inhibitors is dependent, in part, on ALT NHEJ. Studies in Aim 1 will determine the extent to which sensitivity to PARPis is dependent on ALT NHEJ activity in breast and leukemia cell lines that have already been demonstrated with high ALT NHEJ, compared with immortalized non-tumorigenic cells in which ALT NHEJ is low. The first part of this aim will focus on the effects of PARPis on ALT NHEJ activity, using state of the art assays that measure ALT NHEJ. The second part of this aim will determine the extent to which ALT NHEJ activity is required for cell survival. Studie in Aim 2 will focus on AML, for which novel therapies are urgently required. We will determine the relationship between ALT NHEJ and sensitivity to PARPis in primary AML cells using in vitro assays and innovative bioluminescence-based xenograft models of AML in vivo. These studies may shed further light on the molecular mechanisms underlying sensitivity to PARPis. Moreover, these studies may uncover potential novel biomarker concepts for predicting those cancer patients most likely to benefit from PARPis, hopefully provide a compelling rationale for the development of this novel therapeutic strategy for sporadic cancers with high ALT NHEJ activity.

Public Health Relevance

PARP inhibitors have potential clinical promise, but their use has been restricted to a small group of patients with hereditary breast cancer that have BRCA1/2 deficiency. This grant application will test the novel concept that sensitivity to PARP inhibitors is also dependent on a highly error-prone DSB repair pathway, ALT NHEJ, in which PARP-1 participates, but that has abnormally increased activity in many sporadic breast cancer and leukemia cells. These studies will generate key preclinical data validating biomarkers for the identification of this DNA repair defect and provide a compelling rationale for the development of this novel therapeutic strategy for sporadic cancers with high ALT NHEJ activity.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21CA186974-02
Application #
9102038
Study Section
Special Emphasis Panel (ZCA1)
Program Officer
Mufson, R Allan
Project Start
2015-07-01
Project End
2017-06-30
Budget Start
2016-07-01
Budget End
2017-06-30
Support Year
2
Fiscal Year
2016
Total Cost
Indirect Cost
Name
University of Maryland Baltimore
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201