We have recently shown that small molecule inhibitors of Chk1 abrogate the G2 checkpoint and inhibit HRR (homologous recombination repair) in pancreatic cancer cells. Importantly, Chk1 inhibition preferentially sensitizes p53-mutant tumor cells and K-Ras mutation may also confer sensitivity to Chk1 inhibition. PARP inhibitors have demonstrated preferential efficacy as single agents and as radiosensitizers in cells with other DNA damage repair defects. Thus, we hypothesize that inhibition of HRR (by the Chk1 inhibitor MK-8776) and PARP1 (by olaparib) will selectively sensitize pancreatic cancer cells to radiation. The long-term goal of our work is to improve the outcome of patients with pancreatic cancer (and other p53/K- Ras -mutant tumors) by selectively targeting DNA repair pathways (in combination with chemoradiation). The goals of this application are to combine inhibitors of DNA damage response pathways in order to improve gemcitabine-based chemoradiotherapy for pancreatic cancer as well as to understand the mechanisms of sensitization and tumor cell selectivity by Chk1 and PARP1 inhibition.
In Specific Aim 1 we will determine the mechanisms of tumor cell selectivity and radiosensitization by Chk1 and PARP1 inhibition. We will test the hypothesis that combined inhibition of Chk1 and PARP1 produce synergistic sensitization to DNA damage (radiation and gemcitabine-radiation) by increasing unrepaired double strand breaks selectively in p53- and K-Ras mutant pancreatic cancer cells. We will utilize normal cells as well as isogenic p53 and K-Ras cancer cells to determine the roles of p53 and K-Ras in selectivity. To address the mechanisms of radiosensitization in response to the combination of Chk1 and PARP1 inhibition in cancer cells, we will assess DNA damage, DNA damage responses, and HRR. To determine how Chk1 and PARP1 inhibitors interact to produce radiosensitization we will selectively manipulate the inhibitory effects of MK-8776 on HRR versus the G2 checkpoint.
In Specific Aim 2 we will test the hypothesis that combined Chk1 and PARP1 inhibition selectively sensitize p53 and K-Ras mutant pancreatic tumor xenografts to radiation and gemcitabine-radiation with minimal normal tissue sensitization. We will identify p53 and K- Ras -mutant patient-derived pancreatic tumors and determine the efficacy of combined Chk1 and PARP1 inhibition on sensitization to gemcitabine and radiation. To understand the mechanisms associated with sensitization, we will analyze key DNA damage response proteins identified in Aim 1. Duodenal toxicity, the dose limiting toxicity for irradiation of the pancreas, will be assessed in response to Chk1 and PARP1 inhibition in combination with radiation and gemcitabine-radiation. Successful completion of these aims will IMPACT therapy for patients with pancreatic cancer by providing new therapy options as well as biomarkers for patient selection. Our track record and team of investigators make it highly likely that we will succeed in the completion of these aims and their translation to the clinic.

Public Health Relevance

The long-term goal of our work is to improve the outcome of patients with pancreatic cancer by selectively targeting DNA repair pathways (in combination with chemoradiation). The goals of this application are to combine inhibitors of DNA damage response pathways in order to improve gemcitabine-based chemoradiotherapy for pancreatic cancer as well as to understand the mechanisms of sensitization and tumor cell selectivity by Chk1 and PARP1 inhibition. Successful completion of this project will IMPACT therapy for patients with pancreatic cancer by providing new therapy options as well as biomarkers for patient selection.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA163895-01A1
Application #
8372495
Study Section
Radiation Therapeutics and Biology Study Section (RTB)
Program Officer
Bernhard, Eric J
Project Start
2012-09-01
Project End
2017-06-30
Budget Start
2012-09-01
Budget End
2013-06-30
Support Year
1
Fiscal Year
2012
Total Cost
$303,194
Indirect Cost
$108,214
Name
University of Michigan Ann Arbor
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Parsels, Leslie A; Tanska, Daria M; Parsels, Joshua D et al. (2016) Dissociation of gemcitabine chemosensitization by CHK1 inhibition from cell cycle checkpoint abrogation and aberrant mitotic entry. Cell Cycle 15:730-9
Cuneo, Kyle C; Morgan, Meredith A; Davis, Mary A et al. (2016) Wee1 Kinase Inhibitor AZD1775 Radiosensitizes Hepatocellular Carcinoma Regardless of TP53 Mutational Status Through Induction of Replication Stress. Int J Radiat Oncol Biol Phys 95:782-90
Zhang, Qiang; Zhang, Yaqing; Parsels, Joshua D et al. (2016) Fbxw7 Deletion Accelerates Kras(G12D)-Driven Pancreatic Tumorigenesis via Yap Accumulation. Neoplasia 18:666-673
Zhang, Qiang; Karnak, David; Tan, Mingjia et al. (2016) FBXW7 Facilitates Nonhomologous End-Joining via K63-Linked Polyubiquitylation of XRCC4. Mol Cell 61:419-33
Morgan, Meredith A; Lawrence, Theodore S (2015) Molecular Pathways: Overcoming Radiation Resistance by Targeting DNA Damage Response Pathways. Clin Cancer Res 21:2898-904
Chatterjee, Moumita; Ben-Josef, Edgar; Thomas, Dafydd G et al. (2015) Caveolin-1 is Associated with Tumor Progression and Confers a Multi-Modality Resistance Phenotype in Pancreatic Cancer. Sci Rep 5:10867
Kausar, Tasneem; Schreiber, Jason S; Karnak, David et al. (2015) Sensitization of Pancreatic Cancers to Gemcitabine Chemoradiation by WEE1 Kinase Inhibition Depends on Homologous Recombination Repair. Neoplasia 17:757-66
Wei, Dongping; Zhang, Qiang; Schreiber, Jason S et al. (2015) Targeting mcl-1 for radiosensitization of pancreatic cancers. Transl Oncol 8:47-54
Ben-Josef, Edgar; George, Asha; Regine, William F et al. (2015) Glycogen Synthase Kinase 3 Beta Predicts Survival in Resected Adenocarcinoma of the Pancreas. Clin Cancer Res 21:5612-8
Estrada-Bernal, Adriana; Chatterjee, Moumita; Haque, S Jaharul et al. (2015) MEK inhibitor GSK1120212-mediated radiosensitization of pancreatic cancer cells involves inhibition of DNA double-strand break repair pathways. Cell Cycle 14:3713-24

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