Attempts to improve therapy for pancreatic adenocarcinoma patients have largely failed to meaningfully improve survival. Therefore, there is a critical need for identification of specific molecular changes that define prognosis and guide therapy decisions. Mutations in the BRCA1 and BRCA2 cancer susceptibility genes, which are associated with defects in homologous recombination repair (HRR) of DNA double strand breaks, are prime examples of such predictive and prognostic biomarkers. Specifically, BRCA1 and BRCA2 mutations are associated with hypersensitivity to PARP inhibitors, which accentuate the formation of DNA double strand breaks in HRR deficient cells. While mutations in BRCA1, BRCA2, PALB2 and ATM are associated with 5% to 8% of pancreatic cancer patients, alterations in other genes that also confer sensitivity to PARP inhibitors, may be present in 15% to 20% of pancreatic tumors. We hypothesize that PARP inhibitor therapy will improve survival for pancreatic cancer patients, when patients are selected for defects in the HRR machinery. We propose to investigate the impact of rucaparib (CO-338) on HRR deficient pancreatic cancer cells based on preclinical studies showing that rucaparib is cytotoxic to BRCA2 deficient cells and has greater effects on HRR deficient pancreatic cancer cells than other PARP inhibitors.
In Aim 1 we will characterize the influence of mediators of HRR activity on response to PARP inhibitors in pancreatic cancer. In particular, we will assess whether defects in cancer susceptibility genes and somatic alterations in genes implicated in HRR deficiency influence rucaparib response in pancreatic cancer cells.
In Aim 2 we will investigate the ability of DNA instability and gene expression-based models, that identify DNA damage response deficient tumors, to predict response to chemotherapy in pancreatic tumors.
In Aim 3 we will conduct a Phase II study of rucaparib in chemotherapy refractory HRR deficient pancreatic cancer. We will select participants by rapidly screening patients for defects in HRR associated genes using a rapid throughput DNA repair gene sequencing test. In vitro cell line models and patient materials from the phase II trial will then be used to explore mechanisms of resistance to rucaparib.

Public Health Relevance

The study will provide insight into the utility of rucaparib as an effective therapy for pancreatic cancer, in the setting of HRR deficiency, perhaps identifying a substantial subset of patients who can derive significant benefit from the regimen. In addition, laboratory studies identifying the signaling pathways that regulate the response or resistance to rucaparib in pancreatic tumors will allow refinement of the subset of patients most suited to this form of therapy.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
2P50CA102701-11A1
Application #
8738914
Study Section
Special Emphasis Panel (ZCA1-RPRB-0 (M1))
Project Start
2014-09-18
Project End
2019-08-31
Budget Start
2014-09-18
Budget End
2015-08-31
Support Year
11
Fiscal Year
2014
Total Cost
$287,535
Indirect Cost
$106,695
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
Kim, Jungsun; Bamlet, William R; Oberg, Ann L et al. (2017) Detection of early pancreatic ductal adenocarcinoma with thrombospondin-2 and CA19-9 blood markers. Sci Transl Med 9:
Espindola-Netto, Jair Machado; Chini, Claudia C S; Tarragó, Mariana et al. (2017) Preclinical efficacy of the novel competitive NAMPT inhibitor STF-118804 in pancreatic cancer. Oncotarget 8:85054-85067
Pathangey, Latha B; McCurry, Dustin B; Gendler, Sandra J et al. (2017) Surrogate in vitro activation of innate immunity synergizes with interleukin-7 to unleash rapid antigen-driven outgrowth of CD4+ and CD8+ human peripheral blood T-cells naturally recognizing MUC1, HER2/neu and other tumor-associated antigens. Oncotarget 8:10785-10808
Javeed, Naureen; Mukhopadhyay, Debabrata (2017) Exosomes and their role in the micro-/macro-environment: a comprehensive review. J Biomed Res 31:386-394
Blackburn, Patrick R; Tischer, Alexander; Zimmermann, Michael T et al. (2017) A Novel Kleefstra Syndrome-associated Variant That Affects the Conserved TPLX Motif within the Ankyrin Repeat of EHMT1 Leads to Abnormal Protein Folding. J Biol Chem 292:3866-3876
Walz, Amy; Ugolkov, Andrey; Chandra, Sunandana et al. (2017) Molecular Pathways: Revisiting Glycogen Synthase Kinase-3? as a Target for the Treatment of Cancer. Clin Cancer Res 23:1891-1897
Yellow, Winta; Bamlet, William R; Oberg, Ann L et al. (2017) Association between Alcohol Consumption, Folate Intake, and Risk of Pancreatic Cancer: A Case-Control Study. Nutrients 9:
Luo, Kuntian; Li, Yunhui; Yin, Yujiao et al. (2017) USP49 negatively regulates tumorigenesis and chemoresistance through FKBP51-AKT signaling. EMBO J 36:1434-1446
Liou, Geou-Yarh; Bastea, Ligia; Fleming, Alicia et al. (2017) The Presence of Interleukin-13 at Pancreatic ADM/PanIN Lesions Alters Macrophage Populations and Mediates Pancreatic Tumorigenesis. Cell Rep 19:1322-1333
Cho, Dong Seong; Doles, Jason D (2017) Single cell transcriptome analysis of muscle satellite cells reveals widespread transcriptional heterogeneity. Gene 636:54-63

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