Pancreatic cancer is a deadly disease characterized by late diagnosis, aggressive invasion of sun'ounding tissues, eariy metastasis, and resistance to therapy. The molecular basis of pancreatic cancer is incompletely understood. We have recently found that the majority of human pancreatic adenocarcinomas specifically over-express the gene for Ataxia-Telangiectasia Group 0 Complemented (ATDC). The ATDC gene was initially described in association with the genetic disorder ataxia-telangiectasia (AT) but was later found not to be the gene responsible for that disorder, and it's function remained unknown. We have found that high levels of expression of endogenous ATDC confer a growth advantage of pancreatic cancer cells both in vitro and in vivo by stabilization of beta-catenin. We have also identified ATDC as a novel DNA damage response gene that confers a survival advantage to pancreatic cancer cells exposed to iradiation therapy (RT) or the chemotherapeutic drug gemcitabine which are agents used for standard care of pancreatic cancer patients. We show that ATDC traffics to the nucleus and that loss of ATDC results in radioresistant DNA synthesis and a defect in downstream cell cycle checkpoint activation signaling. In this proposal, we will investigate the molecular mechanisms by which ATDC functions in the response to the combination of ionzing gemcitabine and RT. The experiments will test the hypothesis that ATDC is an important stress response regulator in both ATM- and ATR-mediated signaling cascades. Furthermore, we will analyze the effect of targeting ATDC in combination with gemcitabine and RT as a therapeutic modality in pancreatic cancer using a xenograft mouse model and immunoliposomes canning ATDC-targeting shRNA. The results from these preclinical animal studies will be used as a guide in the development of a clinical trial where ATDC will be targeted in pancreatic cancer cells prior to standard treatment with gemcitabine and RT. We propose that ATDC is a promising novel therapeutic target for both slowing the growth of pancreatic tumors as well as making them more susceptible to treatment with the combination of gemcitabine and RT.

Agency
National Institute of Health (NIH)
Type
Specialized Center (P50)
Project #
5P50CA130810-05
Application #
8729830
Study Section
Special Emphasis Panel (ZCA1)
Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Type
DUNS #
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Dong, Liang; Zou, Hechang; Yuan, Chong et al. (2016) Different Fatty Acids Compete with Arachidonic Acid for Binding to the Allosteric or Catalytic Subunits of Cyclooxygenases to Regulate Prostanoid Synthesis. J Biol Chem 291:4069-78
Satagopan, Jaya M; Sen, Ananda; Zhou, Qin et al. (2016) Bayes and empirical Bayes methods for reduced rank regression models in matched case-control studies. Biometrics 72:584-95
Gifford, Gail B; Demitrack, Elise S; Keeley, Theresa M et al. (2016) Notch1 and Notch2 receptors regulate mouse and human gastric antral epithelial cell homoeostasis. Gut :
Umoh, Faith I; Kato, Ikuko; Ren, Jianwei et al. (2016) Markers of systemic exposures to products of intestinal bacteria in a dietary intervention study. Eur J Nutr 55:793-8
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
Kirkconnell, Killeen S; Paulsen, Michelle T; Magnuson, Brian et al. (2016) Capturing the dynamic nascent transcriptome during acute cellular responses: The serum response. Biol Open 5:837-47
Ziemke, Elizabeth K; Dosch, Joseph S; Maust, Joel D et al. (2016) Sensitivity of KRAS-Mutant Colorectal Cancers to Combination Therapy That Cotargets MEK and CDK4/6. Clin Cancer Res 22:405-14
Sidahmed, ElKhansa; Sen, Ananda; Ren, Jianwei et al. (2016) Colonic Saturated Fatty Acid Concentrations and Expression of COX-1, but not Diet, Predict Prostaglandin E2 in Normal Human Colon Tissue. Nutr Cancer 68:1192-201
Dong, Liang; Zou, Hechang; Yuan, Chong et al. (2016) Interactions of 2-O-arachidonylglycerol ether and ibuprofen with the allosteric and catalytic subunits of human COX-2. J Lipid Res 57:1043-50
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

Showing the most recent 10 out of 83 publications