Pancreatic cancer is a deadly disease characterized by late diagnosis, aggressive invasion of surrounding tissues, early metastasis, and resistance to therapy. There is an urgent need to develop highly effective, mechanism-based therapies to improve survival in these patients. We have recently found that the majority of human pancreatic adenocarcinomas specifically over-express the gene for Ataxia-Telangiectasia Group D Associated (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 identified ATDC as a novel DNA damage response gene that confers a survival advantage to pancreatic cancer cells when exposed to chemotherapy. We have shown that following DNA damage, ATDC traffics to the nucleus, is phosphorylated in response to gemcitabine and localizes to DNA repair foci. Loss of ATDC results in increased sensitivity to gemcitabine-induced apoptosis and a defect in downstream cell cycle checkpoint signaling. We have also found that high levels of ATDC confer a growth advantage to pancreatic cancer cells both in vitro and in vivo. The ATDC-mediated stimulation of cell proliferation may be due to enhancement of the beta-catenin pathway since overexpression of ATDC increases beta-catenin mediated transcription. We demonstrate that ATDC interacts with the HIT family protein HINT1, a negative regulator of the beta-catenin pathway, and we hypthesize that ATDC stimulates beta-catenin-mediated proliferation by sequestering HINT1. In this proposal, we will explore the following specific aims: 1) To examine the role of ATDC in the ATR-mediated DNA damage response. 2) To assess if ATDC's tumor promoting ability is linked to stimulation of the beta-catenin pathway through interactions with the HIT1 family protein HINT1. 3) To analyze the efficacy of targeting ATDC as a therapeutic modality in a pre-clinical, primary human pancreatic cancer orthotopic xenograft model.

Public Health Relevance

We propose that ATDC is a promising novel therapeutic target in pancreatic cancer because it's inactivation may lead to both reduced tumor growth and sensitization to chemotherapy.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA131045-04
Application #
8130938
Study Section
Developmental Therapeutics Study Section (DT)
Program Officer
Pelroy, Richard
Project Start
2008-09-01
Project End
2013-07-31
Budget Start
2011-08-01
Budget End
2013-07-31
Support Year
4
Fiscal Year
2011
Total Cost
$308,573
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Surgery
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Palmbos, Phillip L; Wang, Lidong; Yang, Huibin et al. (2015) ATDC/TRIM29 Drives Invasive Bladder Cancer Formation through miRNA-Mediated and Epigenetic Mechanisms. Cancer Res 75:5155-66
Wang, Lidong; Yang, Huibin; Abel, Ethan V et al. (2015) ATDC induces an invasive switch in KRAS-induced pancreatic tumorigenesis. Genes Dev 29:171-83
Wang, Lidong; Yang, Huibin; Palmbos, Phillip L et al. (2014) ATDC/TRIM29 phosphorylation by ATM/MAPKAP kinase 2 mediates radioresistance in pancreatic cancer cells. Cancer Res 74:1778-88
Proctor, Erica; Waghray, Meghna; Lee, Cheong Jun et al. (2013) Bmi1 enhances tumorigenicity and cancer stem cell function in pancreatic adenocarcinoma. PLoS One 8:e55820
Kothari, Vishal; Wei, Iris; Shankar, Sunita et al. (2013) Outlier kinase expression by RNA sequencing as targets for precision therapy. Cancer Discov 3:280-93
Kumar-Sinha, Chandan; Wei, Iris; Simeone, Diane M (2012) Emerging frontiers in pancreatic cancer research: elaboration of key genes, cells and the extracellular milieu. Curr Opin Gastroenterol 28:516-22
Wang, Lidong; Heidt, David G; Lee, Cheong J et al. (2009) Oncogenic function of ATDC in pancreatic cancer through Wnt pathway activation and beta-catenin stabilization. Cancer Cell 15:207-19