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.
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. ? ? ?
