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.
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