The 5-year survival rate for pancreatic cancer patients is only 6%, the lowest of all major cancers, indicating a critical need for increased mechanistic understanding of pancreatic cancer development in order to identify new therapeutic targets. The c-Myc (Myc) oncoprotein is overexpressed in a variety of cancers, including pancreatic ductal adenocarcinoma (PDA), and generally correlates with poor prognosis. Through its global regulation of gene transcription, Myc helps regulate multiple oncogenic processes, including cancer cell intrinsic proliferation, survival, and adhesion/migration, as well as extrinsic tumor microenvironment remodeling including angiogenesis and immune cell reprogramming. The expression and activity of Myc is tightly regulated in normal cells. We have identified Serine 62 (S62) as a critical phosphorylation site, which increases the stability and DNA binding activity of Myc. S62 is phosphorylated downstream of RAS signaling; and activating mutations in KRAS are near universal driver mutations in PDA. The role of Myc in pancreatic cancer, however, is currently poorly understood. We have observed elevated levels of S62 phosphorylated Myc (pS62-Myc) in pancreatic cancer cell lines and primary pancreatic tumor samples. Furthermore, analysis of early precursor lesions (PanIN) peripheral to tumors also shows elevated pS62-Myc as compared to adjacent normal ducts. We have generated a novel mouse model, LSL-KRASG12D;ROSA-LSL-MycWT;Pdx1- or p48-Cre (KMC) mice, which shows that deregulated expression of Myc at physiologic levels is able to cooperate with mutant KRAS to accelerate acinar to ductal metaplasia (ADM), PanIN progression, and conversion to metastatic PDA. Importantly, our preliminary data indicate that KMC tumors develop common mutations seen in the evolution of the human disease, initiate a pronounced stromal reaction, show resistance to standard chemotherapy, and can progress to an aggressive, poorly differentiated PDA with a high metastatic rate. Further, we have established two therapeutics in the lab that target Myc post-translationally, both of which have shown promising activity against pancreatic cancer in vitro and in vivo. The overall hypothesis of this proposal is that KRAS-mediated phosphorylation of Myc at Serine 62 is an important driver of pancreatic cancer cell transformation, that this mechanism of activating Myc significantly contributes to the evolution of metastatic PDA, and that targeting post-translational activation of Myc has therapeutic efficacy in pancreatic cancer. The following aims are proposed:
Aim 1 : Elucidate the role of Myc and KRAS-mediated Serine 62 phosphorylation in the development of pancreatic cancer;
Aim 2 : Characterize KRAS/Myc-driven pancreatic tumor evolution, stromal expansion, heterogeneity, and therapeutic resistance;
Aim 3 : Establish the therapeutic efficacy of targeting post-translational activation of Myc for the treatment of pancreatic cancer. This work will reveal if phosphorylation of Myc downstream of KRAS plays a critical role in pancreatic cancer development and progression, and whether targeting this post-translational activation of Myc could have therapeutic value in the treatment of this devastating disease.
Pancreatic cancer is one of the most deadly of all cancers and it is predicted to become the second leading cause of cancer related deaths by the year 2020. Thus, there is a critical need to increase our understanding of the molecular drivers that cause pancreatic cancer to identify new therapeutic targets. We have identified the c-Myc oncoprotein as an early driver of pancreatic cancer, which has allowed us to develop a new mouse model of pancreatic cancer for preclinical testing, and we are investigating two novel therapeutic approaches to target c-Myc activity to inhibit pancreatic cancer.
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