DESCRIPTION (provided by applicant): The KRAS oncogene is mutated in ~95% of pancreatic ductal adenocarcinoma (PDAC). This, together with the well-established essential role for KRAS in PDAC initiation and maintenance, has placed KRAS targeting as a key priority for pancreatic cancer research. Unfortunately, no effective 'anti-Ras' therapies have been developed yet, prompting scientists to continue searching for the Ras 'Achilles' heel'. The MYC transcription factor is another well-validated potent oncogene, deregulated in gene expression in a majority of human cancers. Although KRAS-initiated lung cancers depend on Myc activity, a role for Myc in PDAC growth has not been demonstrated. In PDAC, unlike other cancer types, there is no evidence for frequent MYC gene amplification or increased gene transcription, yet increased protein expression is frequently detected. It is currently believed that K-Ras can block Myc protein degradation through activation of the PI3K-AKT and Raf- MEK-ERK pathways. This suggests that targeting of Myc protein stability is a possible therapeutic approach for KRAS-dependent PDAC. My preliminary data demonstrated a crucial role for Myc to maintain the in vitro growth of KRAS-mutant human PDAC cell lines and that K-Ras functions to maintain Myc protein stability through a mechanism more complex than currently believed. This provides the rationale for my aims in this proposal. I hypothesize that Myc is the 'Achilles' heel' for undruggable K-Ras in PDAC and that targeting Ras- mediated Myc protein stabilization would be a tractable pharmacologic approach against KRAS-dependent PDAC. Therefore the main objective of my proposal is to further delineate the K-Ras signaling mechanisms and downstream protein kinases that regulate Myc protein stability in PDAC. Toward this goal I will: 1) Define the role of Myc in KRAS-dependent pancreatic cancer growth. 2) Determine the mechanisms of Ras-dependent Myc protein stabilization. I will utilize orthotopic mouse models of PDAC to address the role of Myc in KRAS- dependent PDAC tumorigenic and malignant growth. In addition, a comprehensive immunohistochemical analysis of patient specimens will be performed in order to better evaluate the incidence and relevance of elevated Myc protein in PDAC. I will also determine the mechanisms by which Myc contributes to KRAS- dependent PDAC growth. Finally, I propose precise evaluation of the mechanisms by which K-Ras mediates Myc protein stabilization and mass spectrometry-based site mapping of Myc phosphorylation sites. In summary, I believe that my studies will lead to the identification of novel target kinases for effective anti-K-Ras therapy in this devastating disease. " |