Kinetic analysis of Myc-induced carcinogenesis in vivo

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DESCRIPTION (provided by applicant): Expression of the c-myc oncogene is deregulated in almost all cancers. c-myc encodes a transcription factor, Myc, that coordinates the many diverse intra and extracellular biological programs that underpin normal and tumor cell proliferation, including cell proliferation, metabolism, biosynthesis, invasion, de-differentiation and angiogenesis. Its pivotal role in maintaining so many disparate aspects of cell proliferation make it a superb potential target for therapeutic inhibition in cancer. Recently, we reduced this idea to practice using a genetic mouse model for Myc inhibition by showing that systemic inhibition of Myc triggers rapid and complete tumor regression in a preclinical mouse model of Non Small Cell Lung Cancer driven by mutant K-Ras, while eliciting only mild, well-tolerated and completely reversible side effects in normal proliferating tissues. Our subsequent work has now validated the therapeutic efficacy of Myc inhibition in other tumor types driven by other oncogenes in other tissues, raising the tantalizing possibility that inhibition of Myc might be the basis for a generalized anti-cancer therapeutic. In response to notice number NOT-OD-09-058 "NIH Announces the Availability of Recovery Act Funds for Competitive Revision Applications", we propose to extend these initial studies by ascertaining the therapeutic impact of systemic Myc inhibition in vivo in pancreatic adenocarcinoma, one of the most intractable and deadly cancers, using a well validated preclinical mouse model. We will also ascertain the use of Myc inhibition therapy in combination with several other therapeutic modalities - restoration of the p53 tumor suppressor and standard of care chemotherapy with gemcitabine. In a second aim, we will establish how best to target Myc at the molecular level, so paving the way for the rational design of a Myc inhibitory drug. PUBLIC HEALTH RELEVANCE: Currently, there is great interest in the idea of personalized therapy for cancer, based on the notion that each patient's cancer is distinct. However, despite clear idiopathic differences in individual patients' tumors, there remains substantial evidence that cancers also share common, obligate aberrant elements that, if adroitly targeted, might offer generic therapeutic options. One of these is Myc - a pleiotropic transcription factor whose function is deregulated in almost all human cancers. We have developed unique and sophisticated, switchable genetic pre-clinical mouse model with which to ascertain the therapeutic value of inhibiting Myc in established cancers and shown it to be effective at triggering regression in several tumor types. Hence, Myc inhibition may be an effective therapy for treating many cancers, including those currently incurable. In this proposal, we will ascertain the value of Myc inhibition-based therapy for treating pancreatic adenocarcinoma, one of the most intractable and deadly of all cancers with a mean survival post diagnosis of only 5 months and for which there are no effective therapeutic options.