BASE TITLE: PREVENT PRECLINICAL DRUG DEVELOPMENT PROGRAM: PRECLINICAL EFFICACY AND INTERMEDIATE BIOMARKERSTASK ORDER TITLE: PREVENTING FAP-CRC USING

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The Myc oncogene is thought to play a role in many different types of cancer, including colorectal cancer (CRC). In individuals with familial adenomatous polyposis (FAP), Apc or β-catenin mutations lead to the overexpression of Myc, which in turn drives the metabolic alterations that occur at the adenoma stage of CRC carcinogenesis. The knockdown of Myc has been shown to reset this altered metabolism and in turn suppress cell growth, making Myc an attractive target for CRC prevention, especially in FAP patients. Bacterial Lon protease can reduce c-MYC levels in human cells and murine tissues. In addition, recombinant Lon (rLon) can reduce the number of intestinal polyps and increase the survival of Apcmin/+ mice when administered for 14 days. No gross signs of toxicity were detected during a 14-day treatment period in either wildtype or Apcmin/+ mice. Notably, in healthy rLon protease-treated mice, Myc expression was not strongly affected in intestinal tissue samples. In contrast to Apcmin/+ mice, expression of Myc-related genes in rLon protease-treated healthy mice were not altered, suggesting that the effects of Lon protease may be more potent when Myc is overexpressed. The purpose of this Task Order is to validate and expand upon these findings in the PIRC rat model of CRC.