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

Myc癌基因被认为在许多不同类型的癌症中发挥作用，包括结直肠癌(CRC)。在家族性腺瘤性息肉病患者中，APC或β-catenin突变导致Myc基因的过度表达，进而驱动发生在结直肠癌腺瘤阶段的代谢变化。Myc基因的敲除被证明可以重置这种改变的新陈代谢，进而抑制细胞生长，使Myc成为预防结直肠癌的有吸引力的靶点，特别是在FAP患者中。 细菌Lon蛋白水解酶可以降低人类细胞和小鼠组织中c-myc的水平。此外，重组Lon(RLon)连续给药14天可减少Apcmin/+小鼠的肠息肉数量，提高存活率。在14天的治疗期间，无论是野生型还是Apcmin/+小鼠，都没有检测到明显的毒性迹象。值得注意的是，在健康的rLon蛋白酶处理的小鼠中，Myc的表达在肠道组织样本中没有受到强烈影响。与Apcmin/+小鼠相比，经rLon蛋白酶处理的健康小鼠的Myc相关基因的表达没有改变，这表明当Myc过表达时，Lon蛋白酶的作用可能更强。本任务顺序的目的是在PIRC大鼠结直肠癌模型中验证和扩展这些发现。

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.