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

基本标题：预防临床前药物开发计划：临床前疗效和中间生物标志物订单标题：预防 FAP-CRC 使用

• 批准号: 10652736
• 负责人: CHINTHALAPALLY RAO
• 金额: $ 14.33万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-28 至 2022-12-27
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10652736
• 关键词: Adenocarcinoma; Affect; ApcMin/+ mice; Biological Markers; Cells; Colorectal Cancer; Development; Dose; Familial Adenomatous Polyposis Syndrome; Genes; Human; Individual; Intestinal Polyps; Intestines; Lead; MYC gene; Metabolic; Metabolism; Modeling; Mus; Mutation; Patients; Play; Polyps; Preclinical Drug Development; Program Development; Rattus; Recombinants; Role; Tissue Sample; Tissues; Toxic effect; adenoma; base; beta catenin; c-myc Genes; cancer type; carcinogenesis; cell growth; colorectal cancer prevention; endopeptidase La; knock-down; overexpression; preclinical efficacy; prevent; treatment duration

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.

MYC致癌基因被认为在许多不同类型的癌症（包括结直肠癌（CRC））中发挥作用。在具有家族性腺瘤性息肉病（FAP）的个体中，APC或β-catenin突变导致MYC的过表达，这又驱动了在CRC致癌腺瘤阶段发生的代谢改变。 MYC的敲低已被证明可以重置这种改变的新陈代谢，进而抑制细胞的生长，使MYC成为预防CRC的有吸引力的靶标，尤其是在FAP患者中。 细菌LON蛋白酶可以降低人类细胞和鼠组织中的C-MYC水平。此外，重组LON（RLON）可以减少肠道息肉的数量，并增加14天的APCMIN/+小鼠的存活率。在野生型或APCMIN/+小鼠的14天治疗期间，未检测到毒性的严重迹象。值得注意的是，在健康的RLON蛋白酶治疗的小鼠中，MYC的表达在肠道组织样品中没有受到强烈影响。与APCMIN/+小鼠相反，MYC相关基因在RLON蛋白酶治疗的健康小鼠中的表达没有改变，这表明当Myc过表达MYC时，LON蛋白酶的作用可能更有潜力。该任务顺序的目的是验证和扩展CRC的PIRC大鼠模型中的这些发现。