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 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)。在患有家族性腺瘤性息肉病 (FAP) 的个体中，Apc 或 β-catenin 突变导致 Myc 过度表达，进而驱动 CRC 癌变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代谢，进而抑制细胞生长，使 Myc 成为 CRC 预防的有吸引力的目标，特别是在 FAP 患者中。 细菌 Lon 蛋白酶可以降低人体细胞和小鼠组织中的 c-MYC 水平。此外，重组 Lon (rLon) 给药 14 天后可以减少肠息肉的数量并增加 Apcmin/+ 小鼠的存活率。在 14 天的治疗期间，野生型或 Apcmin/+ 小鼠均未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，肠道组织样本中的 Myc 表达并未受到强烈影响。与 Apcmin/+ 小鼠相比，rLon 蛋白酶处理的健康小鼠中 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有效。本任务指令的目的是在 PIRC 大鼠 CRC 模型中验证并扩展这些发现。