Abrogating a survival pathway in early colon cancer cells

描述（申请人提供）：超过90%的遗传性和散发性结直肠癌是由腺瘤性结肠息肉病（APC）基因的初始突变引起的。随后的肿瘤发生是由染色体不稳定性增加，迅速纳入致癌突变。高度突变的结直肠癌通常是致命的;因此，防止早期细胞恶性化是对抗这种疾病的关键。理论上，APC突变引起的纺锤体和染色体分离缺陷将触发有丝分裂检查点、细胞周期停滞和凋亡细胞死亡，但大部分突变细胞逃脱了 检查点，成为非整倍体和多倍体-结肠癌的标志。最早的癌前细胞如何适应生存？在申请人的实验室中发表的工作已经揭示，Cdc 42，Rho亚家族的小GTdR，对于肠干细胞存活、分裂和分化至关重要。强有力的初步数据进一步证明，Cdc 42在息肉病发作之前在早期APCMin/+小鼠肠上皮中被激活，并且在携带<$-连环蛋白显性活性突变的小鼠的肠微腺瘤中被显著激活。升高的Cdc 42似乎使肿瘤细胞能够存活并在体内构建异常的隐窝样Wnt分泌肿瘤微环境。目的是解决早期结直肠肿瘤发生过程中促生存适应的机制，并探索Cdc 42抑制作为根除早期结直肠癌的一种手段。该假说是Cdc 42在APC和/或β-连环蛋白突变结直肠癌细胞中关键介导促生存适应和生态位构建;靶向Cdc 42将有效地消除体内这些流行类型的结直肠癌。目的I将探索Cdc 42抑制对人结直肠癌肿瘤发生的抑制效果;目的II将探索Cdc 42抑制对饮食致癌物诱导的结直肠癌小鼠模型的肿瘤发生的效果。这项由高风险体内实验组成的探索性项目意义重大，因为它测试了新型Cdc 42小分子抑制剂对结肠癌自然发病机制的有效性，这将为药物发现和改进打开大门。在我们看来，这个项目是创新的，因为它探索了在一种新的小鼠结肠癌模型中通过一种新的小GTdR抑制剂诱导“合成致死性”的概念，该模型重现了人类疾病对应物的自然发病机制。该项目的成功完成有望大大提高我们对结直肠癌细胞适应机制的基础和临床理解。

DESCRIPTION (provided by applicant): Over 90% hereditary and sporadic colorectal cancers are caused by initial mutation in the adenomatous polyposis coli (APC) gene. The subsequent tumorigenesis is fueled by increased chromosomal instability, which rapidly incorporates oncogenic mutations. Hypermutated colorectal cancers are often lethal; therefore preventing early-stage cells from becoming malignant is key to combating this disease. The spindle and chromosomal segregation defects elicited by APC mutations would, in theory, trigger the mitotic checkpoint, cell cycle arrest, and apoptotic cell death, yet a great portion of mutant cells escape the checkpoint, becoming aneuploid and polyploidy-hallmarks of colon cancers. How do the earliest precancerous cells adapt for survival? Published work in the applicant's lab has revealed that Cdc42, a small GTPase of the Rho subfamily, is critical for intestinal stem cell survival, division, and differentiation. Strong preliminary data further demonstrate that Cdc42 is activated in early APCMin/+ mouse intestinal epithelia, prior to the onset of polyposis, and dramatically activated in intestinal microadenomas in mice carrying ¿-catenin-dominant active mutation. Elevated Cdc42 appears to render tumor cells capable of survival and constructing aberrant crypt-like Wnt-secreting tumor microenvironments in vivo. The objective is to tackle the mechanism of pro-survival adaptation during early colorectal tumorigenesis, and to explore Cdc42-inhibition as a means of eradicating early-stage colorectal cancers. The hypothesis is that Cdc42 critically mediates pro-survival adaptation and niche construction in APC and/or ¿-catenin mutant colorectal cancer cells; and targeting Cdc42 will effectively abrogate these prevalent types of colorectal cancer in vivo. Aim I will explore the suppressive efficacy of Cdc42 inhibition on human colorectal cancer tumorigenesis; and Aim II will explore the efficacy of Cdc42 inhibition on the tumorigenesis of a dietary carcinogen-induced colorectal cancer mouse model. This exploratory project composed of high-risk in vivo experiments is significant because it tests the efficacy of novel Cdc42 small molecule inhibitor on the natural pathogenesis of colon cancers, which will open the door for drug discovery and improvement. This project is, in our view, innovative because it explores the concept of inducing "synthetic lethality" by a new small GTPase inhibitor in a novel mouse colon cancer model that recapitulates the natural pathogenesis of human disease counterpart. Successful completion of this project is expected to greatly elevate our basic and clinical understanding of the mechanism of adaptation in colorectal cancer cells.