Targeting SUMO1 degradation for advanced colon cancer therapy

项目总结/摘要 晚期结肠癌伴器官浸润和肝转移是结肠癌最常见的病因 死亡部分是由于对目前标准疗法的抵抗。该项目的最终目标是开发 小泛素相关修饰物1（SUMO 1）的小分子降解剂作为第一类抗癌药物， 治疗晚期结肠癌。为了实现这一目标，我们已经将SUMO 1确定为癌症药物 目标，开发了基于癌细胞的药物筛选，确定了命中化合物，并优化了更有效的 通过对命中化合物进行化学改性来引导化合物。研究药物靶向途径， 我们已经鉴定了结合细胞质活化/增殖相关蛋白-1（CAPRIN 1）的化合物， 并显示CAPRIN 1-CUL 1泛素连接酶复合物。在CAPRIN 1、SUMO 1降解剂结合后， 诱导SUMO 1向CAPRIN 1-CUL 1连接酶的募集，用于SUMO 1在癌症中的泛素化和降解 细胞使用遗传表征的人结肠癌细胞系、三维（3D）类器官和患者的 我们已经提供了原理证明，通过其降解剂靶向SUMO 1是一种有效的方法。 安全有效的结肠癌治疗方法。本项目的目的是研究其机制， SUMO 1降解剂单独和联合治疗晚期结肠癌的疗效 标准化疗为了实现这一目标，我们将首先评估先导化合物的治疗效果 目的1中晚期结肠癌的治疗。为此，我们将测试体内毒性、靶向接合、 使用遗传表征的晚期结肠癌的先导化合物的生物标志物和治疗功效 癌症PDX模型。接下来，我们将确定SUMO 1降解剂如何驱动糖酵解的代谢重编程 和在晚期结肠癌中的氨甲环酸解的抗癌活性（目的2）。我们将揭示 关于降解物如何调节代谢性StAR相关脂质转移的转录的类小泛素化 结构域蛋白7（STARD 7）在晚期结肠癌中的作用。最后，我们将确定机制和治疗 先导化合物联合标准化疗治疗晚期结肠癌的疗效观察 目标3中的癌症。特别是，我们将确定代谢酶G6 PD（葡萄糖-6-磷酸）是否 脱氢酶）被SUMO 1缀合，因此SUMO 1降解剂消除了其缀合和功能 并使结肠癌对标准化疗敏感。接下来，我们将评估 联合使用降解剂和化疗治疗一大批遗传特征的3D 类器官和PDX模型。完成后，我们预计，这个临床前项目将提供坚实的科学 为开发SUMO 1降解剂作为治疗晚期乳腺癌的一流抗癌药物奠定了基础 结肠癌，一种致命的人类疾病。

Project Summary/Abstract The advanced colon cancer with organ invasion and liver metastasis are the most common cause of colon cancer death in part due to the resistance to current standard therapies. The ultimate goal of this project is to develop small-molecule degraders of small ubiquitin-related modifier 1 (SUMO1) as the first-in-class anticancer drugs for treatment of advanced colon cancers. To achieve this goal, we have already identified SUMO1 as a cancer drug target, developed cancer cell-based drug screen, identified the hit compound, and optimized the more potent lead compounds through chemical modification of the hit compound. Investigating the drug-targeted pathway, we have identified the compound binding cytoplasmic activation/proliferation-associated protein-1 (CAPRIN1) and revealed the CAPRIN1-CUL1 ubiquitin ligase complex. Upon the binding of CAPRIN1, SUMO1 degraders induce the recruitment of SUMO1 to CAPRIN1-CUL1 ligase for SUMO1 ubiquitination and degradation in cancer cells. Using genetically characterized human colon cancer cell lines, 3-dimensional (3D) organoids and patient’s derived xenografts (PDXs), we have provided the proof-of-principle that targeting SUMO1 by its degraders is a safe and effective therapy for colon cancer. The objective of this project is to investigate the mechanism and therapeutic efficacy of SUMO1 degraders in treatment of advanced colon cancer, alone and in combination of the standard chemotherapy. To achieve this, we will first evaluate the therapeutic efficacy of the lead compounds in treatment of advanced colon cancer in Aim 1. To this end, we will test the in vivo toxicity, target engagement biomarker and therapeutic efficacy of the lead compounds using genetically characterized advanced colon cancer PDX models. Next, we will determine how SUMO1 degraders drive metabolic reprograming of glycolysis and glutaminolysis in advanced colon cancer for the anticancer activity (Aim 2). We will reveal the mechanism on how the degraders regulate the sumoylation of the transcription of the metabolic StAR-related lipid transfer domain protein-7 (STARD7) in advanced colon cancer. Finally, we will determine the mechanism and therapeutic efficacy of the combination of the lead compounds and standard chemotherapy in treatment of advanced colon cancer in Aim 3. In particular, we will determine whether the metabolic enzyme G6PD (glucose-6-phosphate dehydrogenase) is conjugated by SUMO1 and thus SUMO1 degraders eliminates its conjugation and functions and sensitize colon cancers to the standard chemotherapy. Next, we will evaluate the therapeutic efficacy of the combination of the degraders and chemotherapy in treatment of a large panel of genetically characterized 3D organoid and PDX models. Upon completion, we expect that this preclinical project will provide solid scientific foundation for development of SUMO1 degraders as the first-in-class anticancer drugs for treatment of advanced colon cancer, a deadly human disease.