Targeting SUMO1 degradation for advanced colon cancer therapy

针对晚期结肠癌治疗的 SUMO1 降解

• 批准号: 10654044
• 负责人: Anita Bellail
• 金额: $ 37.4万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10654044
• 关键词: 3-Dimensional; Affinity; Antineoplastic Agents; BRAF gene; Binding; Binding Proteins; Biological Markers; CRISPR screen; CRISPR/Cas technology; CUL1 gene; Cancer Model; Cessation of life; Chemicals; Clinical Treatment; Colon Carcinoma; Complex; Cytoplasm; Data; Development; Diagnosis; Dose; Drug Screening; Drug Targeting; Enzymes; Event; Foundations; Genes; Genetic Transcription; Genomics; Glucosephosphate Dehydrogenase; Glycolysis; Goals; Human; Interferometry; Invaded; Investigation; KRAS2 gene; Lead; Ligase; Lipids; Liquid Chromatography; Mediating; Metabolic; Metastatic Neoplasm to the Liver; Modification; Molecular; Mus; Mutation; No-Observed-Adverse-Effect Level; Nuclear Magnetic Resonance; Organ; Organoids; PF4 Gene; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacotherapy; Plasma; Proliferating; Proteins; Recombinants; Resistance; Solid; Sumoylation Pathway; TCF7L2 gene; Tertiary Protein Structure; Testing; Toxic effect; Toxicology; Treatment Efficacy; Tumor Burden; Ubiquitin; Ubiquitination; anticancer activity; beta catenin; cancer cell; chemotherapy; colon cancer cell line; colon cancer patients; colon cancer treatment; drug action; effective therapy; efficacious treatment; genome wide screen; genome-wide; human disease; in vivo evaluation; metabolomics; metastatic colorectal; mouse model; novel; patient derived xenograft model; pharmacologic; pre-clinical; preclinical study; recruit; refractory cancer; small molecule; tandem mass spectrometry; therapeutically effective; transcription factor; ubiquitin ligase; ubiquitin-protein ligase

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.

项目摘要/摘要 具有器官侵袭和肝转移的晚期结肠癌是结肠癌的最常见原因 死亡部分是由于对当前标准疗法的抵抗力。该项目的最终目标是开发 小分子降解者的小分子降解器与泛素相关的修饰剂1（SUMO1）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SUMO1确定为癌症药物 靶标，开发的基于癌细胞的药物筛查，鉴定了命中化合物，并优化了更有效的功能 铅化合物通过命中化合物的化学修饰。研究以药物为目标的途径， 我们已经确定了化合物结合细胞质激活/增殖相关蛋白-1（Caprin1） 并揭示了Caprin1-Cul1泛素连接酶复合物。 caprin1结合后，sumo1降解器 诱导SUMO1募集到caprin1-Cul1连接酶中用于SUMO1泛素化和降解癌症 细胞。使用一般表征的人类结肠癌细胞系，3维（3D）类器官和患者 派生的Xenographictics（PDXS），我们提供了原理证明的证明，其降级器靶向SUMO1是一个 结肠癌的安全有效疗法。该项目的目的是调查机制和 SUMO1降解者在治疗晚期结肠癌的治疗效率，单独并组合 标准化疗。为此，我们将首先评估铅化合物的治疗效率 在AIM 1中治疗晚期结肠癌时。为此，我们将测试体内毒性，目标参与 铅化合物的生物标志物和治疗效率使用一般表征的高级结肠 癌症PDX模型。接下来，我们将确定SUMO1降解器如何驱动糖酵解的代谢重编程 抗癌活性晚期结肠癌中的谷氨酰胺溶解（AIM 2）。我们将揭示机制 关于降解者如何调节代谢恒星相关脂质转移的转录的sumoylation 晚期结肠癌中的结构蛋白蛋白-7（stard7）。最后，我们将确定机制和治疗 铅化合物和标准化学疗法在治疗晚期结肠的功效 AIM 3中的癌症。特别是，我们将确定代谢酶G6PD（6-磷酸葡萄糖）是否是否 脱氢酶）由SUMO1偶联，因此SUMO1降解器消除了其偶联和功能 和对标准化疗的敏感结肠癌。接下来，我们将评估 降解器和化学疗法的组合在遗传表征3D方面的处理中 器官和PDX模型。完成后，我们预计这个临床前项目将提供扎实的科学 SUMO1降解器开发的基础是治疗晚期的第一类抗癌药物 结肠癌，一种致命的人类疾病。