Harnessing the CRL4 ubiquitin ligase for antagonizing colorectal carcinogenesis

利用 CRL4 泛素连接酶对抗结直肠癌的发生

基本信息

批准号：
9261925
负责人：
Pengbo Zhou
金额：
$ 51.39万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-01-17 至 2021-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9261925
关键词：
Adverse effects American Cancer Society Attention Attenuated Biochemical Biological Markers Biology CUL4A gene Camptothecin Cancer Etiology Cancer Model Cells Cessation of life Chemicals Cleaved cell Clinic Clinical Clinical Trials Collection Colonic Adenoma Colonoscopy Colorectal Cancer Colorectal Neoplasms Combination Drug Therapy Computational Biology DNA DNA Damage Data Decision Making Diagnosis Drug Targeting FDA approved Family Fluorouracil Genes Genetic Hand IL2RA gene In Vitro Intervention Intestines Knockout Mice Laboratories Laboratory Study Lead Lesion Leucovorin Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of ovary Malignant neoplasm of prostate Measures Memorial Sloan-Kettering Cancer Center Normal tissue morphology Nude Mice Oncologist Pathology Patient-Focused Outcomes Patients Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacology Platinum Polyps Premalignant Prognostic Marker Property Prospective Studies Refractory Regimen Research Personnel Resistance Resources Retrospective Studies Safety Sampling Solid Neoplasm Specimen Structure Therapeutic Therapeutic Agents Topoisomerase-I Inhibitor Toxic effect Treatment Efficacy Treatment outcome Tumor Bank Tumor Pathology Tumor-Derived Type I DNA Topoisomerases United States Vertebral column Xenograft Model Xenograft procedure base cancer cell cancer therapy chemotherapeutic agent chemotherapy cohort colon cancer cell line colon cancer patients colon carcinogenesis cytotoxic cytotoxicity diagnostic biomarker high throughput screening in vivo inhibitor/antagonist irinotecan killings malignant breast neoplasm metastatic colorectal mouse model new therapeutic target novel therapeutics oncology overexpression paralogous gene pre-clinical predictive marker prospective response screening small hairpin RNA small molecule small molecule inhibitor structural biology synergism therapeutic target tool treatment planning tumor tumor xenograft ubiquitin ligase

项目摘要

Colorectal cancer (CRC) is the 4th most common cancer and the 2nd leading cause of cancer–related deaths in the United States. The American Cancer Society estimates that 134,490 people will be diagnosed and 49,190 will die from CRC in 2016. Although biologic agents have received much attention, the first-line chemotherapy for treatment of metastatic CRC remains based on a cytotoxic combination chemotherapy backbone of either FOLFIRI (folinic acid+5-FU+irinotecan) or FOLFOX (folinic acid+5-FU+oxilaplatin). It is noteworthy that only 18-25% of CRC patients respond favorably to irinotecan. Although the FDA-approved irinotecan has been used in clinic for 20 years, there is still no diagnostic biomarker to help oncologists decide which of the two regimens is more likely to be effective for a given CRC patient. Our studies suggest that the CULLIN 4B (CUL4B) ubiquitin ligase is a promising predictive biomarker, as well as a therapeutic target for tumor response to irinotecan. The CUL4B gene has been found amplified or overexpressed in a wide range of solid tumors, including colorectal, breast, lung, ovarian, and prostate cancers. Upon treatment with the camptothecin family of chemotherapy drugs, CUL4B, but not its paralog CUL4A, targets topoisomerase I (Top1) for degradation in cancer cells. As a result, CRCs with high levels of CUL4B expression induce excessive destruction of Top1, effectively attenuating the cytotoxicity of this chemotherapy drug. We hypothesize that excessive Top1 degradation by CUL4B is a major mechanism by which CRCs become refractory to irinotecan. Importantly, we showed that inactivation of CUL4B, but not CUL4A, effectively sensitized irinotecan-resistant CUL4Bhigh tumors to cytotoxic killing by Top1-directed chemotherapy drugs. This data suggest that CUL4B is an attractive target for intervention, potentially leading to sensitization of the 75-82% CRC patients who were previously resistant to treatment with a Top1-directed chemotherapeutic agent (e.g. FOLFIRI regimen). In three specific aims, we will (1) assess the value of CUL4B as a biomarker for treatment decisions of CRC using our unique collection of 572 well annotated CRC patient samples treated with irinotecan or FOLFIRI; (2) further develop and validate potent small molecule CUL4B inhibitors we identified via high throughput screening to increase their potency and pharmacological properties; (3) examine our lead CUL4B inhibitors that synergize with irinotecan to enhance its tumoricidal activity in vivo using CRC cell line xenografts, genetic WNT/APC-induced intestinal and colon adenomas, and patient-derived tumor xenograft (PDTX) models of CRC. We are uniquely prepared for both Laboratory-to-Clinic studies to develop a predictive biomarker for irinotecan-based chemotherapy that is immediately applicable for informing decision- making of CRC management in the clinic, and Clinic-to-Laboratory studies aimed at validating CUL4B as a feasible drug target in pre-clinical CRC models, and developing a new therapeutic agent to render CUL4Bhigh CRC patients, which represent approximately 75% of all CRCs, sensitive to irinotecan-based therapy.

结直肠癌 (CRC) 是第四大常见癌症，也是癌症相关死亡的第二大原因美国癌症协会估计将有 134,490 人被诊断出来。 2016年将有49,190人死于结直肠癌。虽然生物制剂备受关注，但一线药物转移性结直肠癌的化疗仍以细胞毒性联合化疗为基础 FOLFIRI（亚叶酸+5-FU+伊立替康）或FOLFOX（亚叶酸+5-FU+奥拉铂）的骨架。值得注意的是，尽管 FDA 批准了伊立替康，但只有 18-25% 的 CRC 患者有良好反应。伊立替康已在临床使用20年，但仍然没有诊断生物标志物可以帮助肿瘤学家做出决定我们的研究表明，这两种治疗方案中哪一种更有可能对特定的 CRC 患者有效。 CULLIN 4B (CUL4B) 泛素连接酶是一种有前途的预测生物标志物，也是以下疾病的治疗靶点已发现 CUL4B 基因在多种肿瘤中扩增或过度表达。实体瘤，包括结直肠癌、乳腺癌、肺癌、卵巢癌和前列腺癌。喜树碱家族化疗药物 CUL4B（但不是其旁系同源物 CUL4A）靶向拓扑异构酶 I (Top1) 癌细胞中的降解结果，具有高水平 CUL4B 表达的 CRC 会诱导产生。 Top1的过度破坏，有效减弱了这种化疗药物的细胞毒性。 CUL4B 导致的 Top1 过度降解是 CRC 变成的主要机制重要的是，我们发现 CUL4B 的灭活有效，但 CUL4A 的灭活则不然。使伊立替康耐药的 CUL4Bhigh 肿瘤对 Top1 定向化疗药物的细胞毒性杀伤敏感。该数据表明 CUL4B 是一个有吸引力的干预目标，可能导致对 75-82% 的 CRC 患者先前对 Top1 定向化疗药物治疗有耐药性（例如 FOLFIRI 方案）。在三个具体目标中，我们将 (1) 评估 CUL4B 作为生物标志物的价值。使用我们独特收集的 572 份经过详细注释的 CRC 患者样本收集的 CRC 治疗决策与伊立替康或 FOLFIRI 一起使用；(2) 进一步开发和验证有效的小分子 CUL4B 抑制剂通过高通量筛选鉴定以提高其效力和药理学特性；（3）检查我们的主要 CUL4B 抑制剂与伊立替康协同作用，利用 CRC 增强其体内肿瘤活性细胞系异种移植、遗传性 WNT/APC 诱导的肠和结肠腺瘤以及患者来源的肿瘤我们为实验室到临床研究的开发做好了独特的准备。一种基于伊立替康的化疗的预测生物标志物，可立即用于为决策提供信息在临床中进行 CRC 管理，以及旨在验证 CUL4B 作为一种治疗方法的临床到实验室研究临床前 CRC 模型中可行的药物靶点，并开发新的治疗剂以提高 CUL4Bhigh CRC 患者约占所有 CRC 的 75%，对基于伊立替康的治疗敏感。