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

• 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
• 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

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，也是导致癌症相关死亡的第二大原因