Targeting defective necroptosis in colorectal cancer

靶向结直肠癌中的缺陷性坏死性凋亡

• 批准号: 9914466
• 负责人: Jian Yu
• 金额: $ 46.14万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-01 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9914466
• 关键词: Antineoplastic Agents; Apoptosis; BCL2 gene; Biology; Bypass; Cancer Etiology; Caspase; Cell Death; Cell Survival; Cells; Cessation of life; Chemicals; Chemotherapy-Oncologic Procedure; Colorectal Cancer; DNA; Data; Development; Dose-Limiting; Down-Regulation; Epigenetic Process; Event; Evolution; Fluorouracil; Foundations; Genetic; Growth; Human; Immune response; Immunocompetent; Immunologic Surveillance; Immunologics; Immunotherapy; Lead; Malignant - descriptor; Malignant Neoplasms; Mediating; Mismatch Repair; Mismatch Repair Deficiency; Modeling; Molecular; Mus; Mutation; Necrosis; New Agents; Nude Mice; Pathway interactions; Patients; Pharmacology; Phosphorylation; Phosphotransferases; Play; Protein Family; Proteins; RIPK1 gene; RIPK3 gene; Relapse; Resistance; Role; Route; Signal Pathway; Signal Transduction; Stress; TP53 gene; Testing; Therapeutic; Toxic effect; Treatment Efficacy; Tumor Immunity; Tumor Suppression; Tumor-Derived; Virus; anti-cancer; anti-tumor immune response; anticancer activity; base; cancer cell; cancer therapy; cancer type; cell killing; chemotherapy; clinically relevant; colon cancer patients; colorectal cancer treatment; immune checkpoint blockade; immunogenicity; improved; in vivo; mitochondrial dysfunction; nanomolar; neoplastic cell; novel; novel anticancer drug; protein activation; response; targeted agent; targeted treatment; therapy resistant; tumor

Most patients with colorectal cancer (CRC) do not respond well to therapeutic treatment. New agents for improving CRC therapy are urgently needed. Induction of programmed cell death or apoptosis is a major effect of anticancer therapy. Recent studies indicate that programmed cell death also includes necroptosis, a regulated form of necrotic death controlled by Receptor-Interacting Protein 1 (RIP1), RIP3, and Mixed Lineage Kinase Domain-Like protein (MLKL). Accumulating evidence suggests that necroptosis, similar to apoptosis, functions as a barrier against tumor development and plays an important role in anticancer therapy. Downregulation or mutations of RIP1, RIP3, and MLKL have been frequently found in tumors and contribute to therapeutic resistance. However, few attempts have been made to target defective necroptosis in cancer cells due to insufficient understanding of the regulatory mechanism and functional role of necroptosis in anticancer therapy. Our recent studies identified a new necroptosis pathway mediated by PUMA, a p53 target and a BH3-only Bcl-2 family protein that is essential for cell death induced by a variety of anticancer drugs. This pathway can be utilized by common chemotherapeutics such as 5-fluorouracil (5-FU) to kill a subset of CRC cells. However, this pathway often cannot be engaged in CRC cells due to frequent loss of RIP3 expression, which prompted us to search for agents that can restore necroptosis in RIP3-deficient CRC cells. Our preliminary data show that OSW-1, a natural compound with potent anticancer activity, activates p53 and PUMA to induce necroptosis in CRC cells. Surprisingly, OSW-1-induced and PUMA-mediated necroptosis does not require either RIP1 or RIP3, suggesting a novel mechanism of action. Importantly, the in vivo antitumor activity of OSW-1 needs to be characterized using immuno-competent tumor models, suggesting a critical role of necroptosis-triggered antitumor immunity. Based on these findings, we propose to use OSW-1 as a chemical probe to test the hypothesis that PUMA-mediated and RIP3-independent necroptosis is efficacious against CRC via both cell-intrinsic and immunologic effects, and can be exploited to improve CRC therapy. Aim 1: Mechanism by which OSW-1 induces PUMA-mediated necroptosis in RIP3-deficient CRC cells; Aim 2: Role of PUMA-mediated and RIP3-independent necroptosis in tumor suppression by OSW-1; and Aim 3: Induction of PUMA-mediated and RIP3-independent necroptosis for improving CRC therapy. The proposed studies will delineate a novel necroptosis pathway underlying the potent anticancer activity of OSW-1. Completion of these studies will lay a foundation for identifying new anticancer agents that target defective necroptosis in CRC cells to enhance tumor cell killing and antitumor immune response, which may ultimately lead to improved treatment of CRC and other cancers.

大多数结直肠癌患者（CRC）对治疗治疗的反应不佳。新代理 迫切需要改善CRC治疗。诱导程序性细胞死亡或凋亡是主要作用 抗癌疗法。最近的研究表明，程序性细胞死亡还包括坏死性，这是一个受调节的 由受体相互作用蛋白1（RIP1），RIP3和混合谱系激酶控制的坏死死亡形式 结构域样蛋白（MLKL）。积累的证据表明，坏死性与凋亡相似，功能 作为反对肿瘤发育的障碍，在抗癌治疗中起着重要作用。下调或 RIP1，RIP3和MLKL的突变经常在肿瘤中发现并有助于治疗 反抗。但是，很少有人尝试针对由于 对坏死性在抗癌治疗中的调节机制和功能作用不足。 我们最近的研究确定了PUMA介导的新的坏死途径，p53靶标和仅BH3的BCl-2 对各种抗癌药物诱导的细胞死亡必不可少的家族蛋白。该途径可以使用 通过常见的化学治疗剂，例如5-氟尿嘧啶（5-FU）来杀死CRC细胞的子集。但是，这条路 由于经常丢失RIP3表达，通常无法从事CRC单元，这促使我们搜索 可以恢复RIP3缺陷CRC细胞中坏死的药物。我们的初步数据表明，OSW-1是自然的 具有有效抗癌活性的化合物，激活p53和PUMA，诱导CRC细胞中坏死。 出乎意料的是，OSW-1诱导的和PUMA介导的坏死性不需要RIP1或RIP3，这表明 一种新颖的作用机理。重要的是，需要使用OSW-1的体内抗肿瘤活性来表征 免疫能力的肿瘤模型，表明坏死性触发抗肿瘤免疫的关键作用。基于 在这些发现中，我们建议将OSW-1用作化学探针来检验PUMA介导的假设 与RIP3非依赖性坏死作用是通过细胞中的和免疫学效应对CRC有效的，并且 可以利用以改善CRC疗法。 AIM 1：OSW-1诱导PUMA介导的机制 RIP3缺陷型CRC细胞中坏死； AIM 2：PUMA介导的和RIP3无关坏死的作用 OSW-1抑制肿瘤；目标3：诱导PUMA介导的与RIP3无关坏死作用 改善CRC疗法。拟议的研究将描述有效的新型坏死途径 OSW-1的抗癌活性。这些研究的完成将为识别新的抗癌者奠定基础 靶向CRC细胞中坏死性有缺陷的药物，以增强肿瘤细胞杀伤和抗肿瘤免疫 反应，最终可能会改善对CRC和其他癌症的治疗。