Role of necroptosis in colorectal cancer therapy

坏死性凋亡在结直肠癌治疗中的作用

基本信息

批准号：
10891823
负责人：
Lin Zhang
金额：
$ 46.18万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-06-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10891823
关键词：
Antineoplastic Agents Antineoplastic Combined Chemotherapy Protocols Apoptosis BCL2 gene Cancer Etiology Caspase Cell Death Cell Death Induction Cell Survival Cells Cessation of life Clinical Colorectal Cancer Combination Drug Therapy Data Drug usage Epigenetic Process Evolution Fluorouracil Genetic Human Immune Immune response Immunologic Surveillance Immunologics Immunotherapy In Vitro Malignant - descriptor Malignant Neoplasms Mediating Metastatic Neoplasm to the Liver Modality Modeling Molecular Profiling Mutation Necrosis Oncogenic Organoids Outcome Pathway interactions Patients Phosphotransferases Play Protein Family Proteins RIPK1 gene RIPK3 gene Relapse Resistance Role Route Signal Transduction Stress TP53 gene Testing Therapeutic Therapeutic Effect Treatment Efficacy Tumor Immunity Virus anti-tumor immune response cancer cell cancer therapy cancer type cell killing chemotherapeutic agent chemotherapy clinically relevant colon cancer patients colorectal cancer treatment immune checkpoint blockade immunogenicity improved in vivo insight mimetics mitochondrial dysfunction neoplastic cell novel pathogen refractory cancer response targeted treatment therapy resistant treatment response tumor tumor xenograft

项目摘要

PROJECT SUMMARY/ABSTRACT This application is responsive to PA-17-440: The Interplay of Cell Death Pathways in Cancer Cell Survival and Resistance to Therapy (R01). Colorectal cancer (CRC) is a leading cause of cancer-related deaths in the US. Most CRC patients are not responsive to therapeutic treatment. Induction of programmed cell death, widely known as apoptosis, is a key effect of anticancer therapy. Recent studies indicate that programmed cell death is not confined to caspase-dependent apoptosis, but 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 functions as a defensive mechanism against oncogenic mutations and pathogens, and can be utilized by a variety of anticancer agents to kill cancer cells. However, the regulatory mechanisms and functional role of necroptosis in anticancer therapy are poorly understood. Despite extensive efforts for restoring apoptosis in cancer cells, few attempts have been made to manipulate necroptosis for improving anticancer therapy, largely due to insufficient understanding of this newly defined cell death modality. Our preliminary data show that frequent loss of RIP3 expression in CRCs is associated with poor clinical outcomes. Necroptosis can be engaged by common chemotherapeutics such as 5-fluorouracil (5-FU) to kill a subset of CRC cells with RIP3 expression, and is associated with a robust antitumor immune response. We also identified a novel necroptosis pathway involving the BH3-only Bcl-2 family protein PUMA, which activates RIP3 and MLKL to initiate necroptosis in response to anticancer agents. Based on these findings, we propose to test the hypothesis that PUMA/RIP3-mediated necroptosis plays a critical role in determining therapeutic response in a subset of CRC cells via both cell intrinsic and immunologic effects, which can be targeted to improve CRC therapy. Aim 1: Define the context and mechanism of necroptosis induction in CRC cells by anticancer agents; Aim 2: Delineate the functional role of necroptosis in the killing of CRC cells by anticancer agents; and Aim 3: Determine if manipulating necroptosis can be used to overcome therapeutic resistance of CRCs. The proposed studies will provide new mechanistic insights on necroptosis induction by anticancer agents in CRC cells. They will clarify how the interplay of apoptosis and necroptosis mediates response to anticancer therapy, and provide proof-of-principle evidence for stimulating necroptosis to enhance tumor cell killing and antitumor immune response for improving CRC treatment.

项目概要/摘要此应用程序响应 PA-17-440：细胞死亡途径在癌细胞存活和中的相互作用对治疗的抵抗（R01）。结直肠癌 (CRC) 是美国癌症相关死亡的主要原因。大多数 CRC 患者对治疗没有反应。广泛诱导程序性细胞死亡称为细胞凋亡，是抗癌治疗的关键作用。最近的研究表明，程序性细胞死亡是不限于半胱天冬酶依赖性细胞凋亡，还包括坏死性凋亡，一种受调节的坏死性死亡形式由受体相互作用蛋白 1 (RIP1)、RIP3 和混合谱系激酶结构域样蛋白控制（MLKL）。越来越多的证据表明坏死性凋亡是一种防御机制致癌突变和病原体，并且可以被多种抗癌剂用来杀死癌细胞。然而，坏死性凋亡在抗癌治疗中的调控机制和功能作用尚不清楚。明白了。尽管为恢复癌细胞的凋亡做出了广泛的努力，但很少有人尝试操纵坏死性凋亡来改善抗癌治疗，很大程度上是由于对这种新的认识不足定义的细胞死亡方式。我们的初步数据表明，CRC 中 RIP3 表达的频繁丢失是与不良的临床结果相关。常见的化疗药物可引起坏死性凋亡，例如 5-氟尿嘧啶 (5-FU) 可杀死表达 RIP3 的 CRC 细胞亚群，并具有强大的抗肿瘤作用免疫反应。我们还发现了一种新的坏死性凋亡途径，涉及仅 BH3 的 Bcl-2 家族蛋白 PUMA，激活 RIP3 和 MLKL 以启动坏死性凋亡以响应抗癌药物。基于这些发现，我们建议检验 PUMA/RIP3 介导的坏死性凋亡在通过细胞内在效应和免疫效应确定 CRC 细胞亚群的治疗反应，可以有针对性地改善 CRC 治疗。目标 1：定义坏死性凋亡诱导的背景和机制抗癌药物对结直肠癌细胞的影响；目标 2：通过以下方式描述坏死性凋亡在杀死 CRC 细胞中的功能作用：抗癌剂；目标 3：确定是否可以通过操纵坏死性凋亡来克服治疗性坏死性凋亡 CRC 的抵抗力。拟议的研究将为通过以下方式诱导坏死性凋亡提供新的机制见解 CRC 细胞中的抗癌剂。他们将阐明细胞凋亡和坏死性凋亡如何相互作用对抗癌治疗的反应，并为刺激坏死性凋亡以增强肿瘤细胞杀伤和抗肿瘤免疫反应，以改善结直肠癌的治疗。