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

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

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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.

项目摘要/摘要该应用对PA-17-440响应：癌细胞存活中细胞死亡途径的相互作用抵抗治疗（R01）。结直肠癌（CRC）是美国与癌症相关死亡的主要原因。大多数CRC患者对治疗治疗没有反应。诱导程序性细胞死亡，广泛被称为凋亡，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仅限于caspase依赖性细胞凋亡，但包括坏死病，一种受调节的坏死死亡形式受受体相互作用蛋白1（RIP1），RIP3和混合谱系激酶结构域样蛋白的控制（MLKL）。积累的证据表明坏死作用是防御机制致癌突变和病原体，可以被多种抗癌药物杀死癌细胞。然而，坏死性的调节机制和功能作用在抗癌治疗中很差理解。尽管为恢复癌细胞的凋亡而进行了广泛的努力，但很少尝试操纵坏死性以改善抗癌疗法，这在很大程度上是由于对这种新的理解不足定义的细胞死亡方式。我们的初步数据表明，CRC中RIP3表达的频繁丧失为与临床结果不佳有关。坏死性可以由常见的化学治疗药物（例如 5-氟尿嘧啶（5-FU）以杀死具有RIP3表达的CRC细胞的子集，并且与强大的抗肿瘤有关免疫反应。我们还确定了一种新的坏死途径，涉及仅BH3的BCl-2家族蛋白 PUMA激活RIP3和MLKL以响应抗癌剂而引发坏死。基于这些调查结果，我们建议检验PUMA/RIP3介导的坏死作用的假设在通过细胞内在和免疫学作用确定CRC细胞子集中的治疗反应，这可以针对改善CRC治疗的目标。目标1：定义坏死诱导的上下文和机制抗癌剂CRC细胞； AIM 2：描述坏死作用在杀死CRC细胞中的功能作用抗癌剂；目标3：确定是否可以使用操纵坏死作用来克服治疗 CRC的抗性。拟议的研究将通过 CRC细胞中的抗癌剂。他们将阐明凋亡和坏死性的相互作用如何介导对抗癌疗法的反应，并为刺激坏死的原则证据证明以增强改善CRC治疗的肿瘤细胞杀伤和抗肿瘤免疫反应。