Characterizing and Targeting BAX- and BAK-Dependent Cell Death in Cancer

癌症中 BAX 和 BAK 依赖性细胞死亡的表征和靶向

基本信息

批准号：
10211264
负责人：
EMILY H CHENG
金额：
$ 51.36万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-01 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10211264
关键词：
APAF1 gene Affect Affinity Antineoplastic Agents Apoptosis Apoptotic Applications Grants BAX gene BCL1 Oncogene BCL2 gene Biochemical Bypass CASP1 gene Caspase Caspase Inhibitor Cell Death Cells Cessation of life Clinic Combined Modality Therapy Complex Cross-Priming Cues Cytosol Data Defect Dendritic Cells Dendritic cell activation Development Disease Doxorubicin Drug Targeting Engineering FDA approved Family Foundations Gel Chromatography HMGB1 gene Human Immune Immune response Immunologic Memory Immunologics Immunotherapy In Vitro Inflammation Mediators Inflammatory Inflammatory Response Injections Inner mitochondrial membrane Interferon Type I MCL1 gene Malignant Neoplasms Mass Spectrum Analysis Mediating Melanoma Cell Mitochondria Mitochondrial DNA Molecular Mus Mutate Outer Mitochondrial Membrane Pathway interactions Physiological Play Process Protein Family Proteins Proteomics Reporting Research Role SLC25A4 gene Sentinel Signal Transduction Site Stimulator of Interferon Genes System Testing Therapeutic Translating Tumor Immunity VDAC1 gene VDAC2 gene adaptive immunity anti-cancer apoptotic protease-activating factor 1 base calreticulin cancer cell cancer immunotherapy cancer therapy cancer type completed suicide cytochrome c design immune checkpoint blockade immunogenic cell death improved in vivo innovation insight melanoma member mutant new therapeutic target novel preservation prevent programs prohibitin protein protein interaction recruit response tumor

项目摘要

PROJECT SUMMARY The incorporation of Immune checkpoint blockade into anticancer armamentarium has revolutionized cancer therapy in recent years, with FDA approved agents in multiple cancer types. Nevertheless, there is an urgent need to identify additional therapeutic strategies to increase durable response rates. Induction of immunogenic cell death is one of such strategies. The BCL-2 family proteins are central regulators of mitochondrial apoptosis and consist of (1) multidomain antiapoptotic BCL-2, BCL-XL, and MCL-1, (2) multidomain proapoptotic BAX and BAK, and (3) proapoptotic BH3-only molecules (BH3s). BAX and BAK are the essential effectors of MOMP whereas BCL-2, BCL-XL, and MCL-1 preserve mitochondrial integrity. BH3s are death sentinels that relay upstream apoptotic signals to initiate apoptosis by either activating BAX/BAK or inactivating BCL-2/BCL- XL/MCL-1. Through an interconnected hierarchical network of interactions, the BCL-2 family proteins integrate developmental and environmental cues to dictate the survival versus death decision of cells. The research on the BCL-2-regulated apoptotic pathway has not only revealed its importance in both normal physiological and disease processes, but has also resulted in the first anti-cancer drug targeting protein-protein interactions. Recent paradigm-shifting discoveries have shown that BAX/BAK activation in the absence of caspases can trigger the release of mitochondrial DNA to the cytosol through a process called “mitochondrial inner membrane permeabilization” (MIMP), which in turn activates the cGAS/STING pathway and type I interferon response. Hence, the BCL-2 family plays a crucial role not only in the decision of cells to live or commit suicide but also in the decision to die in an immunologically silent or inflammatory manner. The discovery of MIMP and its role in activating immunogenic cell death opens up exciting new avenues for cancer cell death research. However, the molecular and biochemical basis of MIMP remains uncharacterized. Furthermore, it is unclear whether induction of MIMP in tumors will affect the tumor-immune crosstalk and immunotherapy response. In this grant application, we have formulated a comprehensive plan to interrogate the biochemical and molecular basis of MIMP and exploit MIMP as a therapeutic strategy to improve and enhance immunotherapy. Our studies will not only provide novel mechanistic insights into the BCL-2-regulated cell death program but also lay the foundation for targeting the BCL-2 family to induce immunogenic cell death and thereby enhance cancer immunotherapy.

项目概要将免疫检查点阻断纳入抗癌武器彻底改变了癌症近年来，FDA 批准了针对多种癌症类型的药物治疗。需要确定额外的治疗策略以提高持久反应率。细胞死亡就是此类策略之一。BCL-2 家族蛋白是线粒体凋亡的核心调节因子。包含 (1) 多域抗凋亡 BCL-2、BCL-XL 和 MCL-1，(2) 多域促凋亡 BAX 和 BAK，以及 (3) 仅促凋亡 BH3 分子 (BH3) 是 MOMP 的重要效应子。而 BCL-2、BCL-XL 和 MCL-1 则保持线粒体完整性，BH3 是传递死亡的哨兵。上游凋亡信号通过激活 BAX/BAK 或灭活 BCL-2/BCL- 启动细胞凋亡 XL/MCL-1。通过互连的相互作用分层网络，BCL-2 家族蛋白进行整合。决定细胞生存与死亡决定的发育和环境线索。 BCL-2 调节的细胞凋亡途径不仅揭示了其在正常生理和疾病过程，但也产生了第一种针对蛋白质-蛋白质相互作用的抗癌药物。最近的范式转变发现表明，在缺乏半胱天冬酶的情况下，BAX/BAK 激活可以通过称为“线粒体内部”的过程触发线粒体 DNA 释放到细胞质中膜通透”(MIMP)，进而激活 cGAS/STING 通路和 I 型干扰素因此，BCL-2家族不仅在细胞生存或自杀的决定中发挥着至关重要的作用。还在于以免疫沉默或炎症方式死亡的决定 MIMP 和的发现。它在激活免疫原性细胞死亡中的作用为癌细胞死亡研究开辟了令人兴奋的新途径。然而，MIMP 的分子和生化基础仍不清楚。肿瘤中 MIMP 的诱导是否会影响肿瘤免疫串扰和免疫治疗反应。在这次拨款申请中，我们制定了一项全面的计划来研究生化和分子生物学 MIMP 的基础，并利用 MIMP 作为改善和增强免疫治疗的治疗策略。研究不仅将为 BCL-2 调节的细胞死亡程序提供新的机制见解，而且为靶向 BCL-2 家族诱导免疫原性细胞死亡奠定基础，从而增强癌症免疫疗法。