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

• 批准号: 10375572
• 负责人: EMILY H CHENG
• 金额: $ 50.33万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 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/10375572
• 关键词: APAF1 gene; Affect; Affinity; Antineoplastic Agents; Apoptosis; Apoptotic; Applications Grants; BAX gene; BCL1 Oncogene; BCL2 gene; BCL2L1 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

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.

项目摘要 将免疫检查点封锁纳入抗癌Armamentarium已彻底改变了癌症 近年来的治疗，FDA批准了多种癌症类型的药物。然而，有一个紧急的 需要确定其他治疗策略以提高耐用的应答率。诱导免疫原性 细胞死亡就是这样的策略之一。 Bcl-2家族蛋白是线粒体凋亡的中心调节剂 由（1）多域抗凋亡Bcl-2，Bcl-XL和Mcl-1组成 和bak，以及（3）促凋亡的仅BH3分子（BH3S）。 Bax和Bak是MOMP的基本影响 而Bcl-2，BCl-XL和MCL-1保持线粒体完整性。 BH3是继电器的死亡前哨 上游凋亡信号通过激活BAX/BAK或灭活Bcl-2/bcl-启动凋亡 XL/MCL-1。通过互连的互动网络，Bcl-2家族蛋白整合 发育和环境线索决定细胞的生存与死亡决定。研究 Bcl-2调节的凋亡途径不仅揭示了其在正常生理和 疾病过程，但也导致了第一个抗癌药物靶向蛋白质 - 蛋白质相互作用。 最近的范式转移发现表明，在没有胱天蛋白酶的情况下，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 膜通透性”（MIMP），进而激活CGA/STING途径和I型Interferon 回复。因此，BCL-2家族不仅在细胞生命或自杀的决定中起着至关重要的作用 而且还决定以免疫学上的沉默或炎症方式死亡。发现MIMP和 它在激活免疫原性死亡中的作用为癌细胞死亡研究的新途径开辟了新的途径。 但是，MIMP的分子和生化基础仍然没有表征。此外，还不清楚 肿瘤中MIMP的诱导是否会影响肿瘤免疫串扰和免疫疗法反应。在 我们制定了一项全面计划来审问生化和分子的综合计划 MIMP和利用MIMP作为改善和增强免疫疗法的治疗策略的基础。我们的 研究不仅将为Bcl-2调节的细胞死亡程序提供新的机械见解，还将提供 为靶向Bcl-2家族诱导免疫原性死亡的基础，从而增强 癌症免疫疗法。