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: 10621724
• 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/10621724
• 关键词: APAF1 gene; Affect; Affinity Chromatography; Antineoplastic Agents; Apoptosis; Apoptotic; Applications Grants; BAX gene; BCL1 Oncogene; BCL2L1 gene; Biochemical; Bypass; Caspase; Caspase Inhibitor; Cell Death; Cell Membrane Permeability; 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; Permeability; Physiological; Play; Probability; 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; 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.

项目总结

项目成果

Combination Therapy With MDM2 and MEK Inhibitors Is Effective in Patient-Derived Models of Lung Adenocarcinoma With Concurrent Oncogenic Drivers and MDM2 Amplification.

MDM2 和 MEK 抑制剂的联合治疗对于同时具有致癌驱动因素和 MDM2 扩增的患者衍生肺腺癌模型有效。

• DOI: 10.1016/j.jtho.2023.05.007
• 发表时间: 2023
• 期刊: Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer
• 作者: Elkrief,Arielle;Odintsov,Igor;Markov,Vladimir;Caeser,Rebecca;Sobczuk,Pawel;Tischfield,SamE;Bhanot,Umesh;Vanderbilt,ChadM;Cheng,EmilyH;Drilon,Alexander;Riely,GregoryJ;Lockwood,WilliamW;deStanchina,Elisa;Tirunagaru,VijayaG

Vepafestinib is a pharmacologically advanced RET-selective inhibitor with high CNS penetration and inhibitory activity against RET solvent front mutations.

• DOI: 10.1038/s43018-023-00630-y
• 发表时间: 2023-09
• 期刊: NATURE CANCER
• 影响因子: 22.7
• 作者: Miyazaki, Isao;Odintsov, Igor;Ishida, Keiji;Lui, Allan J. W.;Kato, Masanori;Suzuki, Tatsuya;Zhang, Tom;Wakayama, Kentaro;Kurth, Renate I.;Cheng, Ryan;Fujita, Hidenori;Delasos, Lukas;Vojnic, Morana;Khodos, Inna;Yamada, Yukari;Ishizawa, Kota;Mattar, Marissa S.;Funabashi, Kaoru;Chang, Qing;Ohkubo, Shuichi;Yano, Wakako;Terada, Ryuichiro;Giuliano, Claudio;Lu, Yue Christine;Bonifacio, Annalisa;Kunte, Siddharth;Davare, Monika A.;Cheng, Emily H.;de Stanchina, Elisa;Lovati, Emanuela;Iwasawa, Yoshikazu;Ladanyi, Marc;Somwar, Romel
• 通讯作者: Somwar, Romel