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Tunneling Nanotube Inhibitors for Cancer Immunotherapy

用于癌症免疫治疗的隧道纳米管抑制剂

基本信息

批准号：
10735019
负责人：
Shiladitya Sengupta
金额：
$ 65.26万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
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：
2023-07-19 至 2028-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10735019
关键词：
3-Dimensional 4T1 Actins Autologous Binding Biopsy Breast Cancer Cell Cell Communication Cell Culture Techniques Cell Death Cell Survival Cells Clinical Clustered Regularly Interspaced Short Palindromic Repeats Coculture Techniques Complex Cryoelectron Microscopy Crystallography Dose Electrons Exhibits Genetic Genus Hippocampus Guanosine Triphosphate Phosphohydrolases Harvest Hour Human Image Immune Immune Evasion Immune checkpoint inhibitor Immune response Immunocompetent Immunologic Memory Immunologics Immunotherapy In Vitro Infiltration Knock-out Label Lead Malignant Neoplasms Mediating Metabolic Minor Mitochondria Mus Nanotechnology Nanotubes Nature Normal tissue morphology Outcome Patients Penetration Pharmacology Physiology Play Publishing Research Role Safety Scanning Science Small Interfering RNA Structure T-Cell Activation T-Lymphocyte Testing Therapeutic Time Toxic effect Toxicokinetics Tumor Antigens Tumor Escape cancer cell cancer immunotherapy cell type cellular engineering effector T cell efficacy testing efficacy validation humanized mouse improved in vivo inhibitor insight knock-down meter mouse model nano nanoscale next generation novel overexpression programmed cell death ligand 1 programmed cell death protein 1 rational design response small molecule small molecule inhibitor survival outcome systemic toxicity therapeutic target trafficking tumor tumor immunology tumor progression

项目摘要

ABSTRACT In a recent study published in Nature Nanotechnology, we demonstrated that cancer cells form physical nanoscales tentacles (nanotubes) to connect with and harvest mitochondria from immune cells. Such mitochondria hijacking metabolically depleted the immune cells and augmented the cancer cells. These findings have significant implications as it emerges as a novel mechanism of immune evasion by cancer cells, which can limit the efficacy of immune checkpoint inhibitors. Here we propose to develop next- generation immunotherapies that can perturb this novel immune evasion phenomenon. We are specifically developing novel small molecule inhibitors of the exocyst complex, which we have implicated in the above phenomenon. Our preliminary results show that such small molecules can exert a powerful antitumor efficacy, augment classical immune checkpoint inhibitors and display an excellent safety profile. In Aim 1. We will synthesize and characterize exocyst inhibitors in vitro to test the hypothesis that rationally designed small molecule inhibitors of the exocyst complex can inhibit nanotube assembly. In Aim. 2. We will establish the safety pharmacology of exocyst inhibitors in vivo. In Aim 3, we will test the hypothesis that exocyst inhibitors can improve antitumor outcomes with immune checkpoint inhibitors. Achieving these aims will lead to fundamental insights into a new mechanism of cancer-immune cell communication. Our preliminary results indicate exocyst inhibitors can emerge as a new class of immunotherapy.

摘要