Targeting GRP94-TGF-beta Pathway for Cancer Immunotherapy

靶向 GRP94-TGF-β 通路的癌症免疫治疗

基本信息

批准号：
10474548
负责人：
Zihai Li
金额：
$ 59.43万
依托单位：
OHIO STATE UNIVERSITY
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：
2021-09-01 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10474548
关键词：
Address Antibodies Area B-Lymphocytes Binding Biochemical Biogenesis Biology Blood Platelets Cancer Biology Cancer Control Cell surface Client Clinical Clinical Trials Collaborations Complex Degradation Pathway Development Docking Endoplasmic Reticulum Eragrostis Foundations GRP94 Goals Growth Factor Receptors Heat-Shock Proteins 90 Human Immune Immune Tolerance Immune checkpoint inhibitor Immunity Immunologics Immunotherapeutic agent Immunotherapy Insulin-Like Growth Factor I Insulin-Like Growth Factor II Integrins LRRC32 gene Laboratories Malignant Neoplasms Manuscripts Mediating Membrane Glycoproteins Molecular Molecular Chaperones Myelogenous Nature Oncogenic PD-1/PD-L1 Pathway interactions Pharmaceutical Preparations Phase Play Pre-Clinical Model Proteins Publishing Quality Control Regulation Regulatory T-Lymphocyte Renaissance Resistance Role Signal Pathway Signal Transduction Structural Biologist Suppressor-Effector T-Lymphocytes Surface T cell therapy T-Lymphocyte Therapeutic Thrombin Transforming Growth Factor beta Translational Research Tumor Escape VWF gene anti-cancer cancer cell cancer immunotherapeutics cancer immunotherapy cancer therapy cell growth cell type chimeric antigen receptor convict design effector T cell engineered T cells genetic approach immune resistance inhibitor insight leucine-rich repeat protein migration new therapeutic target next generation novel novel therapeutics overexpression paralogous gene pre-clinical preclinical study protein degradation receptor response side effect targeted treatment tumor microenvironment tumorigenesis

项目摘要

PROJECT SUMMARY As a ubiquitous HSP90 paralog in the endoplasmic reticulum (ER), GRP94 plays important roles in protein quality control in the secretory pathway by participating in both the unfolded protein response and the ER-associated protein degradation pathway. My laboratory has demonstrated that GRP94 is a strategically important target for cancer, because it controls multiple key molecular pathways in cell growth, migration, immune tolerance and differentiation, including integrins, TLRs, IGF-II, Wnt co-receptor LRP6, and GARP (or LRRC32). GARP (Glycoprotein A Repetitions Predominant) is responsible for surface docking and activation of latent TGFb and a focus of this proposal We have made significant contributions to this area through immunological and biochemical studies, including: 1) that GARP is an important molecule for cancer immune evasion via regulating multiple cell types (e.g., cancer cells, platelets, regulatory T cells, B cells). 2) We discovered a novel mechanism of TGFb activation from cell surface GARP-TGFb complex via proteolytic cleavage of GARP. 3) GARP has been found to be aberrantly expressed in multiple human cancers to promote oncogenesis via both cancer cell-intrinsic and -extrinsic mechanisms. 4) Preclinical studies suggest that GARP is a novel therapeutic target for cancer immunotherapy. These accomplishments have deepened our conviction that the study of GRP94 and its client network will lead to better understanding of this chaperone biology in cancer and to development of novel cancer therapeutics, alone or in combination with approved immunotherapeutic agents. In the next phase of the study, we will address the hypothesis that GRP94/GARP-targeted therapy applied to multiple vulnerable cancers will overcome immune resistance to checkpoint inhibitors. First, we will determine the roles and molecular mechanism involved in GRP94 regulation of TGFb biogenesis, activation and signaling. This aim will focus on structural analysis of the GRP94-GARP complex, and on resolving mechanisms of GRP94 in folding two other molecules important in regulating TGFb signaling: LRRC33 and LRG1. Second, we will develop novel cancer immunotherapeutic strategies targeting GRP94 and GARP. The goal is to advance the top first-in-class agent(s) among several pre-clinical leads through a milestone-driven strategy. This includes agents to inhibit GARP cleavage, GARP-specific antibodies, drug-like GRP94-selective inhibitors, antibodies against the cell surface GRP94 (ectoGRP94) preferentially expressed on cancer cells, and T cells engineered to express chimeric antigen receptor (CAR) composed of a single-chain antibody against ectoGRP94 fused with T cell signaling motifs (GRP94-CAR-T). Overall, the impact of this study lies in fundamental understanding of GRP94 in regulating the TGFb pathway and in developing promising next generation immunotherapeutic agents.

项目摘要作为内质网（ER）中普遍存在的HSP90旁系同源物，GRP94在蛋白质质量中起着重要作用通过参与展开的蛋白质反应和与ER相关的分泌途径中的控制蛋白质降解途径。我的实验室表明，GRP94是战略上重要的目标癌症，因为它控制了细胞生长，迁移，免疫耐受性和分化，包括整联蛋白，TLR，IGF-II，Wnt共受体LRP6和GARP（或LRRC32）。加普（糖蛋白A A重复毒素主要）负责潜在TGFB的表面对接和激活该提案的重点我们通过免疫学和生化研究，包括：1）通过调节，GARP是癌症免疫逃避的重要分子多种细胞类型（例如癌细胞，血小板，调节性T细胞，B细胞）。 2）我们发现了一种新型机制通过GARP的蛋白水解裂解，来自细胞表面GARP-TGFB复合物的TGFB激活。 3）GARP已经发现在多种人类癌症中异常表达以通过两种癌细胞中的癌症发生和 - 肢体机制。 4）临床前研究表明GARP是癌症的新型治疗靶点免疫疗法。这些成就加深了我们对GRP94及其客户的研究的信念网络将更好地了解癌症的这种伴侣生物学和新型癌症的发展单独或与批准的免疫治疗剂结合的治疗剂。在下一阶段，我们将解决以下假设：GRP94/GARP靶向疗法适用于多种易受攻击的癌症克服对检查点抑制剂的免疫阻力。首先，我们将确定GRP94调节TGFB生物发生的作用和分子机制，激活和信号传导。该目标将重点放在GRP94-GARP综合体的结构分析上，并解决 GRP94的机理在折叠两个对调节TGFB信号传导的重要分子：LRRC33和 LRG1。其次，我们将开发针对GRP94和GARP的新型癌症免疫治疗策略。这目标是通过里程碑驱动战略。这包括抑制GARP裂解，GARP特异性抗体的药物，类似药物的GRP94选择性抑制剂，针对细胞表面GRP94（Ectogrp94）的抗体优先表达在癌细胞上，并 T细胞设计为表达由单链抗体组成的嵌合抗原受体（CAR） ECTOGRP94与T细胞信号基序（GRP94-CAR-T）融合。总体而言，这项研究的影响在于对GRP94的基本了解在规范TGFB途径和发展有希望的下一步产生免疫治疗剂。