Targeting GRP94-TGF-beta Pathway for Cancer Immunotherapy

靶向 GRP94-TGF-β 通路的癌症免疫治疗

• 批准号: 10689068
• 负责人: Zihai Li
• 金额: $ 53.79万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 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/10689068
• 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 checkpoint; 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

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.

项目概要 作为内质网 (ER) 中普遍存在的 HSP90 旁系同源物，GRP94 在蛋白质质量中发挥着重要作用 通过参与未折叠蛋白反应和 ER 相关的分泌途径来控制 蛋白质降解途径。我的实验室已经证明 GRP94 是一个具有重要战略意义的目标 癌症，因为它控制着细胞生长、迁移、免疫耐受和 分化，包括整合素、TLR、IGF-II、Wnt 共受体 LRP6 和 GARP（或 LRRC32）。盖普 （糖蛋白 A 重复为主）负责潜在 TGFb 和 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）GARP是通过调节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）我们发现了一种新机制 通过 GARP 的蛋白水解裂解细胞表面 GARP-TGFb 复合物激活 TGFb。 3）GARP已 发现在多种人类癌症中异常表达，通过癌细胞固有的促进肿瘤发生 - 外在机制。 4）临床前研究表明GARP是癌症的新治疗靶点 免疫疗法。这些成就加深了我们对GRP94及其客户端的研究的信念 网络将有助于更好地了解癌症中的伴侣生物学并开发新型癌症 治疗，单独或与批准的免疫治疗剂组合。在下一阶段的研究中， 我们将提出这样一个假设：GRP94/GARP 靶向治疗应用于多种易受影响的癌症将 克服对检查点抑制剂的免疫抵抗。 首先，我们将确定 GRP94 调控 TGFb 生物合成的作用和分子机制， 激活和信号传导。该目标将侧重于 GRP94-GARP 复合物的结构分析，并解决 GRP94 折叠另外两个对调节 TGFb 信号转导很重要的分子的机制：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的方式，在多个临床前先导药物中推进顶级的一流药物 战略。这包括抑制 GARP 裂解的药物、GARP 特异性抗体、类药物 GRP94 选择性 抑制剂、针对优先在癌细胞上表达的细胞表面 GRP94 (ectoGRP94) 的抗体，以及 T 细胞经过改造可表达嵌合抗原受体 (CAR)，该受体由单链抗体组成 ectoGRP94 与 T 细胞信号传导基序融合 (GRP94-CAR-T)。总体而言，本研究的影响在于 对 GRP94 调节 TGFb 通路和开发有前景的下一代药物的基本了解 一代免疫治疗剂。