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:10689068
- 负责人:
- 金额:$ 53.79万
- 依托单位:
- 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:
- 关键词:AddressAntibodiesAreaB-LymphocytesBindingBiochemicalBiogenesisBiologyBlood PlateletsCancer BiologyCancer ControlCell surfaceClientClinicalClinical TrialsCollaborationsComplexDegradation PathwayDevelopmentDockingEndoplasmic ReticulumEragrostisFoundationsGRP94GoalsGrowth Factor ReceptorsHeat-Shock Proteins 90HumanImmuneImmune ToleranceImmune checkpoint inhibitorImmunityImmunologicsImmunotherapeutic agentImmunotherapyInsulin-Like Growth Factor IInsulin-Like Growth Factor IIIntegrinsLRRC32 geneLaboratoriesMalignant NeoplasmsManuscriptsMediatingMembrane GlycoproteinsMolecularMolecular ChaperonesMyelogenousNatureOncogenicPD-1/PD-L1Pathway interactionsPharmaceutical PreparationsPhasePlayPre-Clinical ModelProteinsPublishingQuality ControlRegulationRegulatory T-LymphocyteRenaissanceResistanceRoleSignal PathwaySignal TransductionStructural BiologistSuppressor-Effector T-LymphocytesSurfaceT cell therapyT-LymphocyteTherapeuticThrombinTransforming Growth Factor betaTranslational ResearchTumor EscapeVWF geneanti-cancercancer cellcancer immunotherapeuticscancer immunotherapycancer therapycell growthcell typechimeric antigen receptorconvictdesigneffector T cellengineered T cellsgenetic approachimmune checkpointimmune resistanceinhibitorinsightleucine-rich repeat proteinmigrationnew therapeutic targetnext generationnovelnovel therapeuticsoverexpressionparalogous genepre-clinicalpreclinical studyprotein degradationreceptorresponseside effecttargeted treatmenttumor microenvironmenttumorigenesis
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
GRP 94作为内质网中普遍存在的HSP 90蛋白,对蛋白质的质量起着重要作用
通过参与未折叠蛋白质反应和ER相关蛋白质反应来控制分泌途径。
蛋白质降解途径。我的实验室已经证明GRP 94是一个具有战略意义的目标,
癌症,因为它控制着细胞生长,迁移,免疫耐受和
在一个实施方案中,所述细胞分化抑制剂包括整合素、TLR、IGF-II、Wnt共受体LRP 6和GARP(或LRRC 32)。GARP
(糖蛋白A重复占主导地位)负责表面对接和激活潜伏的TGF β和TGF β受体。
我们已经通过免疫学和生物医学领域的研究,
生物化学研究,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)我们发现了一种新的机制
通过GARP的蛋白水解切割从细胞表面GARP-TGF β复合物活化TGF β。3)GARP一直在
发现在多种人类癌症中异常表达,通过癌细胞内源性
和-外部机制。4)临床前研究表明,GARP是一种新型的肿瘤治疗靶点
免疫疗法。这些成果加深了我们的信念,GRP 94及其客户的研究
网络将导致更好地了解这种伴侣生物学在癌症和发展新的癌症
治疗剂,单独或与批准的免疫抑制剂组合。在研究的下一阶段,
我们将提出一个假设,即GRP 94/GARP靶向治疗应用于多种易受攻击的癌症,
克服对检查点抑制剂的免疫抵抗。
首先,我们将确定GRP 94调节TGF β生物合成的作用和分子机制,
激活和信号传导。该目标将集中于GRP 94-GARP复合物的结构分析,并解决
GRP 94折叠在调节TGF β信号传导中重要的另外两种分子:LRRC 33和
LRG 1。其次,我们将开发针对GRP 94和GARP的新型癌症免疫策略。的
目标是通过里程碑驱动的
战略这包括抑制GARP切割的试剂、GARP特异性抗体、药物样GRP 94选择性抗体、GARP特异性抗体和GARP特异性抗体。
抑制剂,针对优先在癌细胞上表达的细胞表面GRP 94(ectoGRP 94)的抗体,和
T细胞被工程化以表达嵌合抗原受体(CAR),所述嵌合抗原受体由针对人T细胞的单链抗体组成。
与T细胞信号传导基序融合的ectoGRP 94(GRP 94-CAR-T)。总的来说,这项研究的影响在于
基本了解GRP 94在调节TGF β通路和开发有前途的下一个
产生免疫抑制剂。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Zihai Li其他文献
Zihai Li的其他文献
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{{ truncateString('Zihai Li', 18)}}的其他基金
Sexual Dimorphism in T Cell Exhaustion and Bladder Cancer
T 细胞耗竭和膀胱癌中的性别二态性
- 批准号:
10629078 - 财政年份:2023
- 资助金额:
$ 53.79万 - 项目类别:
Targeting GRP94-TGF-beta Pathway for Cancer Immunotherapy Supplement
靶向 GRP94-TGF-β 通路的癌症免疫治疗补充剂
- 批准号:
10818173 - 财政年份:2021
- 资助金额:
$ 53.79万 - 项目类别:
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:
10474548 - 财政年份:2021
- 资助金额:
$ 53.79万 - 项目类别:
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:
10275810 - 财政年份:2021
- 资助金额:
$ 53.79万 - 项目类别:
Integration of inflammation and cancer by molecular chaperone
分子伴侣整合炎症和癌症
- 批准号:
10056559 - 财政年份:2017
- 资助金额:
$ 53.79万 - 项目类别:
Endoplasmic Reticulum Chaperones in Cancer Biology and Therapy
癌症生物学和治疗中的内质网伴侣
- 批准号:
9321008 - 财政年份:2015
- 资助金额:
$ 53.79万 - 项目类别:
Project 1: Definition of grp94-GARP-TGFbeta Axis in Cancer Biology and Clinical Significance
项目1:grp94-GARP-TGFbeta轴在癌症生物学中的定义及其临床意义
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8934513 - 财政年份:2015
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$ 53.79万 - 项目类别:
Novel mechanisms of UPR sensing and nonalcoholic fatty liver disease
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9026108 - 财政年份:2015
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Endoplasmic Reticulum Chaperones in Cancer Biology and Therapy
癌症生物学和治疗中的内质网伴侣
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$ 53.79万 - 项目类别:
Endoplasmic Reticulum Chaperones in Cancer Biology and Therapy
癌症生物学和治疗中的内质网伴侣
- 批准号:
9770790 - 财政年份:2015
- 资助金额:
$ 53.79万 - 项目类别:
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