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: 8934510
• 负责人: Zihai Li
• 金额: $ 133.75万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8934510
• 关键词: ATPase Domain; Achievement; Applications Grants; Area; Basic Science; Binding; Biogenesis; Biological; Biological Markers; Biology; Cancer Biology; Cancer Model; Cell physiology; Cell surface; Characteristics; Chemicals; Client; Clinical; Collaborations; Complex; Data; Development; Disease; Docking; ERBB2 gene; Endoplasmic Reticulum; Family; Generations; Goals; Heat-Shock Proteins 90; Human; Immunology; Institutes; Institution; Integrins; Investigation; Joints; Knock-in Mouse; Knockout Mice; Knowledge; Laboratories; Link; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of ovary; Mammary Neoplasms; Mediating; Medical; Medical Research; Membrane; Memorial Sloan-Kettering Cancer Center; Mitochondria; Modeling; Molecular; Molecular Chaperones; Multiple Myeloma; N-terminal; Neoplasm Metastasis; Oncogenic; Pharmaceutical Preparations; Pharmacology; Phenotype; Post-Translational Protein Processing; Process; Program Research Project Grants; Proteins; Publications; Purines; Recording of previous events; Records; Research; Research Institute; Resources; Role; South Carolina; Staging; Structure; Surface; System; Therapeutic; Time; Toll-like receptors; Transforming Growth Factor beta; Translations; Tumor Biology; Universities; Work; base; cancer addiction; cancer cell; cancer therapy; cancer type; clinically relevant; design; drug discovery; genetic approach; inhibitor/antagonist; interest; lipoprotein receptor-related protein 6; malignant breast neoplasm; melanoma; member; mouse model; neglect; new therapeutic target; novel; paralogous gene; pre-clinical research; preclinical study; programs; protein folding; purine; receptor; response; scaffold; small molecule; structural biology; success; targeted treatment; therapeutic target; tool; tumor progression; tumorigenesis

DESCRIPTION (provided by applicant): The overall goal of this PPG proposal is to advance fundamental understanding of grp94, a major oncogenic chaperone in the endoplasmic reticulum (ER), with the ultimate objective of developing rational grp94-based cancer therapeutics. Also known as gp96, endoplasmin, and Hsp90b1, grp94 is the recently evolved ERresident member of the HSP90 family. Its expression is upregulated by the unfolded protein response that is characteristic of cancer cells. Over-expression of grp94 in cancers uniformly correlates with advanced stage and poor survival. Four recent publications from this PPG group have further cemented the oncogenic roles of grp94. Despite its high relevance in cancer, the understanding of the function and mechanism of grp94 has lagged behind that of other molecular chaperones. This has now begun to change, with several key observations with regard to client repertoire, cellular function, disease implications, structural biology, and speciic inhibitors coming from the laboratories of this PPG team. This team has shown that grp94 is an essential master chaperone for Toll-like receptors (TLRs), integrins, Wnt co-receptor LRP6, HER2 and TGFβ- surface docking molecule GARP. The chaperone function of grp94 depends on its ATPase domain, which has been structurally resolved by the team and shown to be distinct from that of cytosolic Hsp90, enabling the successful development of several highly selective grp94 inhibitors. Two pressing tasks impede further advances in this field: 1) understanding the fundamental roles of grp94 in cancer biology; and 2) developing and validating effective grp94 inhibitors for development and clinical translation as grp94-based cancer therapeutics. This Program Project is designed to overcome both obstacles by uniting, in three Projects and two Cores, three leading laboratories in the field of grp94 research: biology (Li), structural biology (Gewirth) and drug discovery (Chiosis). This collaboration synergizes resources from three leading institutes -MUSC, Memorial Sloan-Kettering and Hauptman-Woodward - and builds on the Project Leaders' inherent shared interests, proven track records (57 joint publications) and complementary expertise. The specific goals of this PPG include: Project 1) Determine the role and significance of grp94 in controlling TGFβ biogenesis and TGFβ-mediated cancer progression via folding GARP and integrins; Project 2) Develop chemical tools that enable a spatio-temporal investigation of grp94-regulated cancer mechanisms in cancer phenotypes; Project 3) Elucidate the chaperone mechanism of grp94 as well as grp94 inhibitors from the structural point-of-view. The success of these projects will significantly advance understanding of how grp94 functions in cancer biology molecularly, why 'grp94-addiction' by cancer appears to span a wide spectrum of cancer types, how grp94 differs structurally and functionally from other HSP90 paralogs in binding to ATP and purine scaffold inhibitors, what are the ideal cancer types for grp94-targeted therapy, and whether a novel class of highly selective grp94 inhibitors can be used to probe the tumor biology and biological significance of grp94-client networks in cancer.

描述（由适用提供）：该PPG提案的总体目标是促进对GRP94的基本了解，GRP94是内质网中主要的致癌伴侣（ER），其最终目标是开发基于理性的GRP94癌症疗法。 GRP94也称为GP96，内质蛋白和HSP90B1，是HSP90家族的最近进化的成员。它的表达是通过癌细胞特征的未折叠蛋白反应来更新的。癌症中GRP94的过表达均匀地与晚期阶段和不良的生存相关。该PPG小组的四本出版物进一步巩固了GRP94的致癌作用。尽管它在癌症方面具有很高的相关性，但对GRP94功能和机制的理解仍落后于其他分子伴侣的功能和机制。现在，这已经开始改变，关于客户曲目，细胞功能，疾病的影响，结构生物学和来自该PPG团队实验室的特定抑制剂的几个关键观察。该团队已经表明，GRP94是通信样受体（TLR），整联蛋白，Wnt共受体LRP6，HER2和TGFβ-表面对接分子GARP的必不可少的主链。 GRP94的链酮函数取决于其ATPase结构域，该结构域已在结构上由团队解决，并显示与细胞溶剂HSP90的链条不同，从而成功地开发了几种高度选择性的GRP94抑制剂。两项紧迫的任务阻碍了这一领域的进一步发展：1）了解GRP94在癌症生物学中的基本作用； 2）开发和验证有效的GRP94抑制剂以开发和临床翻译为基于GRP94的癌症治疗。该计划项目旨在通过在GRP94研究领域的三个项目和两个核心的三个领先实验室中团结两种障碍来克服这两个障碍：生物学（LI），结构生物学（Gewirth）（Gewirth）和药物发现（Chiosic）。这种合作使来自三个领先的机构-MUSC，纪念斯隆 - 凯特林和Hauptman -Woodward的资源协同作用，并建立在项目领导者继承的共同利益，经过验证的往绩记录（57个联合出版物）和补充专业知识的基础上。该PPG的具体目标包括：项目1）确定GRP94在控制TGFβ生物发生和TGFβ介导的癌症进展中的作用和意义；项目2）开发化学工具，使GRP94调节的癌症机制在癌症表型中进行空间时间投资；项目3）从结构观察点阐明了GRP94的伴侣机理以及GRP94抑制剂。这些项目的成功将显着提高人们对GRP94在癌症生物学中的作用的理解，为什么癌症的“ GRP94-添加”似乎跨越了广泛的癌症类型，GRP94在结构上和功能上如何在其他HSP90旁系同源物上与ATP和纯caffort in a a grp94的组合类型以及是否具有GRP94的grp94 conterags在结构上和功能上有所不同，GRP94是否具有GRP94-GRP94-GRP94-grp9 4 GRP94抑制剂可用于探测癌症中GRP94-CLIENT网络的肿瘤生物学和生物学意义。