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（由申请人提供）：本PPG提案的总体目标是推进对grp 94（内质网（ER）中的一种主要致癌伴侣）的基本了解，最终目标是开发合理的基于grp 94的癌症治疗方法。grp 94也被称为gp 96、内质蛋白和Hsp 90 b1，是最近进化的HSP 90家族的ER常驻成员。它的表达被癌细胞特有的未折叠蛋白反应上调。grp 94在癌症中的过度表达与晚期和低生存率一致相关。PPG组最近的4篇出版物进一步巩固了grp 94的致癌作用。尽管grp 94与癌症高度相关，但对其功能和机制的理解仍落后于其他分子伴侣。这一点现在已经开始改变，PPG团队的实验室对客户库、细胞功能、疾病影响、结构生物学和特异性抑制剂进行了几项关键观察。该团队已经证明grp 94是Toll样受体（TLR），整合素，Wnt辅助受体LRP 6，HER 2和TGFβ表面对接分子GARP的重要主分子伴侣。grp 94的伴侣功能取决于其ATP酶结构域，该结构域已被研究小组在结构上解析，并显示出与胞质Hsp 90不同，从而成功开发了几种高选择性的grp 94抑制剂。两个紧迫的任务阻碍了该领域的进一步发展：1）理解grp 94在癌症生物学中的基本作用; 2）开发和验证有效的grp 94抑制剂，用于开发和临床转化为基于grp 94的癌症疗法。该计划项目旨在通过三个项目和两个核心，将grp 94研究领域的三个领先实验室联合起来克服这两个障碍：生物学（Li），结构生物学（Gephalth）和药物发现（Chiosis）。这种合作协同了三个领先机构-MUSC，Memorial Sloan-Kettering和Hauptman-Woodward -的资源，并建立在项目领导人固有的共同利益，经过验证的跟踪记录（57份联合出版物）和互补的专业知识基础上。本PPG的具体目标包括：项目1）确定grp 94在通过折叠GARP和整合素控制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，能够在癌症表型中时空研究grp 94调节的癌症机制;项目3）从结构角度阐明grp 94及其抑制剂的分子伴侣作用机制。这些项目的成功将大大推进对grp 94在癌症生物学中分子功能的理解，为什么癌症的“grp 94成瘾”似乎跨越广泛的癌症类型，grp 94在结构和功能上与其他HSP 90旁系同源物在结合ATP和嘌呤支架抑制剂方面的不同，grp 94靶向治疗的理想癌症类型，以及一类新的高选择性GRP 94抑制剂是否可用于探测肿瘤生物学和GRP 94-客户网络在癌症中的生物学意义。