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）：该PPG提案的总体目标是推进对内质网（ER）中主要致癌伴侣grp94的基本了解，最终目标是开发合理的基于grp94的癌症治疗方法。grp94也被称为gp96、endoplasmin和Hsp90b1，是最近进化的HSP90家族的ERresident成员。它的表达被未折叠蛋白反应上调，这是癌细胞的特征。grp94在癌症中的过表达与晚期和低生存率一致相关。该PPG小组最近发表的四篇文章进一步巩固了grp94的致癌作用。尽管grp94在癌症中具有很高的相关性，但对其功能和机制的了解却落后于其他分子伴侣。这种情况现在已经开始改变，来自PPG团队实验室的一些关于客户库、细胞功能、疾病影响、结构生物学和特异性抑制剂的关键观察结果。该团队已经证明grp94是toll样受体（TLRs）、整合素、Wnt共受体LRP6、HER2和TGFβ-表面对接分子GARP的重要主伴侣。grp94的伴侣功能取决于它的atp酶结构域，该团队已经在结构上解决了这一问题，并证明它与细胞质Hsp90不同，从而成功开发了几种高选择性grp94抑制剂。两个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，以开发和临床转化为基于grp94的癌症治疗药物。该项目旨在通过在三个项目和两个核心中联合grp94研究领域的三个领先实验室来克服这两个障碍：生物学（Li），结构生物学（Gewirth）和药物发现（Chiosis）。这一合作将三个主要研究所（musc、Memorial Sloan-Kettering和Hauptman-Woodward）的资源协同起来，并建立在项目领导者固有的共同兴趣、可靠的业绩记录（57份联合出版物）和互补的专业知识基础上。该PPG的具体目标包括：项目1)确定grp94通过折叠GARP和整合素在控制TGFβ生物发生和TGFβ介导的癌症进展中的作用和意义；项目2)开发能够对grp94调控的癌症表型机制进行时空研究的化学工具；项目3)从结构角度阐明grp94及其抑制剂的伴侣作用机制。这些项目的成功将极大地促进对grp94在癌症生物学中的分子功能的理解，为什么癌症的“grp94成瘾”似乎跨越了广泛的癌症类型，grp94在与ATP和嘌呤支架抑制剂结合方面与其他HSP90相似物在结构和功能上有何不同，grp94靶向治疗的理想癌症类型是什么。以及是否可以利用一类新的高选择性grp94抑制剂来探索grp94-client网络在癌症中的肿瘤生物学和生物学意义。