Endoplasmic Reticulum Chaperones in Cancer Biology and Therapy

癌症生物学和治疗中的内质网伴侣

基本信息

批准号：
9770790
负责人：
Zihai Li
金额：
$ 135.49万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-01 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9770790
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 Collaborations Complex Crystallization Data Development Disease Docking ERBB2 gene Endoplasmic Reticulum Generations Goals Heat-Shock Proteins 90 Human Immunology Individual 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 Biology 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 Structure Surface System Therapeutic Time Toll-like receptors Transforming Growth Factor beta Tumor Biology Universities Work base cancer addiction cancer cell cancer therapy cancer type clinical development clinical translation clinically relevant design drug discovery genetic approach inhibitor/antagonist interest malignant breast neoplasm melanoma member mouse model neglect new therapeutic target novel overexpression paralogous gene pre-clinical research preclinical study programs protein folding receptor response scaffold small molecule inhibitor spatiotemporal structural biology success targeted treatment therapeutic target tool tumor progression tumorigenesis

项目摘要

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 提案的总体目标是增进对 grp94（内质网 (ER) 中主要致癌分子伴侣）的基本了解，最终目标是开发基于 grp94 的合理癌症疗法。 gp96、内质蛋白和 Hsp90b1、grp94 是 HSP90 家族中最近进化的 ER 常驻成员，其表达被上调。该 PPG 小组最近发表的四篇论文进一步证实了 grp94 的致癌作用，这是癌细胞的特征。对 grp94 功能和机制的理解落后于其他分子伴侣，这种情况现在已经开始改变，在客户库、细胞功能、疾病影响、结构生物学和功能方面有一些关键观察。来自该 PPG 团队实验室的特异性抑制剂表明 grp94 是 Toll 样受体 (TLR)、整合素、Wnt 辅助受体 LRP6、HER2 和 TGFβ-表面对接分子 GARP 的重要主伴侣。 grp94的功能取决于其ATPase结构域，该结构域已被团队解析并显示与胞质的不同Hsp90，使得多种高选择性 grp94 抑制剂的成功开发成为阻碍该领域进一步发展的两个紧迫任务：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 抑制剂用于开发和临床转化。基于 grp94 的癌症疗法旨在通过联合 grp94 研究领域的三个领先实验室的三个项目和两个核心来克服这两个障碍。 (Li)、结构生物学 (Gewirth) 和药物发现 (Chiosis)，这项合作整合了三个领先研究所（MUSC、Memorial Sloan-Kettering 和 Hauptman-Woodward）的资源，并建立在项目负责人固有的共同兴趣和可靠的记录基础上。（57 份联合出版物）和补充专业知识该 PPG 的具体目标包括：项目 1) 确定 grp94 在控制 TGFβ 生物发生和 TGFβ 介导中的作用和意义。通过折叠 GARP 和整合素研究癌症进展；项目 2）开发化学工具，对癌症表型中 grp94 调节的癌症机制进行时空研究；项目 3）从结构角度阐明 grp94 和 grp94 抑制剂的伴侣机制 -这些项目的成功将显着促进对 grp94 在癌症生物学中如何发挥分子作用的理解，以及为什么癌症似乎会导致“grp94 成瘾”。涵盖广泛的癌症类型，grp94 在与 ATP 和嘌呤支架抑制剂结合方面与其他 HSP90 旁系同源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，以及一类新型的高选择性 grp94 抑制剂是否可以用于探索癌症中 grp94-client 网络的肿瘤生物学和生物学意义。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

STK33 participates to HSP90-supported angiogenic program in hypoxic tumors by regulating HIF-1α/VEGF signaling pathway.

STK33 通过调节 HIF-1α/VEGF 信号通路参与缺氧肿瘤中 HSP90 支持的血管生成程序。

DOI：
发表时间：
2017-09-29
期刊：
影响因子：
0
作者：
Liu, Yang;Steinestel, Konrad;Rouhi, Arefeh;Armacki, Milena;Diepold, Kristina;Chiosis, Gabriela;Simmet, Thomas;Seufferlein, Thomas;Azoitei, Ninel
通讯作者：
Azoitei, Ninel

Measuring Tumor Epichaperome Expression Using [124I] PU-H71 Positron Emission Tomography as a Biomarker of Response for PU-H71 Plus Nab-Paclitaxel in HER2-Negative Metastatic Breast Cancer.

使用 [124I] PU-H71 正电子发射断层扫描测量肿瘤表层表达，作为 PU-H71 加白蛋白结合型紫杉醇在 HER2 阴性转移性乳腺癌中的反应生物标志物。

DOI：
发表时间：
2020
期刊：
影响因子：
4.6
作者：
Jhaveri, Komal L;Dos Anjos, Carlos H;Taldone, Tony;Wang, Rui;Comen, Elizabeth;Fornier, Monica;Bromberg, Jacqueline F;Ma, Weining;Patil, Sujata;Rodina, Anna;Pillarsetty, Nagavarakishore;Duggan, Susan;Khoshi, Sarhe;Kadija, Nathan;Chiosis, Gabr
通讯作者：
Chiosis, Gabr

Bisubstrate-Type Chemical Probes Identify GRP94 as a Potential Target of Cytosine-Containing Adenosine Analogs.

双底物型化学探针将 GRP94 识别为含胞嘧啶腺苷类似物的潜在靶标。

DOI：
发表时间：
2020
期刊：
影响因子：
4
作者：
Pechalrieu, Dany;Assemat, Fanny;Halby, Ludovic;Marcellin, Marlene;Yan, Pengrong;Chaoui, Karima;Sharma, Sahil;Chiosis, Gabriela;Burlet;Arimondo, Paola B;Lopez, Marie
通讯作者：
Lopez, Marie

GRP94/gp96 in Cancer: Biology, Structure, Immunology, and Drug Development.

GRP94/gp96 在癌症中的作用：生物学、结构、免疫学和药物开发。