Defining and targeting ER quality control dependence in rhabdomyosarcoma

横纹肌肉瘤中 ER 质量控制依赖性的定义和目标

• 批准号: 10442663
• 负责人: Amit J. Sabnis
• 金额: $ 22.88万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-16 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10442663
• 关键词: Apoptosis; Authorship; Award; Biological; Biological Markers; Biology; CRISPR interference; Cell Survival; Cells; Child; Client; Clinical; Clinical Oncology; Clinical Trials; Data; Dependence; Disease; Doctor of Philosophy; Endoplasmic Reticulum; Ensure; Environment; Eukaryotic Cell; Failure; Future; Genetic; Goals; Half-Life; Heat-Shock Proteins 70; Homeostasis; Institution; Instruction; Laboratories; Lead; Malignant Childhood Neoplasm; Malignant Neoplasms; Medical Oncologist; Medicine; Mentors; Mentorship; Modeling; Molecular; Molecular Biology; Molecular Chaperones; Mus; Nature; Oncogenes; Outcome; Patients; Pediatric Oncologist; Pediatric Oncology; Pharmaceutical Preparations; Pharmacology; Phenotype; Positioning Attribute; Postdoctoral Fellow; Pre-Clinical Model; Principal Investigator; Prognosis; Property; Protein Inhibition; Proteins; Publications; Quality Control; Reporter; Research; Research Personnel; Research Support; Rhabdomyosarcoma; Series; Soft tissue sarcoma; Solid Neoplasm; Structure; Testing; Therapeutic; Training; Translating; Translations; Treatment Efficacy; Ubiquitination; United States National Institutes of Health; Work; antitumor effect; base; biomarker-driven; cancer cell; cancer therapy; cancer type; career development; chemotherapy; childhood sarcoma; clinical translation; design; endoplasmic reticulum stress; fighting; genetic manipulation; genotoxicity; high risk; improved; in vivo; in vivo Model; inhibitor; innovation; knock-down; misfolded protein; new therapeutic target; novel; novel strategies; novel therapeutic intervention; p97 ATPase; patient derived xenograft model; patient prognosis; pharmacokinetics and pharmacodynamics; preclinical trial; proteostasis; research clinical testing; response; response biomarker; sarcoma; sensor; small molecule; therapeutic target

Candidate. Dr. Sabnis is a pediatric oncologist with training in genetics and molecular biology whose long-term goal is to lead an independent laboratory defining and targeting vulnerabilities in the protein homeostasis networks of pediatric sarcomas. He has begun to establish himself as a leader in this field through a first author publication in PNAS detailing HSP70 dependence in rhabdomyosarcoma (RMS) and contributing authorship on publications in Nature Medicine and Nature Genetics. This K08 award will be a critical vehicle for his ongoing career development, providing key mentorship and instruction in 1) designing preclinical trials to enable clinical translation of bench research, 2) probing the ER quality control mechanisms cancer cells subvert to support their survival, and 3) using genetic manipulation and cell biologic readouts to interrogate proteostasis in sarcoma biology. Environment. UCSF is an outstanding research environment with 1300 principal investigators and over $500 million in support from the NIH (ranking 2nd among all institutions). Two co-mentors will help Dr. Sabnis achieve his aims. Dr. Trever Bivona, MD PhD, is a medical oncologist with expertise in biologically defining rational polytherapy for oncogene-driven solid tumors. Dr. Bivona has extensive research support including an NIH Innovator’s Award and several R01s, and has mentored five post-doctoral fellows into independent positions in the last five years. Dr. Sabnis will be co-mentored by Dr. Kevin Shannon, MD, a pediatric oncologist who has been the primary mentor for multiple K-series award recipients from the NCI. Dr. Sabnis will also meet semi- annually with a mentoring committee, comprised of Dr. Bivona; Dr. Shannon; Dr. Jonathan Weissman, an expert in ER quality control and mentor to many K-supported trainees; and Dr. Kate Matthay, a pre-eminent pediatric oncology clinical researcher who will support the clinical translation of his discoveries. Research. High-risk RMS patients have dismal outcomes despite maximally intensified chemotherapy, highlighting a need for new, biology-driven treatments. We found that inhibiting the cytosolic protein chaperone HSP70 lethally activates the unfolded protein response (UPR) in RMS, but not in other cancers. I hypothesize that RMS cells rely on HSP70, acting together with its co-chaperone DNAJC17 and the ATPase p97, to lower ER protein load through ER-associated degradation (ERAD). ERAD inhibition in RMS thus defines a novel therapeutic strategy. In aim 1, we will test the pharmacologic parameters and efficacy of two drugs that disrupt ER quality control in murine RMS models. In aim 2, we will identify the structural domains of DNAJC17 that are necessary to maintain ER homeostasis, and test the hypothesis that this HSP70-DNAJC17-p97 axis enables ERAD and thereby ensures RMS cell survival. These aims will provide crucial molecular detail into the basis of the RMS-specific lethality of HSP70 inhibition we discovered. Overall, this work will catalyze a broader effort to discover therapeutic targets in sarcoma proteostasis network that will be the basis for future R01 proposals. !

候选人。 Sabnis 博士是一位儿科肿瘤学家，接受过遗传学和分子生物学方面的培训，长期从事 目标是领导一个独立的实验室，定义和针对蛋白质稳态的脆弱性 小儿肉瘤网络。他已开始通过第一作者确立自己在该领域的领导者地位 在 PNAS 上发表的文章详细介绍了横纹肌肉瘤 (RMS) 中的 HSP70 依赖性和特约作者身份 发表在《自然医学》和《自然遗传学》上的出版物。这个 K08 奖项将成为他的重要工具 持续的职业发展，提供关键的指导和指导：1）设计临床前试验 实现实验室研究的临床转化，2) 探索癌细胞的 ER 质量控制机制 颠覆以支持其生存，以及 3）使用基因操作和细胞生物学读数来审问 肉瘤生物学中的蛋白质稳态。 环境。 UCSF 拥有出色的研究环境，拥有 1300 名主要研究人员和超过 500 美元的经费 来自 NIH 的支持（在所有机构中排名第二）。两位共同导师将帮助 Sabnis 博士实现 他的目标。 Trever Bivona 博士，医学博士，博士，是一位医学肿瘤学家，在生物学定义合理性方面拥有专业知识 癌基因驱动的实体瘤的多疗法。 Bivona 博士拥有广泛的研究支持，包括 NIH 荣获创新者奖和多项 R01，并指导 5 名博士后研究员担任独立职位 过去五年。 Sabnis 博士将由儿科肿瘤学家 Kevin Shannon 博士共同指导。 是 NCI 多个 K 系列奖项获得者的主要导师。 Sabnis 博士还将与半 每年与一个由 Bivona 博士组成的指导委员会合作；香农博士；乔纳森·韦斯曼博士 ER 质量控制专家，并指导许多 K 支持的学员；以及杰出的凯特·马赛 (Kate Matthay) 博士 儿科肿瘤学临床研究员，将支持他的发现的临床转化。 研究。尽管最大限度地强化化疗，高危 RMS 患者的结局仍令人沮丧， 强调需要新的、生物学驱动的治疗方法。我们发现抑制胞浆蛋白伴侣 HSP70 在 RMS 中致命地激活未折叠蛋白反应 (UPR)，但在其他癌症中则不然。我假设 RMS 细胞依赖 HSP70 与其共伴侣 DNAJC17 和 ATPase p97 一起作用，以降低 通过内质网相关降解 (ERAD) 加载内质网蛋白。因此，RMS 中的 ERAD 抑制定义了一种新的 治疗策略。在目标 1 中，我们将测试两种破坏药物的药理学参数和功效。 小鼠 RMS 模型中的 ER 质量控制。在目标 2 中，我们将确定 DNAJC17 的结构域，它们是 维持 ER 稳态所必需的，并测试该 HSP70-DNAJC17-p97 轴能够实现的假设 ERAD 从而确保 RMS 细胞存活。这些目标将为基础提供关键的分子细节 我们发现 HSP70 抑制的 RMS 特异性致死率。总体而言，这项工作将促进更广泛的努力 发现肉瘤蛋白质稳态网络中的治疗靶点，这将成为未来 R01 提案的基础。 ！

项目成果

Rare FGFR Oncogenic Alterations in Sequenced Pediatric Solid and Brain Tumors Suggest FGFR Is a Relevant Molecular Target in Childhood Cancer.

• DOI: 10.1200/po.22.00390
• 发表时间: 2022-11
• 期刊: JCO precision oncology
• 影响因子: 4.6

Clinical characteristics and outcomes of infants compared with children diagnosed with rhabdomyosarcoma: Analysis of surveillance, epidemiology and end results data from 2000 to 2016.

• DOI: 10.1002/cnr2.1503
• 发表时间: 2022-05
• 期刊: CANCER REPORTS
• 影响因子: 1.7
• 作者: Rees, Hannah D.;Hills, Nancy K.;Sabnis, Amit J.;Tulpule, Asmin B.;Shimotake, Tom K.;Goldsby, Robert E.
• 通讯作者: Goldsby, Robert E.

Germline Sequencing Improves Tumor-Only Sequencing Interpretation in a Precision Genomic Study of Patients With Pediatric Solid Tumor.

在儿科实体瘤患者的精确基因组研究中，种系测序改善了仅肿瘤测序的解释。

• DOI: 10.1200/po.21.00281
• 发表时间: 2021
• 期刊: JCO precision oncology
• 影响因子: 4.6
• 作者: Schienda,Jaclyn;Church,AlannaJ;Corson,LauraB;Decker,Brennan;Clinton,CatherineM;Manning,DanielleK;Imamovic-Tuco,Alma;Reidy,Deirdre;Strand,GiannaR;Applebaum,MarkA;Bagatell,Rochelle;DuBois,StevenG;Glade-Bender,JuliaL;Kang,W
• 通讯作者: Kang,W