Determining the role of RALA and RALB in soft tissue sarcoma tumor growth and metastasis

确定 RALA 和 RALB 在软组织肉瘤肿瘤生长和转移中的作用

基本信息

批准号：
9759887
负责人：
Steven T. Sizemore
金额：
$ 18.68万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-08 至 2020-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9759887
关键词：
Address Adult Award Biological Biological Models Breast cancer metastasis Cancer Research Project Cell Line Cells Cessation of life Clinic Clinical Pathways Collection Complex Comprehensive Cancer Center Coupling Data Department of Defense Disease Doctor of Philosophy Drug Targeting Effectiveness Electrons Exhibits Faculty Foundations Future Gene Expression Genetic Goals Grant Growth Guanosine Triphosphate Phosphohydrolases In Vitro Incidence Laboratories Lung Malignant Neoplasms Mediating Mesenchymal Metastatic Neoplasm to the Lung Metastatic to Microscopic Modeling Molecular Monomeric GTP-Binding Proteins Mus National Cancer Institute Neoplasm Metastasis Normal tissue morphology Nude Mice Ohio Operative Surgical Procedures PPP2R1B gene Pathway interactions Patients Phosphoproteins Phosphoric Monoester Hydrolases Phosphorylation Play Population Postdoctoral Fellow Production Protein Isoforms Protein Phosphatase 2A Regulatory Subunit PR53 Protein phosphatase Proteins RALA gene Radiation Research Role Sampling Seeds Signal Pathway Soft tissue sarcoma Stains Testing Time Tissue Sample Tissues Training Tumor Suppressor Proteins Universities Western Blotting Work Xenograft procedure advanced disease base clinical application cohort collaborative environment effective therapy exosome experimental study extracellular vesicles improved improved outcome in vivo inhibitor/antagonist innovation knock-down malignant breast neoplasm mutant novel overexpression prognostic prospective tenure track therapeutic target three dimensional cell culture tumor tumor growth tumor xenograft

项目摘要

Project Summary/Abstract The K22 applicant, Dr. Steven Sizemore, obtained his Ph.D. in the laboratory of Dr. Graham Casey at the Cleveland Clinic Foundation. His dissertation research focused on the fundamental mechanisms underlying breast cancer metastasis. The candidate's training continued as a Department of Defense CDMRP Breast Cancer Research Program supported postdoctoral fellow at Case Western Reserve University. This work concentrated on identifying the molecular drivers of basal-like breast cancer. Currently, the candidate is a Senior Research Associate at The Ohio State University James Comprehensive Cancer Center (OSUCCC). The OSUCCC is ranked by the National Cancer Institute as an “exceptional” center and provides a vibrant and collaborative environment in which the candidate has continued his training towards his long-term goal of becoming tenure-track faculty at a Research I level university. The candidate's current work, on which this proposal is based, centers on identifying the master regulators of soft tissue sarcoma (STS) metastasis and is supported through a seed grant from the OSUCCC. STS is a diverse collection of cancers of mesenchymal origin. The 5-year survival for patients with metastatic STS is a dismal 16% and there are few treatment options for these patients. The long-term objective of this research is to address the urgent, unmet need for a better understanding of the key molecular pathways that drive metastasis in STS and identify inhibitors of these pathways to improve the treatment options for advanced STS. In pursuit of this objective, the candidate identified the phosphatase subunit PPP2R1B as a suppressor of STS metastasis and one of its phosphoprotein targets, RALA, as a putative actionable target for treating advanced STS. This proposal will thoroughly test the hypothesis that RALA, and the closely related RALB, are important and targetable drivers of STS tumor growth and metastasis that regulate STS progression, at least in part, by controlling exosome production. Specific Aim 1: will test the functional requirement of the RAL isoforms and their effectors in STS growth and metastasis in vitro and in vivo by coupling genetic silencing of these isoforms with rescue experiments utilizing specific interaction-deficient RAL mutants. Specific Aim 2: will investigate the essential requirement of the RAL isoforms and their effectors in exosome production by STS cells and determine if these RAL-dependent exosomes control tumor growth and metastasis. Specific Aim 3: will utilize STS cell lines and patient derived xenografts to determine the effectiveness of RAL-targeting inhibitors as innovative treatments for STS. Successful completion of this proposal will identify an important actionable target for improved treatment of advanced STS and identify a novel mechanism regulating cancer exosomes. This award will allow the candidate the protected time required to transition his research from a breast cancer- focus to the understudied field of STS metastasis and acquire the additional training required to become a leader in the field of cancer-associated exosomes.

项目概要/摘要 K22 申请者 Steven Sizemore 博士在 Graham Casey 博士的实验室获得博士学位。他的论文研究重点是克利夫兰诊所基金会的基本机制。候选人继续接受国防部 CDMRP 乳腺癌培训。癌症研究计划支持凯斯西储大学的博士后研究员这项工作。目前，该候选者致力于识别基底样乳腺癌的分子驱动因素。俄亥俄州立大学詹姆斯综合癌症中心 (OSUCCC) 高级研究员。 OSUCCC 被美国国家癌症研究所评为“杰出”中心，并提供充满活力和候选人继续接受培训以实现其长期目标的协作环境成为研究一级大学的终身教授。该提案的基础是，重点是确定软组织肉瘤（STS）转移的主要调节因子，并且是由 OSUCCC 的种子资助支持的是多种间充质癌症。转移性 STS 患者的 5 年生存率仅为 16%，而且治疗方法很少。这项研究的长期目标是解决迫切的、未满足的需求。更好地了解驱动 STS 转移的关键分子途径并识别抑制剂这些途径可以改善晚期 STS 的治疗选择。为了实现这一目标，候选人。确定磷酸酶亚基 PPP2R1B 是 STS 转移的抑制因子及其之一磷蛋白靶标 RALA 作为治疗晚期 STS 的假定可行靶标。彻底检验 RALA 和密切相关的 RALB 的重要性和可针对性的假设 STS 肿瘤生长和转移的驱动因素至少部分地调节 STS 进展控制外泌体的产生。具体目标 1：测试 RAL 亚型的功能要求和通过耦合这些亚型的基因沉默，在体外和体内的 STS 生长和转移中发挥效应子利用特定相互作用缺陷的 RAL 突变体进行救援实验特定目标 2：将研究 STS 细胞产生外泌体时 RAL 亚型及其效应物的基本要求确定这些 RAL 依赖性外泌体是否控制肿瘤生长和转移：将利用具体目标 3。 STS 细胞系和患者来源的异种移植物，以确定 RAL 靶向抑制剂的有效性 STS 的创新治疗方法的成功完成将确定一个重要的可操作的方法。改善晚期 STS 治疗的目标，并确定调节癌症外泌体的新机制。该奖项将为候选人提供将其研究从乳腺癌转移到所需的受保护时间- 专注于 STS 转移的研究领域，并获得成为 STS 转移所需的额外培训癌症相关外泌体领域的领导者。