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

项目摘要/摘要 K22申请人Steven Sizemore博士在Graham Casey博士的实验室获得博士学位 克利夫兰诊所基金会。他的论文研究集中在潜在的基本机制上 乳腺癌转移。候选人的训练继续作为国防部CDMRP乳房 癌症研究项目资助了凯斯西储大学的博士后研究员。这部作品 专注于识别基底细胞样乳腺癌的分子驱动因素。目前，候选人是一名 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，它提供了一个充满活力和 应聘者继续接受培训以实现其长期目标的协作环境 成为研究型I级大学的终身教职员工。候选人目前的工作，这一点 提案的基础是，重点是确定软组织肉瘤(STS)转移的主要调节因素，并 由OSUCCC提供的种子赠款支持。STS是间充质细胞癌的多样化集合。 起源。转移的STS患者的5年存活率只有16%，令人沮丧，而且几乎没有治疗方法。 这些患者的选择。这项研究的长期目标是解决迫切的、未得到满足的对 更好地了解STS中驱动转移的关键分子途径，并确定抑制STS转移的因素 这些途径可以改善晚期STS的治疗选择。为了追求这一目标，候选人 发现磷酸酶亚单位PPP2R1B是STS转移的抑制因子，也是其 磷酸蛋白靶点，RALA，作为治疗晚期STS的假定可操作靶点。这项提议将 彻底测试假设，即Rala和密切相关的RALB是重要的和有针对性的 STS肿瘤生长和转移的驱动因素调节STS进展，至少部分是通过 控制外切体的生产。具体目标1：将测试al异构体的功能要求和 它们通过偶联这些异构体的遗传沉默在STS生长和转移中的作用 利用特定的相互作用缺陷的ral突变体进行抢救实验。具体目标2：将调查 STS细胞和细胞外切体生产中对ral异构体及其效应物的基本要求 确定这些依赖RAR的外切体是否控制肿瘤的生长和转移。具体目标3：将利用 STS细胞株和患者来源的异种移植以确定RAR靶向抑制剂AS的有效性 STS的创新治疗方法。成功完成这项提案将确定一个重要的可操作的 以改善晚期STS的治疗为目标，并确定调节癌症外切体的新机制。 这项奖励将允许候选人获得所需的保护时间，将他的研究从乳腺癌转移到 专注于研究不足的STS转移领域，并获得成为 癌症相关外切体领域的领导者。

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.