Elucidating and exploiting the mechanisms by which IL-6 and IL-8 facilitate osteosarcoma metastasis

职业发展建议摘要 该职业发展奖将支持瑞安·D·罗伯茨博士的工作，医学博士，博士。它将为他提供 有独特的机会在受保护和指导的环境中发展他的调查技能。它将促进 产生足够的研究核心机构，使他能够成功地竞争R01- 资金水平和向独立的过渡。 瑞安是儿科血液学、肿瘤学和骨髓移植的研究员，在他生命的最后几个月 训练。他在俄亥俄州立大学获得了综合生物医学博士学位，并在那里学习 肿瘤-宿主相互作用与肿瘤免疫学。他的研究生工作展示了乳腺肿瘤细胞如何 以促进肿瘤生长和扩散的方式与巨噬细胞相互作用。他证明了这一点 治疗性细胞因子疗法可以使这些巨噬细胞具有抗肿瘤的行为。 年，他在全国儿童医院担任儿科研究住院医生时开始了目前的工作 在他担任研究员期间，他继续着这项工作。他的实验室表明，IL-6和IL-8在 在促进骨肉瘤细胞从循环中招募到血液中的动力学中的重要作用 肺和这些组织的生长。拟议的研究计划旨在通过以下方式描述这些机制 这些细胞因子驱动了转移过程，并探索了针对这些途径的可能性 对于防止转移形成和治疗现有的肺转移可能有作用： 目标1将确定肿瘤来源和肺来源的IL-6和IL-8在转移中的相对重要性。 Aim 2将确定介导这一过程的细胞间信号环，即哪个常驻肺 肿瘤细胞与之相互作用的细胞以及其他什么细胞因子参与其中。 Aim 3将测试IL-6和IL-8途径中断对防止转移的治疗潜力 并确定在肿瘤切除周围是否存在这样的治疗方法的机会 可能特别相关。 与这项研究建议相结合的是一项全面的职业发展计划，该计划建立在 坚实的导师关系。Ryan将享受来自以下人员的系统和持续的指导： 史蒂芬·莱斯尼克，医学博士，他的中心主任，国际知名的肉瘤生物学家， 独立描述了导致尤文肉瘤恶性的大部分分子病理生理学。 蒂莫西·克里普，医学博士，他的部门主席，国际上受人尊敬的溶瘤病毒和 儿科肉瘤，他领导着自己的几个I期临床试验。 彼得·霍顿博士，他的前中心主任和主要导师， 临床前药物评估和NCI儿科临床前试验项目负责人。 Denis Guttridge博士，肌肉生物学和横纹肌肉瘤方面的非常成功的专家 在剖析炎症信号通路方面具有特殊的专业知识。 林家玉，博士，他所在部门的同事，在炎症受体方面有丰富的经验 生物化学，包括靶标验证。 查尔斯·凯勒，医学博士，儿科肉瘤小鼠模型的国际专家。 他的职业发展计划概述了结构化的导师、课程和研讨会的组合，以及 参与既定的常设研究计划，旨在帮助他实现以下目标：1) 提高他在细胞间和细胞内信号通路的机械解剖方面的技能，2)利用 基因工程小鼠模型以解决机制问题，3)熟悉这一过程 临床前药物开发，4)融入了儿童肉瘤的科学界 研究，和5)成为一个高效和有效的作家。该计划包括负责任的行为培训 通过他的机构要求的正在进行的课程和一门研究伦理课程来进行研究。 肿瘤-宿主相互作用在骨肉瘤转移中的研究提供了一个理想的模型系统 研究实体瘤转移的生物学特性。这份提案中使用的模型不仅 有助于阐明调节这一过程的生物机制，但也是极好的 可评估治疗干预措施的临床前评估的系统。有很大的需求 针对骨肉瘤和许多其他固体的转移过程的临床可行的治疗策略 肿瘤。将这项研究与明确和全面的职业发展计划相结合 再加上经验丰富和有能力的导师的支持，瑞安将做好充分的准备，这样他就可以像 他准备并开始作为一名内科科学家向独立的有组织的过渡。

CAREER DEVELOPMENT PROPOSAL SUMMARY This Career Development award will support the work of Dr. Ryan D. Roberts, MD, PhD. It will provide him with unique opportunities to develop his investigative skills in a protected and mentored setting. It will facilitate the generation of a sufficient core body of research so that he will be able to compete successfully for R01- level funding and transition to independence. Ryan is a Fellow in Pediatric Hematology, Oncology, and Bone Marrow Transplant in his final months of training. He completed a PhD in Integrated Biomedical Sciences at the Ohio State University, where he studied tumor-host interactions and tumor immunology. His graduate work demonstrated how breast tumor cells interact with macrophages in ways that facilitate the growth and spread of those tumors. He demonstrated that therapeutic cytokine modalities could make those same macrophages adopt anti-tumor behaviors. He began his current line of work while a Pediatric Research Resident at Nationwide Children's Hospital in Columbus, Ohio and has continued that work during his fellowship. His lab has shown that IL-6 and IL-8 play important roles in the dynamics that facilitate recruitment of osteosarcoma cells from the circulation into the lung and growth with those tissues. The proposed research plan aims to characterize the mechanisms by which these cytokines drive the metastatic process and to explore the potential that targeting these pathways might have for preventing metastases from forming and for treating existing lung metastases:  Aim 1 will determine the relative importance of tumor-derived and lung-derived IL-6 and IL-8 to metastasis.  Aim 2 will identify the intercellular signaling loops that mediate the process, namely, which resident lung cells the tumor cells interact with and what other cytokines are involved.  Aim 3 will test the therapeutic potential of IL-6 and IL-8 pathway disruption for the prevention of metastasis and determine whether there is a period of opportunity surrounding tumor resection where such therapies might be particularly relevant. Integrated with this research proposal is a comprehensive career development plan, built on a backbone of solid mentorship. Ryan will enjoy structured and ongoing mentorship from:  Stephen Lessnick, MD, PhD, his Center Director, an internationally-renown sarcoma biologist who has independently described much of the molecular pathophysiology driving malignancy in Ewing sarcoma.  Timothy Cripe, MD, PhD, his Division Chair, an internationally respected expert in oncolytic viruses and pediatric sarcomas who heads several of his own phase I clinical trials.  Peter Houghton, PhD, his former center director and primary mentor during, an international expert in preclinical drug evaluation and head of the NCI's Pediatric Preclinical Testing Program.  Denis Guttridge, PhD, an extremely successful expert in muscle biology and rhabdomyosarcoma with particular expertise in the dissection of inflammatory signaling pathways.  Jiayuh Lin, PhD, a colleague within his Division who has extensive experience with inflammatory receptor biochemistry, including target validation.  Charles Keller, MD, an international expert in murine models of pediatric sarcomas. His career development plan outlines a combination of structured mentorship, coursework and workshops, and participation in established standing research programs designed to help him attain the following goals: 1) improve his skill in the mechanistic dissection of inter- and intra-cellular signaling pathways, 2) utilize genetically-engineered murine models to address mechanistic questions, 3) become familiar with the process of preclinical drug development, 4) become integrated into the scientific community of pediatric sarcoma research, and 5) become an efficient and effective writer. The plan includes training in the responsible conduct of research through ongoing coursework required by his institution and a course in research ethics. The study of tumor-host interactions that mediate metastasis in osteosarcoma provides an ideal model system in which to investigate the biology of solid tumor metastasis. The models used in this proposal not only facilitate elucidation of the biologic mechanisms which mediate this process, but also serve as excellent systems in which preclinical evaluation of therapeutic interventions can be assessed. There is great need for clinically viable treatment strategies that target the metastatic process in osteosarcoma and many other solid tumors. The integration of this research with a well-defined and comprehensive career development plan together with support from experienced and capable mentors will prepare Ryan well, so that he can thrive as he prepares for and begins a structured transition toward independence as a physician-scientist.