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

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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.