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 disse...