The goal of this career development award is for the applicant to expand her knowledge and technical expertise in tumor immunology and bioinformatic analyses in order to apply these new skills to investigation of the childhood cancer Ewing sarcoma. Relapsed Ewing sarcoma is nearly uniformly fatal, and thus new treatment approaches are desperately needed. A growing number of immune-based therapies are now being incorporated into pediatric cancer treatment protocols. Thus, in order to be a successful clinician scientist directing a cutting- edge research program in Ewing sarcoma, it is essential that the applicant gain expertise in tumor immunobiology. Currently, very little is understood about regulation of the Ewing sarcoma tumor immune microenvironment. This proposal addresses the interplay of two broadly important facets of pediatric cancer research: DNA damage repair and tumor immune response. This proposed work specifically examines the ability of DNA damage to activate Ewing tumor cell immunoregulatory pathways. The proposed aims will utilize a combination of in vitro cell co-culture analyses, in vivo tumor animal modeling and human specimen analyses in order to address this important topic. The applicant has chosen a primary mentor who is an expert in immune/inflammatory signaling in cancer, and a co-mentor with expertise in T-cell biology and advanced immunology techniques. Additionally, the applicant has constructed a physician-scientist career mentoring committee and network of collaboartors including individuals with expertise in Ewing sarcoma, humanized mouse models, DNA damage repair, the tumor immune-microenvironment, and bioinformatic analyses. As a team, the mentor, co-mentor, committee members and collaborators are dedicated to providing the applicant with technique training in tumor immunology and advanced cancer biology, as well as critical feedback on grants and manuscripts and career guidance. The primary mentor and co-mentor are invested in guiding the applicant toward a highly successful career as physician scientist by transitioning her to senior authorship on manuscripts, preparing her to start an independent laboratory and encouraging her to directly mentor scientists and clinicians at various levels of training. The University of Pittsburgh is an outstanding environment in which to develop a career and expand a research program in tumor immunobiology. The applicant’s career development plan takes full advantage of the many unique offerings at Pittsburgh including face-to-face career development workshops with seasoned scientists, participation in the Pittsburgh Women in Science forum, graduate level tumor immunobiology and bioinformatics courses and opportunities for presentation of work-in-progress at the University of Pittsburgh Cancer Immunology Program meetings. With the enthusiastic support and exceptional scientific expertise of her mentor and co-mentor, the applicant is eager to gain specific training in tumor immunobiology and bioinformatic analyses and to launch an independent research career as a pediatric oncologist physician scientist studying Ewing sarcoma at the University of Pittsburgh.

This work aims to better understand the pediatric cancer Ewing sarcoma, specifically investigating the immunobiology in the setting of tumor DNA damage. The studies will be performed by examining the cancer cells themselves as well as by examining the immune cells in proximity to the tumor that can influence growth and spread of the cancer. This career development grant will provide the applicant with training in tumor immunology and bioinformatic analyses, an area of growing importance in pediatric oncology.