Dissecting the Role of DNA Damage Repair Deficiency in Ewing Sarcoma Pathogenesis Through Integrative Computational Biology
Abstract
Scientific Objective and Rationale: Ewing sarcoma is the second most common bone and soft tissue cancer impacting children and adolescents worldwide. It is an aggressive malignancy requiring multimodal treatment that confers significant morbidity, and cure rates for metastatic and relapsed disease remain poor. The inherited genetic events that contribute to the tumor features of Ewing sarcoma and how different patterns of tumor features can impact treatment approaches remain largely unknown. I led a study of genetic predisposition in a large cohort of pediatric sarcomas and found that inherited changes in DNA damage repair genes occur more than would be expected by chance in patients with Ewing sarcoma. Work is still needed to understand the full extent to which defects in DNA damage repair increase risk for Ewing sarcoma, as well as how these changes impact the features of Ewing sarcoma tumors. The primary objectives of this research proposal are to (1) identify the inherited genetic changes in DNA damage repair genes that increase risk for Ewing sarcoma to improve approaches to prevention and (2) analyze the tumor features related to DNA damage to improve risk stratification, predict treatment resistance, and lay the foundation for more informed treatment in Ewing sarcoma. Career Goals: I am committed to a career as a pediatric oncology physician-scientist. In my scientific career, I will develop and apply novel computational approaches to strive toward a better biological and clinical understanding of pediatric and young adult cancers more broadly, and sarcomas specifically. The proposed research will move the field toward better patient care for two PRCRP Overarching Challenge Categories: (1) Identify and elucidate the mechanisms behind cancer epigenetics/ genetics and cancer development to improve prevention methods (2) Identify strategies to predict treatment resistance, recurrence, and the development of advanced disease This research program will provide me with the skills I need to develop more fully as a translational researcher who can carry out computational work with clinical relevance and to establish myself as an expert in the germline (normal tissue) and tumor genomics of pediatric sarcomas. Following the completion of this research program, I will have the experience to apply for advanced funding to screen for and validate DNA damage biomarkers among patients with Ewing sarcoma and further study the impact of germline variants on tumor features through embedded biology aims in future Ewing sarcoma clinical trials. Clinical Applicability: Our proposal bridges the genetic and mechanistic underpinnings of Ewing sarcoma to clinically relevant biomarkers with prognostic and potential therapeutic implications in the treatment of this aggressive pediatric cancer. Through a better understanding of the underlying biology contributing to Ewing sarcoma, the pediatric oncology community will be able to develop more informed and less toxic treatment regimens, as well as better screen children at risk for disease, opening the door to opportunities for earlier detection and even prevention. In the short-term, we anticipate that this research will lead to better genetic screening and risk stratification for Ewing sarcoma. In the long-term, we anticipate that the insights into DNA damage repair mechanisms will lead to more tailored treatment approaches for subsets of patients with Ewing sarcoma. Our work will inform clinical trial priorities for patients with Ewing sarcoma, and spur innovation in research and clinical care extending to other pediatric and young adult cancers. Proposed Impact on Military Health: The proposed research to dissect the role of DNA damage repair deficiency in Ewing sarcoma pathogenesis through integrative computational biology is of high relevance to the health of military Service Members and their families. In a study conducted over 2 years in the early 2000s, over 50
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310471
Entities
People
- Riaz Gillani
Organizations
- Dana–Farber Cancer Institute
- United States Army