Chromatin Accessibility and the Convergent Oncogenic Pathways of Angiosarcomas
Abstract
The Principal Investigator, Dr. Kim, seeks to develop an independent research program to advance our understanding of why cancer happens and how we can treat, manage, and eventually prevent it. His career goal is to become an international leader in the field of sarcoma research. This project will address the Fiscal Year 2019 (FY19) Peer Reviewed Cancer Research Program (PRCRP) Topic Area “Rare Cancers.” This award will enable Dr. Kim to achieve his career goals to (1) acquire new, state-of-the-art experimental skills; (2) learn how to build diverse portfolios of research and funding; and (3) hone his lab management skills. Scientific Objective and Rationale: The project is designed to understand how angiosarcomas start and what is responsible for their aggressive behavior. Soft tissue sarcomas are rare cancers that develop in tissues such as muscle, fat, blood and lymph vessels, nerves, and tendons. Angiosarcomas arise from blood vessel-forming cells, and fewer than 300 cases are diagnosed yearly, with only 2 to 3 new cases per one million in the US. Tumor-related death is extremely high because the tumor spreads to other organs, leading to many years of life lost. There have not been many advances in the treatment of angiosarcomas for several decades, and no fixed standard of care has been established. The foundation for this project comes from our recent work showing that mutation patterns are complex in angiosarcoma cancers, but they seem to activate convergent biological pathways toward vascular malignancy. We propose that the progenitor cells that form vascular tissues have unique ways to package their DNA. The DNA package box, or chromatin, can be opened to expose or closed to hide DNA sequences (open chromatin vs. closed chromatin), and the “open chromatin” appears to be prone to mutation during cell replication. At the same time, open chromatin could be a key determinant of pathogenic convergence. Since vascular cells originate from pluripotent stem cells, we can make adult cells go back to this primitive stage using cutting-edge gene and cell engineering techniques and use our engineered cells to determine the role of open chromatin in enabling the mutations and functional activation that lead to vascular cancers. Applicability of the research: This is a basic research project; however, our results have potential for translation in the areas of diagnosis and treatment. In addition to potentially fostering a paradigm shift in our thinking about the oncogenesis of angiosarcoma, our results could enable the development of gene panels for precise, early detection by narrowing the possible regions of the genome that drive pathogenic downstream events that cause this tumor. Furthermore, our models could create opportunities to develop and test targeted and personalized therapies, establishing better therapeutic protocols. Finally, this concept is exportable to other sarcomas that originate from distinct cell types. This project will address the FY19 PRCRP Military Relevance Focus Area “Gaps in cancer prevention, early detection/diagnosis, prognosis, treatment, and/or survivorship that affect the general population but have a particularly profound impact on the health and well-being of military Service members, Veterans, and their beneficiaries.” Angiosarcomas are a rare subtype of soft tissue sarcoma that can occur in any soft tissue or visceral organ at any age. Early detection and definitive diagnosis may be delayed due to the rarity and genetic heterogeneity of these tumors, and differential diagnosis with benign lesion is also challenging. Clinical behaviors in patients with this sarcoma are unpredictable with a lack of reliable prognostic markers. Angiosarcoma may develop in people following exposure to hazardous agents such vinyl chloride, thorium dioxide, arsenic, radium, and radiation that often contaminate military bases. In addition, there is a positive association between soft tissue sarcomas in Ve
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010294
Entities
People
- Jong Hyuk Kim
Organizations
- United States Army
- University of Minnesota