Transcription, R-Loops, and RNA Splicing in Ewing Sarcoma
Abstract
Career Goals in Cancer Research: My career goal is to become an independent investigator studying cancer in children and young adults. The Peer Reviewed Cancer Research Program (PRCRP) Horizon Award will provide vital training towards achieving this goal. I am currently a predoctoral candidate at University of Texas Health San Antonio. My mentor, Dr. Alexander Bishop, is an established investigator in the field of DNA damage response and repair and how it relates to cancer, particularly Ewing sarcoma. He will oversee my training and ensure successful completion of this project. I will also build my knowledge and technical skills through seminars, journal clubs, workshops, scientific meetings, and collaboration with other pediatric cancer researchers. Scientific Objective and Rationale: Ewing sarcoma is a rare but very aggressive tumor of the bone and soft tissue that occurs most frequently in children, adolescents, and young adults. It is treated with chemotherapy along with radiation or surgery. Although most patients respond well to this aggressive treatment regimen, there is no second-line treatment when it fails, and there are severe side effects in children that can continue to affect them long after treatment has ended. Consequently, effective, less toxic, targeted treatment strategies are much needed. Our lab performed a genome-wide screen to identify genes required for Ewing sarcoma cells to survive. We found that Ewing sarcoma cells are particularly sensitive to loss of genes involved in RNA splicing. RNA splicing is additional processing that occurs after a gene is copied from DNA to RNA (transcription), before it can be used to make proteins. We recently published that the fusion oncogene that drives Ewing sarcoma, EWS-FLI1, increases the overall level of transcription activity in a cell. This results in problems in transcription, with some of the newly made RNA sticking to the DNA, creating a structure called an R-loop. Worse, the whole transcription process is normally turned off/down in response to cellular damage, but this does not happen in Ewing sarcoma. My proposal aims to understand the relationship between altered regulation of transcription and splicing in Ewing sarcoma. A number of splicing inhibitors have been developed, one of which is currently in clinical trials for hematologic malignancies. I will therefore also test splicing inhibitors in Ewing sarcoma cells to determine whether this could be used as a new treatment strategy, either alone or in combination with standard chemotherapeutics. We have the opportunity to move promising drugs or combinations to preclinical animal models. This research has the potential to benefit all Ewing sarcoma patients, especially those with chemo-resistant disease. Military relevance: The proposed research will directly benefit Service members who are diagnosed with Ewing sarcoma or their family members who are diagnosed. Because Ewing sarcoma disproportionately impacts male Caucasian children and young adolescents, it is particularly relevant to Service members and their families.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jul 16, 2019
- Source ID
- W81XWH1910180
Entities
People
- Liesl A Lawrence
Organizations
- United States Army
- University of Texas Health Science Center at San Antonio