Characterizing and Targeting Circulating Tumor Cells in Pediatric Liver Cancer
Abstract
Liver tumors, primarily hepatoblastoma (HB) and hepatocellular carcinoma (HCC), are a leading cause of cancer-related deaths. Children are affected primarily by HB, which has a less than 50% overall survival rate, especially for patients that have metastasis or are resistant to chemotherapy. Notably, HB has the fastest growing incidence of all pediatric solid tumors. Active duty military members are greatly affected when their beneficiaries, especially their children, are fighting liver cancer, and this clearly affects mission readiness. By addressing critical gaps in pediatric liver cancer research, this proposal will undoubtedly help active duty service members, Veterans, and their beneficiaries facing liver cancer diagnoses. Not surprisingly, the major cause of cancer-related death is the spreading of cancer cells from the primary tumor to distant organs, or metastasis. Metastasis happens when cells from the primary tumor enter the bloodstream. These cells, known as circulating tumor cells (CTCs), are able to invade and establish tumors in other organs and are potentially more resistant to chemotherapy than primary tumor cells. Even though CTCs have been studied in many common tumors, there is still nothing known about CTCs in pediatric liver cancer. Therefore, the overall objective of this proposal is to characterize CTCs in HB to inform their use in models to predict prognosis and to develop new strategies to specifically target these cells with therapy. Since so little is known about CTCs in pediatric liver cancer, the first goal of this project is to collect CTCs from pediatric patients with HB and identify features of the cells that predict worse outcomes for all patients. Results from these experiments will be used to design a follow-on clinical trial for this new prognostic test to predict long-term patient outcomes. Such a prognostic test, if successful, could see clinical implementation in as little as 3-5 years. The second goal is to use a state-of-the-art technique called single cell RNA sequencing to look at the specific genes expressed by CTCs and primary tumor cells from HB patients. This RNA “fingerprint” will show how CTCs differ from primary tumor cells and will indicate what genes may allow them to become aggressive and chemoresistant. Identifying and validating these genes in the present work could pinpoint new druggable targets that can be tested in preclinical animal models and eventually in clinical trials. Along these lines, the final goal is to test new therapies, including more than 50 experimental drugs, on novel chemoresistant animal models and directly on CTCs to see if CTCs are susceptible to any other drugs currently in use. Ideally, the results of this screening experiment will indicate a group of drugs that are particularly effective in killing CTCs, which can then be tested further in preclinical models and finally in clinical trials. Eventually, these drugs could be used in patients in combination with standard chemotherapy to eradicate chemoresistant CTCs that, if left untreated, could cause cancer relapse. All of this work, while it will not directly change clinical practice by the end of the project, has a high likelihood of spinning off multiple preclinical studies and clinical trials. It is our goal to apply all of the data gathered from this research to directly benefit patients through better prognostic predictions and improved therapies to increase survivorship. Leading this proposal is Dr. Sarah Woodfield, who is currently a tenure-track Assistant Professor in the Department of Surgery at Texas Children’s Hospital (TCH)/Baylor College of Medicine (BCM). She first began her career in pediatric cancer research in 2012, and her passion as a scientist is to learn more about how liver cancer resists therapy to improve diagnosis and treatment for children with high-risk liver cancer. Her long-term goal is to establish an independent, successful academic research program focus
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110396
Entities
People
- Sarah Woodfield
Organizations
- Baylor College of Medicine
- United States Army