Single-Cell Characterization and Organoid Development of Pediatric Hepatoblastomas
Abstract
Background and Preliminary Data: Pediatric hepatoblastoma (HB) is the most common primary liver cancer in infants and children. Children with HB have some of the highest risk for death among all childhood cancers, and this is due mostly to those children with high-risk HB that are resistant to chemotherapy or not amenable to surgery. There is an urgent need to improve our ability to accurately identify these high-risk tumors, and for better models to study and develop effective treatments for high-risk HB. HB are well-known to be made up of a variety of different types of cancer cells based on appearance. We have used a technique that captures individual cells from HB to identify and characterize HB cancer cells. This method showed that HB are composed of five common cancer cell types. The relative proportions of these common HB cancer cell types explain the differences in the composition of each HB. Importantly, we showed that risk of poor clinical outcome was associated with specific cancer cell types. We developed a method to grow HB cancer cells from individual patients as spheroids, or 3-dimensional cell clumps, for more than 6 months in cell culture. These spheroids accurately maintain characteristics of the cancer cell type it grew from. This allowed us to use the spheroids to prediction response to treatment with different chemotherapy drugs. Objective and Rationale: We have two main goals in these studies. The first is to improve the ability to accurately identify high-risk HB cancers. The second is to develop a model for high-risk HB cancer cells and use it to develop new treatment options against high-risk HB cancers. To address the first goal, our hypothesis is that HB cancers that develop earlier during the development of the fetus will result in higher risk of poor clinical outcome. We propose a set of studies that will identify additional HB cancer cell types and determine which cancer cell types, when present, will result in poor clinical outcomes. To address the second goal, we will establish a collection of HB cancer cell spheroids. We will show that each spheroid accurately models the behavior of a different HB cancer cell types. We will use these spheroids in drug testing to determine the optimum drug combination that will effectively kill each HB cancer cell type. The results of these studies will allow us to identify effective treatment strategies for HB cancer cells, especially those associated with high-risk of a poor clinical outcome. Lastly, we will perform genetic correction of the mutation that is present in different HB spheroids. We hypothesize that correcting mutations in the CTNNB1 gene will cause HB spheroid cells to stop growing and die. These studies will make personalized treatment possible for HB patients. Fiscal Year 2021 (FY21) Rare Cancers Research Program (RCRP) Focus Areas: The proposed studies address all three FY21 RCRP Focus Areas. In the Biology and Etiology area, our studies will show the connection between timing of when the cancer starts in the fetal liver and tumor aggressiveness. Our studies will also determine if genetic mutations in the CTNNB1 gene are required for HB cancer cells to grow. In the Research Model area, our studies will establish HB spheroids as a pre-clinical model for use in development of new treatments for HB. In the Therapy area, our studies will identify the optimum treatment combination for each HB cancer cell type. Applicability: In summary, the studies proposed in this study will address two of the most important clinical problems in HB. The results of the studies will improve our ability to identify children who have HB cancer that have a high likelihood to lead to death. The studies will also develop models to better understand high-risk HB cancer cells. These models will be used to identify optimum treatment options for high-risk HB cancer cells. These important pre-clinical studies, if successful, will pa
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2211093
Entities
People
- Bruce Wang
Organizations
- United States Army
- University of California, San Francisco