Characterizing Tumor Evolution and Therapy Resistance in High-Risk Neuroblastoma
Abstract
Background and Strategy for the Research: Neuroblastoma is a rare cancer, but it is the most common solid tumor in children that occurs outside of the brain and spinal cord. Survival for children with the most aggressive type of neuroblastoma (termed “high-risk”) is poor, despite intensive therapy. Much remains to be learned about how some tumors are able to resist intensive therapy and give rise to relapses, which are almost always fatal. To study how tumors are able to evolve over time and become resistant to therapy, scientists need to be able to compare the biology of tumor material obtained at initial diagnosis with material obtained at relapse. However, access to such paired pre-treatment/relapsed material has been limited, because surgical biopsies are inherently risky to children and only performed when they are clinically necessary. One new technology that has the potential to overcome this limitation is the development of assays called “liquid biopsies.” Scientists have recently discovered that tumors constantly release small amounts of tumor genetic material into the blood of patients with cancer. Isolation and profiling of this “circulating tumor DNA” allow scientists to identify the DNA mutations that drive cancer and to study how tumors change over time to become resistant to therapy. Members of our study team have adapted these liquid biopsy assays to detect circulating tumor DNA in children with neuroblastoma. In this first part of the proposal, scientists will take advantage of blood samples and clinical information being collected on the largest frontline trial for high-risk neuroblastoma ever conducted in the United States (a Children’s Oncology Group trial called ANBL1531). They will use blood samples from approximately 400 children to study how tumor cells evolve to develop resistance to therapy and give rise to relapse. Another recent advance that may help us understand treatment resistance is the ability to more easily develop models of cancer from trace amounts of tumor cells. To establish these models, scientists grow tumor cells in dishes or as tumors in mice. These models provide a renewable source of cancer cells to analyze. Recently, members of our study team have developed new techniques that allow the development of models from small numbers of cancer cells that are present as metastatic disease in the bone marrow of patients with high-risk neuroblastoma. Bone marrow testing is a routine part of the care of patients with neuroblastoma and will be collected at multiple times from patients enrolled on ANBL1531. In this second part of the proposal, we will develop neuroblastoma models from patient samples obtained at the time of diagnosis and relapse. We will use these models to understand how tumors change over time to give rise to resistant relapse disease. We will also utilize these models to perform experiments that will confirm the ways by which changes identified from both liquid biopsy samples and the paired cancer models cause these tumors to resist the effects of treatment. Applicability of the Research: This research is expected to help children with high-risk neuroblastoma, because it will provide insights into why, for some patients, treatment stops working, or never works in the first place. Moreover, this work is expected to identify new treatments that can be used to prevent therapy resistance. Thus, understanding resistance will lead to new therapies for children with neuroblastoma who need them most. Our project relates to the FY19 topic areas because it directly addresses the treatment of neuroblastoma, which is a cancer in children. Because only about 800 patients per year are diagnosed with neuroblastoma in the US, it is also a rare cancer. Relevance to Military Health and Impact: The proposed work addresses the Fiscal Year 2019 (FY19) Peer Reviewed Cancer Research Program Military Health Focus Areas as it will lead to more effective therapies for children with ne
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010814
Entities
People
- Charles Reynolds
Organizations
- Texas Tech University Health Sciences Center
- United States Army