In Vivo Modeling of Neuroblastoma Epigenetic States to Improve Immunotherapy
Abstract
Objective and rationale: Neuroblastoma is a common childhood tumor that accounts for approximately 15% of childhood cancer deaths. We need to better understand why our current therapies do not work well enough and to develop better therapies. One recent advance in understanding why some treatments fail is that a neuroblastoma tumor can be composed of multiple different types of neuroblastoma cells, including some that are more resistant to our current treatments than others. A treatment might kill most of the cells, but the resistant cells can grow back and cause a relapse. We have found that these resistant cells are more inflamed, which suggests we might be able to kill them using the body’s immune system, a type of treatment called an immunotherapy. We have developed new mouse models of these different types of neuroblastoma cells and this proposal will use these models to better understand the characteristics of the different types of cancer cells, to explore how they interact with each other and with the immune system, and to test how they respond differently to currently used and new immunotherapies. How project will advance Principal Investigator’s career goals: This work will be led by Dr. Adam Wolpaw, M.D./Ph.D., currently an Instructor in the Division of Oncology at the Children’s Hospital of Philadelphia, where he takes care of pediatric patients with solid tumors, including those with neuroblastoma, and performs research on neuroblastoma. His goal is to establish an independent laboratory program studying how the different cancer cells within tumors respond differently to immunotherapy and how to better treat them based on this information. The current proposal will provide essential protected time to perform crucial experiments on neuroblastoma heterogeneity, immune interactions, and responses to immunotherapy. It will also provide additional training in laboratory techniques, critical scientific thinking, grant and paper writing, and laboratory management that will be critical to Dr. Wolpaw’s success as an independent scientist. This training will be provided in large part by his co-career guides, Dr. Chi Dang and Dr. Michael Hogarty, two world-renowned scientists and experienced mentors who are committed to furthering the development of Dr. Wolpaw’s career. Patients who will benefit: The research described in the current proposal is most readily applicable to patients with neuroblastoma. Among patients with high-risk disease, approximately half of them will eventually suffer a fatal relapse of their disease. The proposed experiments may help identify which patients are more likely to suffer a relapse if given our current standard therapy, providing prognostic information and identifying those that would benefit from more or different treatments. We will also directly test whether some treatments in early clinical development might be helpful to these patients. In addition, our experiments in neuroblastoma will have important implications for other cancers, as tumor heterogeneity is an important cause of treatment failure across oncology. Overarching challenge addressed: This project directly addresses the Fiscal Year 2021 Peer Reviewed Cancer Research Program Overarching Challenge to Transform cancer treatment through the identification of novel biomarkers and new targets, especially for advanced disease (metastatic and/or recurrence); improve immunotherapy; and eliminate the risks of therapy-associated toxicity. We will test how the presence of resistant populations impacts tumor response to immunotherapy, which may identify biomarkers of recurrence. In addition to testing current immunotherapies, we will also test how preclinical immunotherapies can help target resistant populations and prevent recurrence. Benefit to active-duty Service Members, Veterans, and beneficiaries: Neuroblastoma is a leading cause of death in children, including the children of active-duty Service Members. Having a critically il
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210474
Entities
People
- Adam J Wolpaw
Organizations
- United States Army