DEPARTMENT OF DEFENSE - CONGRESSIONALLY DIRECTED MEDICAL RESEARCH PROGRAMS

The Role of CD155 in Leptomeningeal Dissemination and Oncolytic Virus Susceptibility in the Medulloblastoma Microenvironment

Principal Investigator: THOMPSON, ERIC
Institution Receiving Award: DUKE UNIVERSITY
Program: PRCRP
Proposal Number: CA171067
Award Number: W81XWH-18-1-0270
Funding Mechanism: Career Development Award
Partnering Awards:
Award Amount: $577,611.00


PUBLIC ABSTRACT

Brain cancer is now the overall leading cause of mortality for children. Medulloblastoma, the most common malignant brain tumor of childhood, is the most common solid cancer in childhood overall. Medulloblastoma also comprises 3% of adult brain tumors. Treatment for medulloblastoma consists of surgical resection followed by chemotherapy and radiation to brain and spinal cord. This treatment combination is toxic, resulting in permanent cognitive issues, hormone abnormalities, and hearing loss. Additionally, when medulloblastoma spreads from the brain through the spinal fluid, it is frequently resistant to chemotherapy and radiation. There is a dire need for less toxic treatments that improve survival in children with medulloblastoma.

One new method to treat medulloblastoma is by injecting a virus that kills brain tumor cells and uses the body’s immune system to prevent the tumor from returning. Our group uses a genetically modified poliovirus, PVSRIPO, which has been shown to be safe and effective in the treatment of adult brain tumors. Our group has shown that PVSRIPO has the ability to target medulloblastoma. The success of PVSRIPO is thought to be due to the reaction it elicits in the brain’s immune system. However, the actual mechanism is not clear. Additionally, our group has found that the receptor on tumor cells that allows PVSRIPO to enter the cells may also be important for allowing tumor cells to spread through the spinal fluid.

This project will determine the mechanism and importance of the PVSRIPO receptor on the ability of tumor cells to spread throughout the spinal fluid. It will also assess the ability of PVSRIPO to safely treat medulloblastoma using mouse tumor models with immune systems that are similar to the human immune system. Lastly, this project will also ascertain the immunologic mechanism of PVSRIPO in order to optimize its use with other immunologic agents and for other tumors of the brain and spinal cord. PVSRIPO has the potential to be a game-changer in how medulloblastoma is treated, improving survival while eliminating the toxic side effects of radiation and chemotherapy.

As a pediatric neurosurgeon, I am in the unique position to (1) capitalize on the robust brain tumor immunotherapy program at Duke University and (2) translate the knowledge gained from preclinical research directly into clinical trials. I have been accruing the skills necessary to have a productive translational research career in the field of pediatric brain tumor research and will expand my into brain tumor immunotherapy skills. A Career Development Award would provide the critical resources necessary to protect my research and educational efforts necessary to complete the proposed research project. With this protection, I will attain the necessary tools to make significant contributions as an independent researcher. My short-term career goals are to gain the skills to (1) turn off select genes in tumor cells to understand how those genes affect others, (2) perform sophisticated studies of the immune system to understand how viruses work to treat pediatric brain tumors, and (3) successfully obtain funding to continue my research. My long-term career goals are to (1) carry out a clinical trial of PVSRIPO to treat pediatric medulloblastoma, (2) run research lab focusing on optimizing the use of viral therapy for other pediatric central nervous system tumors, and (3) become a mentor and leader in the field of pediatric brain tumor research.

This project seeks to unravel the mechanism behind medulloblastoma cell spread into the spinal fluid, the primary cause of death in patients with medulloblastoma. It will also serve as the foundation for further studies to enhance the efficacy and safety of viral immunotherapy for pediatric brain tumors. Because this research uses an agent (PVSRIPO) that is already Food and Drug Administration (FDA) approved for use in children with other types of brain cancer, the results of this study will be used to propose an analogous study in children with medulloblastoma. Given our previous experience with the FDA, we anticipate that FDA approval of an amendment of this kind will take less than 1 year.

Findings from this project may directly benefit active duty military personnel, Veterans, and the beneficiaries of military personnel. The incidence of pediatric brain tumors is increasing. Children of fathers who served in the Air Force are at increased brain tumor risk compared to the general population. These tumors cause considerable sickness and often death. Brain cancer, such as medulloblastoma, in a Warfighter, Veteran, or the child of a Warfighter can interfere with the Warfighter’s capacity to complete missions. Moreover, young military personnel and the children of military personnel living in the USA and abroad may be exposed to unknown agents that could contribute to the development of brain tumors such as medulloblastomas. Thus, a better understanding of how PVSRIPO receptor facilitates tumor spread through the spinal fluid and how to optimize viral immunotherapy to treat brain tumors is critical for improving the quality of life and overall survival of individuals with brain tumors. Additionally, findings from this study will likely be applicable to most other types of central nervous system tumors in individuals of all ages.