Improving the Oncolytic Immunovirotherapy of Malignant Glioma by Targeting the Glioma Secretome
Abstract
This proposal is focused on the Topic Area of Brain Cancer. Malignant brain tumor remains a fatal disease. With standard therapy, prognosis is still unfavorable, with a median survival of less than 2 years. We developed oncolytic herpes simplex virus (oHSV) to treat both adult and pediatric brain tumor patients, given its potential to selectively kill tumor cells while sparing normal brain cells. Although the therapy shows some promise based on the results from our phase 1 trials, all patients die of tumor relapse and growth. We studied the factors that may comprise the oHSV therapeutic efficacy, and found that a factor, called acyl-CoA-binding protein (ACBP), was secreted from the virus-killed tumor cells, inducing the aggressive behavior of remaining tumor cells and impairing immune system in fighting tumor, and subsequently leading to impaired mice survival. To prevent the ACBP-induced secondary effects and to improve the oHSV therapeutic efficacy while bypassing the hurdles from directly targeting soluble ACBP, we found that inhibition of Bmi1, a tumor-promoting factor, in glioma cells could suppress glioma growth, reduce ACBP expression/secretion, and promote anti-tumor immune response. Here we propose to define the underlying mechanisms for the ACBP’s pro-tumoral and immunosuppressive activity, and how inhibition of Bmi1 modulates the immune cells within the tumor beyond its conventional role in tumor cells. This comprehensive understanding of the pros and cons of oHSV and Bmi1 inhibition benefited us to develop a new strategy by timely combining these agents to treat brain cancer and to evaluate its therapeutic efficacy in preclinical and patient-derived xenograft models, which we anticipate should be readily translatable to the clinic and create a near-term impact, since both oHSV and Bmi1 inhibitor are currently evaluated in clinical trials. We believe that the proposed research will uncover new mechanisms for promoting the malignancy of brain tumor, and have the potential long-term outcome to develop a biomarker (i.e., ACBP) to predict treatment resistance and recurrence, which can be exploited to strategically direct a combined therapeutic approach to mitigate adverse effects in brain tumor patients post-oHSV therapy; thereby, transforming cancer treatment in the field of oncolytic virus therapy of brain tumor toward a new direction (fiscal year 2022 FY22 Peer Reviewed Cancer Research Program PRCRP Overarching Challenges). Military personnel, particularly Gulf War Veterans, are significantly associated with high risk of brain tumors. This study will address the gaps in cancer prognosis and treatment that may impact mission readiness and lead to improvements in survival while minimizing late effects and cancer relapse for the military personnel and the general population with brain cancer (FY22 PRCRP Military Health Focus Areas).
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310792
Entities
People
- Jianmei W Leavenworth
Organizations
- United States Army
- University of Alabama at Birmingham