Research And Grants

Identifying Oncolytic Viral Therapy Resistance Mechanisms in Brain Tumors

Current adjuvant therapy for the malignant brain tumors medulloblastoma (MB) and pediatric high grade glioma (HGG) is marginally effective and often toxic. With standard chemotherapy and radiation, the 5-year overall survival (OS) of MB is 50-80%, however, nearly all patients experience lifelong neurocognitive and endocrine morbidity. The median OS of pediatric HGG is only 19 months. There is currently a profound knowledge gap in understanding how to improve the survival and quality of life in children with MB and HGG. A promising alternative to current radiochemotherapy is oncolytic virotherapy (OV). The polio:rhinovirus chimera, PVSRIPO, and the oncolytic herpes virus (oHSV), G207, are currently in Phase I clinical trials to treat children with MB and HGG. However, the mechanism of oncolysis of these OVs are currently unclear. Furthermore, it is unclear why some patients have durable OS benefits in response to OV, while many patients experience no real benefit.

We have recently discovered that oncolytic viruses cause profound oxidative stress on tumor cells, resulting in robust reactive oxygen species generation and tumor cell lysis. Glutathione (GSH) is a critical cellular anti-oxidant. It appears that OV overwhelms a GSH-mediated anti-oxidant response, resulting in oncolysis. Interestingly, MB and pediatric HGG have starkly similar expression profiles of oxidative stress response genes and is the rationale to study OV in both of these malignant tumor types.

Given that a key mechanism of oncolysis is the induction of profound oxidative stress, we hypothesize that MB and pediatric HGG resistance to OV is mediated by robust anti-oxidant capacity. Given that pro-oxidants deplete GSH, we hypothesize that resistance to OV will be overcome by combining pro-oxidants with OV. Because both wild type Enteroviruses (PVSRIPO) and Herpes viruses (G207) mediate oxidative stress, we hypothesize that resistance mechanisms will be generalizable across these OVs. 

The aims of this project are to 1) determine the specific molecular pathways of oxidative stress of MB and pediatric HGG that confer resistance to OV and 2) define oxidative stress modulating agents that overcome resistance to OV for treatment of MB and pediatric HGG. This study will 1) identify oxidative stress response genes that make MB and HGG sensitive resistant to OV, 2) identify oxidative stress response genes that are expressed in response to OV treatment in MB and pediatric HGG, 3) identify genes in human specimens from OV trials that putatively confer resistance to OV, and 4) genetically silence key oxidative stress “resistance” genes to confirm their role in resistance to OV. In parallel, we will 1) identify pro-oxidant agents that overcome OV resistance in vitro and 2) identify which oxidative stress enzymes are effected by pro- and anti-oxidants to identify additional therapeutic targets. This study is impactful because it will elucidate mechanism of resistance to OV  and improve the efficacy of OV by harnessing the oxidative stress response.