Pediatric glioma stem cells: biologic strategies for oncolytic HSV virotherapy

Abstract

While glioblastoma multiforme (GBM) is the most common adult malignant brain tumor, GBMs in childhood represent less than 10% of pediatric malignant brain tumors and are phenotypically and molecularly distinct from adult GBMs. Similar to adult patients, outcomes for children with high-grade gliomas (HGGs) remain poor. Furthermore, the significant morbidity and mortality yielded by pediatric GBM is compounded by neurotoxicity for the developing brain caused by current therapies. Poor outcomes have been attributed to a subpopulation of chemotherapy and radiotherapy resistant cells, termed “glioma stem cells” (GSCs), “glioma progenitor cells,” or “glioma-initiating cells,” which have the ability to initiate and maintain the tumor and to repopulate the recurring tumor after conventional therapy. Future innovative therapies for pediatric HGG must be able to eradicate these therapy-resistant GSCs. Oncolytic herpes simplex viruses (oHSV), genetically engineered to be safe for normal cells and to express diverse foreign anti-tumor therapeutic genes, have been demonstrated in preclinical studies to infect and kill GSCs and tumor cells equally while sparing normal brain cells. In this review, we discuss the unique aspects of pediatric GSCs, including markers to identify them, the microenvironment they reside in, signaling pathways that regulate them, mechanisms of cellular resistance, and approaches to target GSCs, with a focus on the promising therapeutic, genetically engineered oHSV.

Pediatric Brain Tumors

“…18 Novel and specific therapies currently being investigated for pediatric high-grade glioma include small-molecule inhibitors of epidermal growth factor receptor, platelet-derived growth factor receptor, histone deacetylase, the Ras/AKT pathway, telomerase, integrin, insulinlike growth factor receptor, and ,-secretase, as well as immunotherapy such as vaccines and virotherapy (converting viruses into therapeutic agents). 49,50 Recurrent high-grade glioma carries a dismal prognosis.…”

ATN-224 enhances antitumor efficacy of oncolytic herpes virus against both local and metastatic head and neck squamous cell carcinoma

“…However, the effectiveness of oHSVs in patients has not lived up to the expectations generated from the results observed in preclinical studies. 19 Combing oHSV with chemotherapeutic agents presents an opportunity to increase oncolytic activity by either bolstering virus replication or suppressing systemic innate immune responses that can lead to rapid virus clearance. 20 , 21 Despite augmenting virus replication, combination of oncolytic viral therapy with chemotherapy has only been well tolerated with few dose limiting toxicities.…”

Viral therapy of glioblastoma multiforme

“…To summarize, the tumor microenvironment, particularly as it relates to the potential contribution of immune suppression, heterogeneity of cells, and, potentially, GSCs, underscores the nature of the problem. Previous studies have suggested that GSCs are susceptible to treatment with oncolytic HSV (12,13). Until this study, syngeneic models of GSCs were sparse, and none that were suitable for examination of oHSV existed.…”