Targeting Glioma Cancer Stem Cells for the Treatment of Glioblastoma Multiform

Glioblastoma multiforme (GBM) is the most common malignant brain tumor characterized by high vascularity and invasion of tumor cells into the surrounding brain parenchyma. Despite surgery, radiation and chemotherapy with temozolomide (TMZ), a DNA alkylating agent, the prognosis for GBM remains poor with a median survival time of 12-15 months. Tumor recurrence is a major cause for mortality in GBM and glioma cancer stem cells (GSCs) have been implicated as the source of origin and tumor recurrence. TMZ, the current standard-of-care does not affect the GSCs and therefore, therapies directed towards this critical drug resistant cell population are sorely needed.;In this study, we have identified two subtypes of GSCs differing in their growth characteristics, marker expression, genetic profile and tumorigenic potential. The proneural and mesenchymal patient-derived GSCs together represent approximately 80% of human GBM. Thus, these GSCs recapitulate the heterogeneity of human tumors and provide a clinically representative model to evaluate novel therapeutic strategies. Elimination of GBM will require chemotherapies that target both subtypes of GSCs particularly the clinically aggressive mesenchymal subtype.;The significant finding of this study is the efficacy of a novel chemotherapy NEO212, a conjugate of TMZ and perillyl alcohol (POH), a drug shown to have moderate effects against resistant GBM. We found that NEO212 is cytotoxic to both proneural and mesenchymal GSCs in vitro and in an orthotopic xenograft model. NEO212 specifically affects GSCs through targeting two critical properties of cancer stem cells---self-renewal and chemoresistance. NEO212 decreases the expression of key self-renewal factors Bmi-1 (in proneural GSCs) and Sox2 (in mesenchymal GSCs) and induces extensive DNA damage independent of MGMT, an important protein involved in DNA repair and drug resistance.;Our results showing the efficacy of NEO212 against both proneural and mesenchymal GSCs make it a promising new therapy for GBM. NEO212 can be effective as a first line therapy to prevent tumor recurrence or can be administered following drug resistance to eliminate GSCs and delay tumor recurrence. Thus, NEO212 has significant clinical implications for the treatment of GBM.