Targeting SOX2 as a Therapeutic Strategy in Glioblastoma

Abstract

Glioblastoma is the most common and malignant brain cancer in adults. Current therapy consisting of surgery followed by radiation and temozolomide has a moderate success rate and the tumor reappears. Among the features that a cancer cell must have to survive the therapeutic treatment and reconstitute the tumor is the ability of self-renewal. Therefore, it is vital to identify the molecular mechanisms that regulate this activity. Sex-determining region Y (SRY)-box 2 (SOX2) is a transcription factor whose activity has been associated with the maintenance of the undifferentiated state of cancer stem cells in several tissues, including the brain. Several groups have detected increased SOX2 levels in biopsies of glioblastoma patients, with the highest levels associated with poor outcome. Therefore, SOX2 silencing might be a novel therapeutic approach to combat cancer and particularly brain tumors. In this review, we will summarize the current knowledge about SOX2 in glioblastoma and recapitulate several strategies that have recently been described targeting SOX2 in this malignancy.

Keywords: SOX2; glioblastoma; glioma stem cells; self-renewal inhibition; temozolomide resistance; tumor-initiating cells.

Figure 1

Significance of glioma stem cells (GSCs) and SOX2 targeting in the recurrence of glioblastoma. (A) Glioblastoma is a heterogeneous tumor composed of GSCs (in red, chemo-, and radiotherapy resistant) and of differentiated tumor cells (in blue, chemo-, and radiotherapy responsive). GSCs need to be targeted before current standard approaches to achieve tumor regression. TMZ, temozolomide; RT, radiotherapy. (B) In order to avoid tumor recurrence, genetic, epigenetic, and pharmacological approaches targeting GSCs expressing high levels of SOX2 have been postulated.