MDB-07. A Suicide Gene Therapy Targeting Sox9-Positive Therapy-Resistant Medulloblastoma Cells

The transcription factor SOX9 is a stem cell factor and a glial fate marker in the developing brain. SOX9 levels correlate with worse prognosis and relapse in Group 3 medulloblastoma, a malignant pediatric brain tumor with poor survival. SOX9 activation promotes epidermal to mesenchymal transition and leptomeningeal spread. It is also upregulated by and facilitates cisplatin resistance in medulloblastoma cells. Direct SOX9 inhibition has proven difficult and few targeted substances have emerged from drug screening efforts. SOX9 acts as a selective and potent activator of a minimal collagen type II alpha 1 enhancer element. We here show that cells with SOX9 activity can be efficiently and specifically labeled when this SOX9 response element is coupled to a minimal promoter (S9RE-minP) driving GFP or luciferase. We further show that S9RE-minP construct can be used to drive herpes simplex virus thymidine kinase (TK) in a suicide gene construct that can convert ganciclovir to a cytotoxic drug in mitotic SOX9-positive cells. The gene therapy worked efficiently together with cisplatin to eradicate SOX9-positive medulloblastoma cells in vitro and could be safely combined and synergize with fractionated radiation in vivo. We suggest that this could be an attractive approach to target therapy-resistant cells in malignant pediatric brain tumors.