CNSC-22. Targeting Sox9-Positive Therapy-Resistant Medulloblastoma With a Novel Suicide Gene Therapy

The transcription factor SOX9 is a marker of poor prognosis and therapy resistance in medulloblastoma, one of the most common malignant brain tumor types in children. Knockdown or downregulation of SOX9 inhibits medulloblastoma recurrence in animal models but there are currently no direct SOX9 inhibitors available for clinical use. SOX9 acts as a selective and potent activator of a minimal COL2A1 enhancer. Here, we show that cells with SOX9 activity can be efficiently labeled when four copies of this response element are coupled to a minimal promoter (S9RE-minP) driving enhanced green fluorescent protein and luciferase. We further show that S9RE-minP can be used in an adeno-associated virus (AAV) to drive herpes simplex virus thymidine kinase in a suicide gene therapy where ganciclovir can be converted to cytotoxically target mitotic SOX9-positive cancer cells. This AAV gene therapy could be safely combined with fractionated radiation and worked efficiently together with standard therapy to eradicate SOX9-positive medulloblastoma cells in vitro and in vivo. We suggest this treatment as an attractive approach to target therapy-resistant malignant pediatric brain tumors.