RBIO-04 - Inhibiting the SHH pathway and PARP1 in combination enhances the radiation sensitivity of pediatric sonic hedgehog medulloblastoma

Medulloblastoma accounts for 20-25% of all pediatric brain tumors. These patients undergo craniospinal and focal radiation therapy during their treatment, resulting in negative long-term consequences such as bone and tissue hypoplasia and decreased neurocognitive functioning. One of the most concerning effects is the significantly increased risk for secondary radiation induced cancers later in life. Thus, there is a critical need for novel approaches to radiation therapy that can effectively target and kill tumor cells while minimizing long lasting toxic effects. Here, we investigate a novel approach to radiation therapy that relies on the combination of two classes of therapeutic agents, Sonic Hedgehog (SHH) inhibitors and Poly (ADP-ribose) Polymerase (PARP) inhibitors. The SHH pathway plays a key role in medulloblastoma tumorigenesis and affects the radiation sensitivity of various cancer types such as basal cell carcinoma. The PARP family, specifically PARP1, plays a key role in DNA damage repair and affects the radiation sensitivity of pediatric brain cancers such as high-grade glioma and medulloblastoma. We hypothesize that combining these approaches by inhibiting Smo and Gli1 in the SHH pathway, and PARP1 simultaneously, will enhance medulloblastoma tumor cell killing following radiation therapy. We found that in vitro treatment with Sonidegib, GANT61, and Veliparib alone and in combination with was sufficient to significantly decrease tumor cell viability and self-renewal as measured by clonogenic survival assays (p < 0.01). 24 hours following these targeted treatments, 2 Gy of radiation was administered which resulted in a greater degree of decreased cell viability and self-renewal (p < 0.01), as well as in increased cell death. Together, this data suggests that inhibition of Smo, Gli1, and PARP1 either alone as single agents, or in combination is a promising therapeutic strategy for increasing the radiation sensitivity of pediatric SHH medulloblastoma.