A CK1{alpha} activator penetrates the brain, and shows efficacy against drug-resistant metastatic medulloblastoma

Purpose: Although most children with medulloblastoma (MB) are cured of their disease, SONIC HEDGEHOG (SHH) subgroup MB driven by TRP53 mutations is essentially lethal. Casein Kinase 1α (CK1α) phosphorylates and destabilizes GLI transcription factors, thereby inhibiting the key effectors of SHH signaling. We therefore tested a second-generation CK1α activator against TRP53 mutant, MYCN amplified MB. Experimental Design: The ability of this CK1α activator to block SHH signaling was determined in vitro using GLI reporter cells, granular precursor primary cultures and PATCHED (PTCH1) mutant sphere cultures. While in vivo efficacy was tested using two different MB mouse models: PTCH1 and ND2:SMOA1. Finally, the clinical relevance of CK1α activators was demonstrated using a TRP53 mutant, MYCN amplified patient derived xenograft. Results: SSTC3 inhibited SHH activity in vitro, acting downstream of the vismodegib target SMOOTHENED (SMO), and reduced the viability of sphere cultures derived from SHH MB. SSTC3 accumulated in the brain, inhibited growth of SHH MB tumors, and blocked metastases in a genetically-engineered vismodegib resistant mouse model of SHH MB. Importantly, SSTC3 attenuated growth and metastasis of orthotopic patient-derived TRP53 mutant, MYCN amplified, SHH subgroup MB xenografts, increasing overall survival. Conclusions: A CK1α agonist penetrates into the brain, and shows efficacy against metastatic TRP53 mutant MB, which is resistant to existing therapies including the SMO inhibitors currently being evaluated clinically.

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