A CK1α Activator Penetrates the Brain and Shows Efficacy Against Drug-resistant Metastatic Medulloblastoma.

Abstract

Although most children with medulloblastoma are cured of their disease, Sonic Hedgehog (SHH) subgroup medulloblastoma driven by <i>TRP53</i> 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 <i>TRP53</i>-mutant, <i>MYCN</i>-amplified medulloblastoma. The ability of this CK1α activator to block SHH signaling was determined <i>in vitro</i> using GLI reporter cells, granular precursor primary cultures, and <i>PATCHED1</i> (<i>PTCH1</i>)-mutant sphere cultures. While <i>in vivo</i> efficacy was tested using 2 different medulloblastoma mouse models: <i>PTCH1</i> and <i>ND2:SMOA1</i>. Finally, the clinical relevance of CK1α activators was demonstrated using a <i>TRP53</i>-mutant, <i>MYCN</i>-amplified patient-derived xenograft. SSTC3 inhibited SHH activity <i>in vitro</i>, acting downstream of the vismodegib target SMOOTHENED (SMO), and reduced the viability of sphere cultures derived from SHH medulloblastoma. SSTC3 accumulated in the brain, inhibited growth of SHH medulloblastoma tumors, and blocked metastases in a genetically engineered vismodegib-resistant mouse model of SHH medulloblastoma. Importantly, SSTC3 attenuated growth and metastasis of orthotopic patient-derived <i>TRP53</i>-mutant, <i>MYCN</i>-amplified, SHH subgroup medulloblastoma xenografts, increasing overall survival. Using a newly described small-molecule, SSTC3, we show that CK1a activators could address a significant unmet clinical need for patients with SMO inhibitor-resistant medulloblastoma, including those harboring mutations in TRP53.