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

Abstract

Purpose: Although most children with medulloblastoma are cured of their disease, Sonic Hedgehog (SHH) subgroup medulloblastoma driven by TRP53 mutations is essentially lethal. Casein kinase 1a (CK1a) phosphorylates and destabilizes GLI transcription factors, thereby inhibiting the key effectors of SHH signaling. We therefore tested a secondgeneration CK1a activator against TRP53-mutant, MYCNamplified medulloblastoma.Experimental Design: The ability of this CK1a activator to block SHH signaling was determined in vitro using GLI reporter cells, granular precursor primary cultures, and PATCHED1 (PTCH1)-mutant sphere cultures. While in vivo efficacy was tested using 2 different medulloblastoma mouse models: PTCH1 and ND2:SMOA1. Finally, the clinical relevance of CK1a 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 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 TRP53-mutant, MYCN-amplified, SHH subgroup medulloblastoma xenografts, increasing overall survival.Conclusions: Using a newly described small-molecule, SSTC3, we show that CK1a activators could address a significant unmet clinical need for patients with SMO inhibitorresistant medulloblastoma, including those harboring mutations in TRP53. Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis):

Casein kinase 1α inhibits p53 downstream of MDM2‑mediated autophagy and apoptosis in acute myeloid leukemia

“…Casein kinase 1α (CK1α), encoded by CSNK1A1 , is a classical negative regulator for the Wnt/β-catenin signaling pathway ( 14 ). In addition to Wnt/β-catenin signaling, CK1α also regulates p53, GLI transcription factors and other important signaling pathways ( 15 – 17 ). CK1α has been reported to be implicated in apoptosis, survival, senescence and other cellular physiological processes, thus regulating the occurrence and development of multiple tumors ( 17 , 18 ).…”

“…In addition to Wnt/β-catenin signaling, CK1α also regulates p53, GLI transcription factors and other important signaling pathways ( 15 – 17 ). CK1α has been reported to be implicated in apoptosis, survival, senescence and other cellular physiological processes, thus regulating the occurrence and development of multiple tumors ( 17 , 18 ). Recently, CK1α was reported to act as a key negative regulator of oncogenic RAS-induced autophagy, suggesting that targeting CK1α-regulated autophagy provides a promising therapeutic opportunity to treat oncogenic RAS-driven cancers ( 19 ).…”

Casein Kinase 1α as a Regulator of Wnt-Driven Cancer

“…Indeed, it was previously demonstrated that pyrvinium and SSTC3 could also inhibit the growth of Sonic Hedgehog-driven (Shh-driven) medulloblastoma [129,134]. Even though CK1α can regulate both Shh and Wnt pathways, both CK1α activators attenuate Shh activity without affecting Wnt signaling in these medulloblastoma models [129,134]. This suggests that the primary function of these drugs is not limited to Wnt inhibition and is likely context-dependent.…”

“…SSTC3, but not its structural analog SSTC111 ( Figure 4 A), inhibits the growth of Wnt-driven CRC cell lines and patient-derived CRC organoids ex vivo [ 97 ]. Consistent with its improved bioavailability, SSTC3 remains in plasma for 24 h after intraperitoneal injection in mice and is able to penetrate the blood-brain barrier [ 97 , 129 ]. Furthermore, SSTC3 significantly inhibits the growth of primary and metastatic tumors that develop from patient CRCs or a Wnt-driven CRC cell line implanted in mice [ 97 ].…”

The SHH/GLI signaling pathway: a therapeutic target for medulloblastoma

“…Recently, SSTC3 has been described as a second-generation of CK1α activator. The compound inhibits HH signaling both in vitro and in vivo and possess improved pharmacokinetic and antioncogenic properties (crossing the BBB, attenuating the growth and metastases of SHH-MB mouse models and prolonging their survival) compared to pyrvinium [124]. Most importantly, SSTC3 is effective against an orthotopically implanted SHH-MB PDX with a TRP53 mutation and MYCN amplification [124].…”