A CK1a Activator Penetrates the Brain and Shows Efficacy Against Drug-resistant Metastatic Medulloblastoma

Jezabel Rodriguez-Blanco, Bin Li, Jun Long, Chen Shen, Fan Yang, Darren Orton, Sara Collins, Noriyuki Kasahara, Nagi G. Ayad, Heather J. McCrea, Martine F. Roussel, William A. Weiss, Anthony J. Capobianco, David J. Robbins

Research output: Contribution to journalArticle

2 Scopus citations

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 second-generation CK1a activator against TRP53-mutant, MYCN-amplified 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 inhibitor–resistant medulloblastoma, including those harboring mutations in TRP53.

Original languageEnglish (US)
Pages (from-to)1379-1388
Number of pages10
JournalClinical Cancer Research
Volume25
Issue number4
DOIs
StatePublished - Feb 15 2019

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint Dive into the research topics of 'A CK1a Activator Penetrates the Brain and Shows Efficacy Against Drug-resistant Metastatic Medulloblastoma'. Together they form a unique fingerprint.

  • Cite this