Combination of Ribociclib and Gemcitabine for the Treatment of Medulloblastoma

Author:

Pribnow Allison1ORCID,Jonchere Barbara1ORCID,Liu Jingjing2ORCID,Smith Kyle S.3,Campagne Olivia4ORCID,Xu Ke5ORCID,Robinson Sarah1ORCID,Patel Yogesh3,Onar-Thomas Arzu6,Wu Gang5ORCID,Stewart Clinton F.4,Northcott Paul A.3ORCID,Yu Jiyang2ORCID,Robinson Giles W.7ORCID,Roussel Martine F.1ORCID

Affiliation:

1. 1Department of Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, Tennessee.

2. 2Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee.

3. 3Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, Tennessee.

4. 4Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee.

5. 5Department of Center for Applied Bioinformatics, St. Jude Children's Research Hospital, Memphis, Tennessee.

6. 6Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, Tennessee.

7. 7Department of Neuro-Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee.

Abstract

Abstract Group3 (G3) medulloblastoma (MB) is one of the deadliest forms of the disease for which novel treatment is desperately needed. Here we evaluate ribociclib, a highly selective CDK4/6 inhibitor, with gemcitabine in mouse and human G3MBs. Ribociclib central nervous system (CNS) penetration was assessed by in vivo microdialysis and by IHC and gene expression studies and found to be CNS-penetrant. Tumors from mice treated with short term oral ribociclib displayed inhibited RB phosphorylation, downregulated E2F target genes, and decreased proliferation. Survival studies to determine the efficacy of ribociclib and gemcitabine combination were performed on mice intracranially implanted with luciferase-labeled mouse and human G3MBs. Treatment of mice with the combination of ribociclib and gemcitabine was well tolerated, slowed tumor progression and metastatic spread, and increased survival. Expression-based gene activity and cell state analysis investigated the effects of the combination after short- and long-term treatments. Molecular analysis of treated versus untreated tumors showed a significant decrease in the activity and expression of genes involved in cell-cycle progression and DNA damage response, and an increase in the activity and expression of genes implicated in neuronal identity and neuronal differentiation. Our findings in both mouse and human patient-derived orthotopic xenograft models suggest that ribociclib and gemcitabine combination therapy warrants further investigation as a treatment strategy for children with G3MB.

Funder

National Cancer Institute

American Lebanese Syrian Associated Charities

Publisher

American Association for Cancer Research (AACR)

Subject

Cancer Research,Oncology

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