Reprogramming medulloblastoma-propagating cells by a combined antagonism of Sonic Hedgehog and CXCR4

Stacey A. Ward, Nicole M. Warrington, Sara Taylor, Najla Kfoury, Jingqin Luo, Joshua B. Rubin

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

Abstract

The CXCR4 chemokine and Sonic Hedgehog (SHH) morphogen pathways are well-validated therapeutic targets in cancer, including medulloblastoma. However, single-agent treatments with SHH or CXCR4 antagonists have not proven efficacious in clinical trials to date. Here, we discovered that dual inhibition of the SHH and CXCR4 pathways in a murine model of SHH-subtype medulloblastoma exerts potent antitumor effects. This therapeutic synergy resulted in the suppression of tumor-propagating cell function and correlated with increased histone H3 lysine 27 trimethylation within the promoters of stem cell genes, resulting in their decreased expression. These results demonstrate that CXCR4 contributes to the epigenetic regulation of a tumor-propagating cell phenotype. Moreover, they provide a mechanistic rationale to evaluate the combination of SHH and CXCR4 inhibitors in clinical trials for the treatment of medulloblastoma, as well as other cancers driven by SHH that coexpress high levels of CXCR4. Cancer Res; 77(6); 1416-26.

Original languageEnglish
Pages (from-to)1416-1426
Number of pages11
JournalCancer research
Volume77
Issue number6
DOIs
StatePublished - Mar 15 2017

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