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

The CXCR4 chemokine and sonic hedgehog (SHH) morphogen pathways are validated therapeutic targets in many cancer types, including medulloblastoma. However, single agent treatments with SHH or CXCR4 antagonists have not proven efficacious in clinical trials to date. Here we show that dual inhibition of the SHH and CXCR4 pathways exerts potent antitumor effects in a murine model of SHH-subtype medulloblastoma. This therapeutic synergy resulted in 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. Our results demonstrate that CXCR4 contributes to the epigenetic regulation of a pro-tumor cell phenotype. Moreover, they provide a rationale to evaluate combinatorial inhibition of SHH and CXCR4 in patients with medulloblastoma as well as other cancers driven by SHH that coexpress high levels of CXCR4.

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