title: Reprogramming Medulloblastoma-Propagating Cells by a Combined Antagonism of Sonic Hedgehog and CXCR4.
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. ©2016 AACR.
authors.affiliation: Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Stacey A
authors.initials: SA
authors.lastname: Ward
authors.affiliation: Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Nicole M
authors.initials: NM
authors.lastname: Warrington
authors.affiliation: Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Sara
authors.initials: S
authors.lastname: Taylor
authors.affiliation: Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Najla
authors.initials: N
authors.lastname: Kfoury
authors.affiliation: Department of Surgery, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Jingqin
authors.initials: J
authors.lastname: Luo
authors.affiliation: Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri. rubin_j@kids.wustl.edu.|Department of Neuroscience, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Joshua B
authors.initials: JB
authors.lastname: Rubin
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D065150:Cellular Reprogramming; D002528:Cerebellar Neoplasms / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D008527:Medulloblastoma / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; C514936:CXCR4 protein, mouse; D053823:Hedgehog Proteins; D019718:Receptors, CXCR4; C465570:Shh protein, mouse