Ward Stacey A, Warrington Nicole M, Taylor Sara, Kfoury Najla, Luo Jingqin, Rubin Joshua B
Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri.
Department of Surgery, Washington University School of Medicine, St. Louis, Missouri.
Cancer Res. 2017 Mar 15;77(6):1416-1426. doi: 10.1158/0008-5472.CAN-16-0847. Epub 2016 Dec 28.
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. .
CXCR4趋化因子和音猬因子（SHH）形态发生素信号通路是包括髓母细胞瘤在内的癌症中经过充分验证的治疗靶点。然而，迄今为止，在临床试验中，使用SHH或CXCR4拮抗剂进行单药治疗尚未证明有效。在此，我们发现，在SHH亚型髓母细胞瘤小鼠模型中对SHH和CXCR4通路进行双重抑制可产生强大的抗肿瘤作用。这种治疗协同作用导致肿瘤增殖细胞功能受到抑制，并与干细胞基因启动子内组蛋白H3赖氨酸27三甲基化增加相关，从而导致其表达降低。这些结果表明，CXCR4有助于肿瘤增殖细胞表型的表观遗传调控。此外，它们为在治疗髓母细胞瘤以及由SHH驱动且共表达高水平CXCR4的其他癌症的临床试验中评估SHH和CXCR4抑制剂的联合应用提供了机制依据。
