TY - JOUR
T1 - Reprogramming medulloblastoma-propagating cells by a combined antagonism of Sonic Hedgehog and CXCR4
AU - Ward, Stacey A.
AU - Warrington, Nicole M.
AU - Taylor, Sara
AU - Kfoury, Najla
AU - Luo, Jingqin
AU - Rubin, Joshua B.
N1 - Publisher Copyright:
© 2016 AACR.
PY - 2017/3/15
Y1 - 2017/3/15
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85015843745&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-16-0847
DO - 10.1158/0008-5472.CAN-16-0847
M3 - Article
C2 - 28031228
AN - SCOPUS:85015843745
SN - 0008-5472
VL - 77
SP - 1416
EP - 1426
JO - Cancer research
JF - Cancer research
IS - 6
ER -