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Cancer Genet. 2014 Sep;207(9):403-11. doi: 10.1016/j.cancergen.2014.09.002. Epub 2014 Sep 16.

Effect of telomerase inhibition on preclinical models of malignant rhabdoid tumor.

Author information

1
Center for Cancer and Immunology Research, Children's National Medical Center, Washington, DC, USA; Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
2
Research Animal Facility, Children's National Medical Center, Washington, DC, USA.
3
Center for Cancer and Immunology Research, Children's National Medical Center, Washington, DC, USA.
4
Center for Translational Science, Children's National Medical Center, Washington, DC, USA.
5
Center for Cancer and Immunology Research, Children's National Medical Center, Washington, DC, USA. Electronic address: jdome@childrensnational.org.

Abstract

Novel treatment approaches are desperately needed for malignant rhabdoid tumor (MRT). Telomerase is an attractive therapeutic target because it is specific to cancer and critical for cancer cell immortality. We evaluated the effect of the telomerase inhibitor imetelstat in preclinical models of MRT. Three MRT cell lines, BT-12, G401, and RT-peri, were treated with the telomerase inhibitor imetelstat. The effects of imetelstat on telomere length, DNA damage response, and cell proliferation were assessed. The efficacy of imetelstat in vivo was evaluated in subcutaneous xenografts derived from each of the cell lines. Treatment with imetelstat resulted in inhibition of telomerase activity, marked telomere shortening, and activation of the DNA damage response pathway, as measured by formation of γ-H2AX nuclear foci, phosphorylation of ATM, and phosphorylation of TP53. Imetelstat-treated G401 cells underwent complete growth arrest after 16 passages. The other two cell lines exhibited growth inhibition. Imetelstat resulted in 40-50% growth inhibition compared to placebo-treated controls in all three xenograft models. The activity of imetelstat as a single agent suggests that further studies of telomerase inhibitors in combination with other agents may be warranted.

KEYWORDS:

DNA damage; GRN163L; H2AX; Telomere; atypical teratoid/rhabdoid tumor; imetelstat

PMID:
25441685
DOI:
10.1016/j.cancergen.2014.09.002
[Indexed for MEDLINE]

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