Perifosine as a potential novel anti-telomerase therapy

Brody Holohan, Moriah M. Hagiopian, Tsung Po Lai, Ejun Huang, Daphne R. Friedman, Woodring E. Wright, Jerry W. Shay

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

Abstract

Most tumors circumvent telomere-length imposed replicative limits through expression of telomerase, the reverse transcriptase that maintains telomere length. Substantial evidence that AKT activity is required for telomerase activity exists, indicating that AKT inhibitors may also function as telomerase inhibitors. This possibility has not been investigated in a clinical context despite many clinical trials evaluating AKT inhibitors. We tested if Perifosine, an AKT inhibitor in clinical trials, inhibits telomerase activity and telomere maintenance in tissue culture and orthotopic xenograft models as well as in purified CLL samples from a phase II Perifosine clinical trial. We demonstrate that Perifosine inhibits telomerase activity and induces telomere shortening in a wide variety of cell lines in vitro, though there is substantial heterogeneity in long-term responses to Perifosine between cell lines. Perifosine did reduce primary breast cancer orthotopic xenograft tumor size, but did not impact metastatic burden in a statistically significant manner. However, Perifosine reduced telomerase activity in four of six CLL patients evaluated. Two of the patients were treated for four to six months and shortening of the shortest telomeres occurred in both patients' cells. These results indicate that it may be possible to repurpose Perifosine or other AKT pathway inhibitors as a novel approach to targeting telomerase.

Original languageEnglish (US)
Pages (from-to)21816-21826
Number of pages11
JournalOncotarget
Volume6
Issue number26
DOIs
StatePublished - 2015

Keywords

  • CLL
  • Perifosine
  • Targeted therapy
  • Telomerase
  • Telomeres

ASJC Scopus subject areas

  • Oncology

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