Oncotarget

Priority Research Papers:

Perifosine as a potential novel anti-telomerase therapy

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

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Oncotarget. 2015; 6:21816-21826. https://doi.org/10.18632/oncotarget.5200

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Abstract

Brody Holohan1, Moriah M. Hagiopian2, Tsung-Po Lai1, Ejun Huang1, Daphne R. Friedman3, Woodring E. Wright1 and Jerry W. Shay1,4

1 Department of Cell Biology, UT Southwestern Medical Center, Dallas TX, USA

2 Department of Surgery, UT Southwestern Medical Center, Dallas TX, USA

3 Duke University and Durham VA Medical Center, Durham, NC, USA

4 Center for Excellence in Genomics Medicine Research, King Abdulaziz University, Jeddah, Saudi Arabia

Correspondence to:

Jerry W. Shay, email:

Keywords: telomeres, telomerase, targeted therapy, perifosine, CLL

Received: July 02, 2015 Accepted: August 07, 2015 Published: August 15, 2015

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.


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