title: Perifosine as a potential novel anti-telomerase therapy.
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.
authors: Department of Cell Biology, UT Southwestern Medical Center, Dallas, TX, USA.
authors: Brody
authors: B
authors: Holohan
authors: Department of Surgery, UT Southwestern Medical Center, Dallas, TX, USA.
authors: Moriah M
authors: MM
authors: Hagiopian
authors: Department of Cell Biology, UT Southwestern Medical Center, Dallas, TX, USA.
authors: Tsung-Po
authors: TP
authors: Lai
authors: Department of Cell Biology, UT Southwestern Medical Center, Dallas, TX, USA.
authors: Ejun
authors: E
authors: Huang
authors: Duke University and Durham VA Medical Center, Durham, NC, USA.
authors: Daphne R
authors: DR
authors: Friedman
authors: Department of Cell Biology, UT Southwestern Medical Center, Dallas, TX, USA.
authors: Woodring E
authors: WE
authors: Wright
authors: Department of Cell Biology, UT Southwestern Medical Center, Dallas, TX, USA.|Center for Excellence in Genomics Medicine Research, King Abdulaziz University, Jeddah, Saudi Arabia.
authors: Jerry W
authors: JW
authors: Shay
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics; D045744:Cell Line, Tumor; D017322:Clinical Trials, Phase II as Topic; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D010767:Phosphorylcholine / Q000031:analogs & derivatives* / Q000494:pharmacology; D019098:Telomerase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016615:Telomere / Q000187:drug effects / Q000201:enzymology; D023041:Xenograft Model Antitumor Assays
chemical_list: D004791:Enzyme Inhibitors; D010767:Phosphorylcholine; C105905:perifosine; D019098:Telomerase
keywords: CLL; perifosine; targeted therapy; telomerase; telomeres