The Akt Inhibitor Perifosine Strongly Enhances The Antitumor And Antivascular Activity Of Cd34+Cells Engineered To Express Membrane-Bound Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (Trail)

Introduction. We have previously demonstrated that adenovirus-transduced CD34+ cells expressing membrane-bound (m)TRAIL (CD34-TRAIL+ cells) exert potent antitumor activity against a variety of hematopoietic tumors by targeting both tumor cells and tumor vasculature (Blood, 115:2231-40, 2010). Recently, we have identified non-Hodgkin lymphoma cell lines which are resistant to the in vivo antitumor activity of mTRAIL. Perifosine has been shown to increase the toxicity of soluble TRAIL against cancer cell lines by inhibiting the PI3K/Akt pathway as well as enhancing pro-apoptotic TRAIL receptors. We therefore investigated the efficacy of Perifosine in modulating the antitumor activity of CD34-TRAIL+ cells using as model systems the TRAIL-resistant SU-DHL-4V and the TRAIL-sensitive KMS-11 cell lines. Methods and Results. In vitro, Perifosine significantly enhanced the cytotoxic activity of CD34-TRAIL+ cells against both SU-DHL-4V and KMS-11 cell lines by increasing the expression of TRAIL receptors and down-modulating phospho-Akt, cFLIP and Mcl-1 expression. In vivo, in NOD/SCID mice bearing subcutaneous nodules, Perifosine significantly increased the antitumor activity of CD34-TRAIL+ cells against both tumor types. In fact, CD34-TRAIL+ cells used as single agent exerted a limited if any activity against TRAIL-resistant SU-DHL-4V nodules, whereas, when combined with Perifosine, transduced cells reduced SU-DHL-4V growth by 43% (p Conclusions. Our results demonstrate that: (i) TRAIL-R2 expression by TECs correlates with the in vivo antivascular activity of CD34-TRAIL+ cells; (ii) Perifosine potentiates the antitumor activity of TRAIL-armed CD34+ cells and is able to overcome in vivo resistance to mTRAIL by inducing TRAIL-R2 expression on tumor endothelial cells. These results may open new perspectives in view of clinical applications of CD34-TRAIL+ cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 640. doi:10.1158/1538-7445.AM2011-640