Abstract 3504: Targeting the Akt pathway and HDAC signaling in prostate cancer

Loss of the tumor suppressor phosphatase and tensin homolog protein (PTEN), a negative regulator of the survival Akt pathway, and elevated levels of histone deacetylase (HDAC) enzymes which regulate DNA transcription, correlated positively with the prostate cancer progression, recurrence and metastasis. MK-2206 is an allosteric Akt inhibitor with a broad antitumor activity; clinical studies have recently been completed in patients with solid tumors, showing MK-2206 good tolerability and evidences of clinical activity. vorinostat, an HDAC inhibitor, is involved in more than 100 clinical trials in solid tumors and it showed antitumor activity in different prostate cell lines. In this study we hypothesized that combination of MK-2206 and vorinostat may provide a greater antitumor efficacy, targeting different survival pathways activated in prostate cancer. Different prostate cell lines were tested in both in vitro and in vivo xenograft models. LuCaP23.1. hormone-sensitive tumors were placed subcutaneously into male SCID mice. Tumor growth was assessed twice weekly by using serial caliper measurements. Luciferase-transfected PC3 hormone-independent tumor cells were injected in the right tibiae of male SCID mice and tumor progression was monitored weekly by bioluminescence assay using the Xenogen IVIS Living Imaging System. At the end of the experiment, Faxitron radiographs of the tibiae were taken. Mice were treated with MK-2206 at 120 mg/kg/d by oral gavage and i.p. injection of vorinostat at 100 mg/kg/d, 5 days per week. In vitro treatment of PC3 cells showed that both MK-2206 and vorinostat affected cell proliferation in a dose and time dependent manner, with a greater effect in combination. Western blot experiments validated p-Akt protein level inhibition due to MK-2206 treatment. Preliminary PC3 and LuCaP23.1. xenograft in vivo experiments confirmed the therapeutic activity of MK-2206 and vorinostat as single agents. The combination therapy showed a modest but greater inhibition of tumor growth in the PC3 xenograft bone metastatic model though not statistically significant. The antiproliferative effect of this combination was more evident in the subcutaneously LuCaP 23.1. xenograft model. This study showed for the first time the therapeutic association of MK-2206 and vorinostat in prostate cancer. We expect to further investigate the MK-2206 +/- vorinostat therapy and to provide new insight into the role of HDACs signaling and Akt pathway in prostate canc