The Ki 67 list was also lower in perifosine treated tumors in accordance with car treated controls, however the difference did not achieve statistical significance. Development of APC/PTEN murine OEAs is inhibited in vivo by conventional chemotherapy and drugs targeting activated PI3K/AKT/mTOR signaling The response of mouse OEAs to AKT and/or mTOR inhibitors in vivo would help demonstrate the models Imatinib CGP-57148B potential application for screening novel drugs targeting activated PI3K/ AKT/mTOR signaling. It would also be useful to know whether the murine APC/PTEN tumors react to cisplatin/ paclitaxel in vivo, because clinical studies in ovarian cancer patients would likely compare the activity of targeted agents to that of traditional cytotoxic chemotherapy. Tumor bearing mice were therefore tested by us for reaction to rapamycin, a first-generation mTOR chemical that directly binds mTORC1, a downstream effector of activated AKT. Tumor reaction to mainstream combination therapy with cisplatin and paclitaxel and two mechanistically different AKT inhibitors was also evaluated. API 2, also referred to as triciribine, is just a cell permeable tricyclic nucleoside that selectively inhibits the cellular phosphorylation/ activation of AKT, while perifosine targets cell membranes and inhibits Cholangiocarcinoma PKB mediated AKT activation. Perifosine has also been shown to facilitate degradation of mTOR signaling pathway elements including mTOR, raptor, rictor, S6K, and 4E BP1. For these experiments, AdCre was injected into the right ovarian bursa of Apcflox/flox, Ptenflox/flox mice and drug therapy was initiated after 6 weeks, when all of the mice were likely to have developed at least small cancers based on the studies described above. Data obtained after 30 days of treatment with rapamycin, API 2, perifosine and cisplatin/paclitaxel are shown in Figures 5AD, respectively. Therapy with each regime, including both low and high Dovitinib structure doses of rapamycin, triggered statistically significant inhibition of tumor growth over 4 weeks centered on measurements of tumor volume at necropsy. Microscopic analysis of H&E stained sections showed that residual drug treated tumors were morphologically similar to vehicle treated tumors. None of the drug treated animals developed liver metastases throughout the treatment time, and only 2 of 36 drug treated mice developed ascites, compared to 12 of 33 vehicle treated mice. These data are summarized in Dining table 2. Aftereffects of drug therapy on cell proliferation in the residual ovarian tumors were assessed by IHC staining for Ki 67 in tumefaction tissue sections. The Ki 67 index was defined as the percentage of Ki 67 positive cells in the absolute most cellular regions of tumor. Information from two 400X fields were obtained and averaged. The Ki 67 index was dramatically paid down in rapamycin treated tumors in contrast to vehicle treated tumors in control mice. API 2 had no significant impact on the Ki 67 index.