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• W2783262509 abstract "2516 Prostate cancer is the most commonly diagnosed non-skin malignancy and the second leading cause of cancer related deaths in US men. The majority of patients present with localized hormone dependent disease. Following progression or in those presenting with regional or metastatic disease, androgen ablation is often temporally successful in preventing or delaying progression of disease. However, approximately 70% of patients’ eventually progress to hormone refractory prostate cancer (HRPC). Multiple mechanisms of progression to HRPC have been proposed including mutations in the androgen receptor (AR), over-expression of AR and promiscuous activation via growth factor signaling pathways. Previously presented data demonstrates the activation of both the PI3K/Akt/mTOR and AR pathways in a hormone dependent prostate cancer model (LNCaP cells). In the current studies, we have shown that HRPC models have significantly increased activation of the mTOR pathway compared to hormone dependent LNCaP models. We have also identified a compensatory signaling mechanism and cross-talk pathway between AR and PI3K/Akt/mTOR pathway using co-immunoprecipitation of Akt and AR. Inhibition of mTOR via Rapamycin and RAD-001 resulted in decreased p-mTOR (Ser2448) and a 40% increase of AR protein expression at 1 hour in treated cell lysates. RAD-001 has similar properties to rapamycin, though it is more potent (IC50=54pM) in hormone dependent prostate cancer cells. RAD-001 also significantly increased (4 fold) androgen regulated promoter activation compared to vehicle treated controls. Competitive binding studies have shown no significant changes in binding to the AR, confirming RAD-001 does not bind to the AR and is not agonistic. Combination treatment with VN/124-1, a novel anti-androgen synthesized in our lab, and RAD-001 demonstrated significant inhibition of cell proliferation in a HRPC model. Increased activation of p-mTOR in HRPC models as well as compensatory signaling and cross-talk mechanisms between the AR and mTOR pathways in hormone dependent prostate cancer models provide compelling evidence to implicate this pathway as a mechanism in the progression to HRPC. A better understanding of the mechanisms of disease progression will allow for the development of targeted treatments that may delay, re-sensitize or prevent HRPC." @default.
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• W2783262509 date "2007-05-01" @default.
• W2783262509 modified "2023-09-28" @default.
• W2783262509 title "Cross talk between the PI3K/Akt/mTOR pathway and the androgen receptor in hormone dependent prostate cancer and its implication in the progression to androgen independence" @default.
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