A Novel Therapeutic Modality for Advanced-Stage Prostate Cancer Treatment
Technical Report,22 Sep 2014,21 Sep 2018
University of Tennessee Health Science Center (UTHSC) Memphis United States
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Prostate cancer PrCa is the second leading cause of cancer death in American men. There is an increasing need to develop effective therapies for advanced stage PrCa due to their limited or no response to androgen ablation therapy. Chemotherapy is an alternative approach for the treatment of advanced stage PrCa. However, the available chemotherapeutic agents used to treat PrCa are non-selective and provide only limited response rate Thus, novel treatment modalities are needed to treat advanced stage PrCa. In this proposal, we intend to develop a novel therapeutic modality for advanced stage metastatic prostate cancer. There is an urgent need to develop effective therapies for the treatment of advanced stage prostate cancer PrCa due to their limited or no response to androgen ablation therapy. In this proposal, we intend to develop a novel therapeutic agent Ormeloxifene ORM for the treatment of advanced stage metastatic PrCa. Our results illustrated that ORM treatment effectively inhibited invasion and motility of PrCa cells. Further, we observed that ORM treatment induced the expression of tumor suppressor PKD1 a modulator of nuclear Beta-catenin signaling in PrCa cells. Interestingly, ORM treatment inhibited expression of oncogenic isoform of PKD PKD3 in PrCa cells. We have also observed that ORM mediated overexpressionactivation of PKD1 effectively inhibits metastasis associated protein 1 MTA1 in PrCa cells. MTA1 has been reported to be very tightly associated with cancer metastasis in various cancer types including PrCa. To further investigate association of ORM with MTA1 suppression, we performed molecular docking studies with MTA1 which illustrated potential binding sites of ORM on MTA1 protein. Considering effective therapeutic index of ORM, we are also making more potent analogues of ORM. These findings suggest that ORM could be a potential therapeutic molecule to inhibit growth of advanced stage PrCa and its metastasis.
- Medicine and Medical Research