Progression to castration resistance is lethal in veterans with prostate cancer. Seminal Veterans Administration cooperative group studies established androgen ablation as effective palliative treatment for veterans with advanced prostate cancer. Most treatments for patients with advanced prostate cancer is centered on androgen receptor (AR) signaling, which continues to play a major role through castration resistance in prostate cancer because exquisite sensitivity of cancer cells to extremely low levels of tissue androgens. Newer treatments for advanced prostate cancer including Docetaxol chemotherapy and Sipuleucel-T cancer vaccine produce improvement in survival of about 2-4 months, highlighting need for dramatic improvement in survival for patients with metastatic prostate cancer. We propose to investigate a novel regulatory mechanism of AR signaling in prostate cancer that will provide newer opportunities to develop biomarkers and therapeutic targets. Protein Kinase D1 (PKD1) is a novel tumor and metastasis suppressor in prostate cancer that interacts with E-cadherin, a major cell adhesion protein, to regulate cell proliferation, invasion and migration in prostate cancer. Through interaction with E-cadherin and substrate phosphorylation, PKD 1 influences subcellular localization and transcriptional function of beta-catenin, a major co-activator of AR. In this proposal, we will investigate the effect to PKD1 and E-cadherin interaction and dysregulation on prostate cancer progression and alteration in AR co activation by beta-catenin using state of the art molecular and cell biological techniques and transgenic mouse models. Establishing novel signaling pathway that regulates AR activity in prostate cancer will provide additional opportunities to identify new biomarkers and influence AR function in castration resistant prostate cancer.
Risk factors for increased incidence and aggressive form of prostate cancer include family history, African American race and exposure to Agent Orange, which are frequent among veterans. It is estimated that over 5000 veterans are diagnosed with prostate cancer each year. Androgen ablation is now well established to provide rapid palliative relief from pain associated with metastasis and newer chemotherapeutic agents such as Docetaxol and cancer vaccine Siplutecel T produce improvement in survival of about 2 months in patients with castration resistant disease. There remains a critical need to identify novel molecules with therapeutic potential in prostate cancer to further improve outcomes. Our study proposes to investigate a novel Protein Kinase D1/E- cadherin/Androgen receptor signaling pathway to identify new biomarkers and therapeutic targets for management of veterans with prostate cancer.
|NickKholgh, Bita; Fang, Xiaolan; Winters, Shira M et al. (2016) Cell line modeling to study biomarker panel in prostate cancer. Prostate 76:245-58|