PROJECT SUMMARY: PROJECT-1 Despite recent advancements in diagnosing and treating prostate cancer (PCa), it remains the most common epithelial malignancy and is the 2nd most common cause of cancer death in men in the U.S. High throughput technologies have enabled identifying several driving molecular aberrations in prostate cancer. Research suggests diverse genetic, epigenetic and environmental factors influence prostate cancer initiation and growth eventually leading to incurable metastatic disease. To understand the different forms of PCa, classify indolent from aggressive conditions, and develop effective therapeutic strategies, it is essential to investigate the underlying complex molecular events. Using an integrative approach and multiple high throughput data sets, we nominated AAA ATPase TRIP13 as a potential oncogene in prostate cancer growth and progression. Preliminary data revealed an amplification and overexpression of TRIP13 in prostate cancer samples and suggested a role for TRIP13 in PCa cell proliferation and tumor growth. Thus, our central hypothesis is that amplification and overexpression of TRIP13 contribute to PCa aggressiveness and progression. The specific aims of this project will validate the role of TRIP13 in prostate cancer progression and determine its value as a therapeutic target. As TRIP13 harbors enzymatic activity, it may be amenable to inhibition by small molecules. The aims of this proposal are as follows: Aim 1. Characterize TRIP13 expression and regulation during PCa progression. This aim will evaluate the expression pattern of TRIP13 during prostate cancer progression, evaluate if TRIP13 expression can predict disease progression, and investigate the mechanism of dysregulation of TRIP13 in prostate cancer. These investigations are critical to target TRIP13 effectively. Aim 2. Determine the mechanism of action of TRIP13 in PCas. This aim will provide insight into the role of TRIP13 and downstream molecular pathways in prostate cancer cell proliferation, invasion, and epithelial-mesenchymal transition, thus validating it as a useful therapeutic target. Aim 3. Determine the therapeutic efficacy of TRIP13 using its inhibitor in combination with docetaxel loaded-planetary ball milled (PBM) nanoparticles specific to PCa. In this aim, we will optimize the PBM nanoparticle formulation and the process condition for TRIP13 specific small-molecule inhibitor (DCZ0415) delivery in vivo along with docetaxel or Erlotinib. This proposal has a significant translational impact for managing a subset of prostate cancer patients as TRIP13 can be directly targeted by developing novel compounds or via downstream effectors and pathways such as EGFR using currently available therapies.