Project 1: Elucidating the role of AAA ATPase TRIP13 in prostate cancer

项目概要：项目-1 尽管最近在诊断和治疗前列腺癌（PCa）方面取得了进展，但它仍然是最常见的前列腺癌。 上皮恶性肿瘤，是美国男性癌症死亡的第二大常见原因。 技术已经能够鉴定前列腺癌中的几种驱动分子畸变。研究 表明不同的遗传、表观遗传和环境因素影响前列腺癌的发生和生长 最终导致无法治愈的转移性疾病。为了了解PCa的不同形式，将无痛性PCa 从侵略性的条件，并制定有效的治疗策略，这是至关重要的调查， 复杂分子事件的潜在原因使用综合方法和多个高通量数据集，我们 提名AAA ATP酶TRIP 13作为前列腺癌生长和进展中的潜在致癌基因。初步 数据显示TRIP 13在前列腺癌样品中的扩增和过表达，并提示TRIP 13在前列腺癌中的作用。 TRIP 13在PCa细胞增殖和肿瘤生长中的作用。因此，我们的中心假设是，放大和 TRIP 13过表达有助于PCa的侵袭性和进展。该项目的具体目标 将验证TRIP 13在前列腺癌进展中的作用，并确定其作为治疗靶点的价值。 由于TRIP 13具有酶活性，因此它可能易于被小分子抑制。这样做的目的是 建议如下：目标1。表征PCa进展期间TRIP 13的表达和调节。这 目的是评估TRIP 13在前列腺癌进展过程中的表达模式，评估TRIP 13 TRIP 13的表达可以预测疾病的进展，并研究TRIP 13在糖尿病中的失调机制。 前列腺癌这些调查对于有效地针对TRIP 13至关重要。目标二。确定机制 TRIP 13在前列腺癌中的作用。这一目标将为TRIP 13和下游分子的作用提供深入了解。 前列腺癌细胞增殖、侵袭和上皮-间质转化中的通路，从而验证了 作为有用的治疗靶点。目标3：使用TRIP 13的抑制剂测定TRIP 13在 与多西他赛负载的行星式球磨（PBM）纳米颗粒的组合对PCa特异。为此，我们会 优化TRIP 13特异性小分子抑制剂PBM纳米粒的处方和工艺条件 （DCZ 0415）与多西他赛或厄洛替尼一起沿着体内递送。这一提议具有重大的翻译影响 用于管理前列腺癌患者的子集，因为TRIP 13可以通过开发新的 化合物或通过下游效应物和途径如EGFR使用目前可用的疗法。

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.