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

项目 1：阐明 AAA ATPase TRIP13 在前列腺癌中的作用

• 批准号: 10328129
• 负责人: Sooryanarayana Varambally
• 金额: $ 17.08万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-23 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10328129
• 关键词: ATP phosphohydrolase; African American; Alabama; Automobile Driving; Binding; Biology; Cancer Etiology; Cancer Patient; Caucasians; Cell Proliferation; Cells; Cessation of life; Chemoresistance; Clinical Management; Complex; Comprehensive Cancer Center; Data; Data Set; Detection; Diagnosis; Disease; Disease Outcome; Disease Progression; EZH2 gene; Environmental Risk Factor; Enzymes; Epidermal Growth Factor Receptor; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; Epigenetic Process; Epithelial; Erlotinib; Event; Fluorescent in Situ Hybridization; Formulation; Gene Expression Profiling; Gene Family; Gene Fusion; Genes; Genetic; Goals; Growth; Head and Neck Cancer; Indolent; Investigation; Joints; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Mesenchymal; Metastatic Prostate Cancer; MicroRNAs; Microarray Analysis; Mitotic Checkpoint; Molecular; Molecular Abnormality; Molecular Target; Morehouse School of Medicine; Neoplasm Metastasis; Not Hispanic or Latino; Oncogenes; Oncogenic; Pathway interactions; Patients; Pattern; Phenotype; Pilot Projects; Predictive Value; Process; Proteomics; Regulation; Research; Role; Sampling; Signal Transduction; Therapeutic; Therapeutic Intervention; Tissue Microarray; Treatment Efficacy; United States; Universities; Validation; Work; cancer health disparity; cancer initiation; docetaxel; high throughput technology; histone methyltransferase; in vivo; in vivo Model; inhibitor/antagonist; innovation; insight; men; molecular marker; mortality; nanoparticle; novel; novel diagnostics; novel marker; overexpression; patient subsets; prognostic; prostate cancer cell; prostate cancer progression; small molecule; small molecule inhibitor; targeted treatment; therapeutic target; therapeutically effective; transcription factor; translational impact; tumor; tumor growth; tumorigenesis

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.

项目摘要：项目1 尽管最近在诊断和治疗前列腺癌（PCA）方面取得了进步，但它仍然是最常见的 上皮恶性肿瘤，是美国男性癌症死亡的第二大原因 技术已使鉴定前列腺癌中的几种驱动分子像差。研究 提出各种遗传，表观遗传和环境因素会影响前列腺癌的启动和生长 最终导致无法治愈的转移性疾病。要了解不同形式的PCA，请懒惰地分类 从积极的条件和制定有效的治疗策略中，必须调查 基础复杂分子事件。使用集成方法和多个高吞吐量数据集，我们 提名的AAA ATPase TRIP13是前列腺癌生长和进展中的潜在癌基因。初步的 数据揭示了前列腺癌样品中Trip13的扩增和过表达，并提出了作用 用于PCA细胞增殖和肿瘤生长中的Trip13。因此，我们的中心假设是放大和 TRIP13的过表达有助于PCA的侵略性和进展。该项目的具体目的 将验证Trip13在前列腺癌进展中的作用，并确定其作为治疗靶标的价值。 作为TRIP13具有酶活性，可能会受到小分子的抑制作用。这个目的 建议如下：AIM 1。表征TRIP13表达和PCA进展过程中的调节。这 AIM将评估前列腺癌进展过程中TRIP13的表达模式，评估Tip13是否 表达可以预测疾病进展，并研究Trip13失调的机制 前列腺癌。这些研究对于有效的Trip13至关重要。目标2。确定机制 Trip13在PCAS中的作用。这个目标将提供有关Trip13和下游分子的作用的洞察力 前列腺癌细胞增殖，侵袭和上皮 - 间质转变的途径，从而验证它 作为有用的治疗靶标。目标3。使用其抑制剂在 与多西他赛的铣削球（PBM）纳米颗粒结合使用。在这个目标中，我们将 优化PBM纳米颗粒公式和TRIP13特异性小分子抑制剂的过程条件 （DCZ0415）与多西他赛或厄洛替尼一起在体内递送。该提案具有重大的翻译影响 通过开发新颖的新型，可以直接针对前列腺癌患者的一部分前列腺癌患者 化合物或通过使用当前可用疗法的下游效应子和途径（例如EGFR）。