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: 10693351
• 负责人: Rajesh Singh
• 金额: $ 22.27万
• 依托单位: MOREHOUSE SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-30 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10693351
• 关键词: ATP phosphohydrolase; African American; Alabama; Automobile Driving; Binding; Biology; Cancer Etiology; Cancer Patient; Caucasians; Cell Proliferation; Cells; Cessation of life; Chemoresistance; Classification; 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; Epithelium; Erlotinib; Event; Fluorescent in Situ Hybridization; Formulation; Gene Expression Profiling; Gene Family; Gene Fusion; Genes; Genetic; Goals; Growth; Head and Neck Cancer; Indolent; Institution; Invaded; 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; innovation; insight; men; molecular marker; mortality; nanoparticle; novel; novel diagnostics; 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 (This Project is identical for all three Partnering Institutions) 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（该项目对于所有三个合作机构来说都是相同的） 尽管前列腺癌 (PCa) 的诊断和治疗最近取得了进展，但它仍然是最常见的癌症 上皮恶性肿瘤，是美国男性癌症死亡的第二大原因 高通量 技术已经能够识别前列腺癌中的几种驱动分子畸变。研究 表明多种遗传、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。要了解 PCa 的不同形式，请将惰性分类 摆脱侵袭性条件并制定有效的治疗策略，有必要研究 潜在的复杂分子事件。使用综合方法和多个高通量数据集，我们 提名 AAA ATPase TRIP13 作为前列腺癌生长和进展的潜在癌基因。初步的 数据揭示了前列腺癌样本中 TRIP13 的扩增和过度表达，并表明了其作用 TRIP13 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 TRIP13 的过度表达有助于 PCa 的侵袭性和进展。该项目的具体目标 将验证 TRIP13 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 TRIP13 具有酶活性，因此它可能容易受到小分子的抑制。本次活动的目的 建议如下： 目标 1. 表征 PCa 进展过程中 TRIP13 的表达和调节。这 目的将评估TRIP13在前列腺癌进展过程中的表达模式，评估TRIP13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。这些调查对于有效针对 TRIP13 至关重要。目标 2. 确定机制 TRIP13 在 PCas 中的作用。这一目标将深入了解 TRIP13 和下游分子的作用 前列腺癌细胞增殖、侵袭和上皮间质转化的途径，从而验证它 作为有用的治疗靶点。目标 3. 使用 TRIP13 抑制剂确定 TRIP13 的治疗效果 与 PCa 特异性负载多西紫杉醇的行星球磨 (PBM) 纳米粒子组合。为了这个目标，我们将 优化TRIP13特异性小分子抑制剂的PBM纳米颗粒配方和工艺条件 (DCZ0415) 与多西紫杉醇或厄洛替尼一起体内递送。该提案具有重大转化影响 用于管理前列腺癌患者的子集，因为 TRIP13 可以通过开发新的药物直接靶向 化合物或通过下游效应器和途径（例如 EGFR）使用当前可用的疗法。