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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

基本信息

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
项目类别：
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

项目摘要

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.

项目总结：Project -1