Androgen signaling and sterol metabolism in metastatic prostate cancer: Functional and therapeutic implication

转移性前列腺癌中的雄激素信号传导和甾醇代谢：功能和治疗意义

基本信息

批准号：
10201013
负责人：
Girish C Shukla
金额：
$ 41.24万
依托单位：
CLEVELAND STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10201013
关键词：
Academic Research Enhancement Awards Affect American Anabolism Androgen Antagonists Androgen Receptor Androgens Animal Model Animals Binding Binding Proteins Biochemistry Biology CWR22Rv1 Cancer Etiology Cancer Patient Castration Cell model Cessation of life Cholesterol Coenzyme A Cytoplasm Development Disease Down-Regulation Educational process of instructing Enzymes Failure Gene Expression Regulation Genes Genetic Polymorphism Genetic Transcription Grant Growth Hydroxymethylglutaryl-CoA reductase Laboratories Ligands Link Longevity Luteinizing Hormone-releasing Hormone Agonist Malignant Neoplasms Malignant neoplasm of prostate Mediating Membrane Metabolism Metastatic Prostate Cancer Methods MicroRNAs Molecular Nature Neoplasm Metastasis Oncogenes Oncogenic Outcome Pathway interactions Patients Play Post-Transcriptional Regulation Prognosis Prognostic Marker Prostate Cancer therapy Proteins RNA Regulation Regulatory Element Relapse Research Resistance Resources Role Sampling Serum Signal Transduction Single Nucleotide Polymorphism Sterol Biosynthesis Pathway Sterols Testing Testosterone Therapeutic Time Transactivation Tumor Suppressor Proteins Up-Regulation Xenograft procedure abiraterone androgen deprivation therapy biomarker discovery cancer diagnosis cancer therapy castration resistant prostate cancer curative treatments design doctoral student druggable target graduate student improved innovation men mouse model negative affect novel novel therapeutics prognostic prognostic significance prognostic value prostate cancer cell prostate cancer cell line prostate cancer model prostate cancer progression prostate carcinogenesis public health relevance testosterone biosynthesis therapeutic evaluation transcription factor tumor undergraduate student

项目摘要

Abstract Prostate cancer (PCa) is the most commonly diagnosed cancer in men and the second leading cause of cancer-related deaths in the USA. Relapsed androgen signaling and intratumoral sterol biosynthesis are hallmarks of castration-resistant PCa (CRPC). PCa growth and proliferation depend on androgen signaling by the Androgen Receptor (AR). Targeting the androgen synthesis pathways and transactivation function of AR is a primary therapeutic approach to treat PCa. The progression of PCa from castration-sensitive to the castration-resistant stage (CRPC) depends on the failure of androgen signaling antagonists and the dysregulation of AR-centric molecular mechanisms in a high percentage of patients. Recent studies show that microRNAs (miRNAs) exert post-transcriptional regulation of gene expression by targeting oncogenes and performing tumor-suppressive functions in various cancers, including PCa. Scientific premise: The fundamental discovery motivating the proposed study is that miR-149-5p targets the expression of two major transcription factors AR and sterol regulatory element-binding transcription factor 1 (SREBF1), both are druggable targets and are implicated in CRPC. Our central hypothesis entails that miR-149-5p post-transcriptionally downregulates AR and SREBF1, and inactivation of miR-149-5p expression during the prostate carcinogenesis leads to the upregulation of androgen signaling and sterol biosynthesis, which promotes CRPC. We will test our hypothesis by pursuing three integrated Specific Aims. In aim 1 we will test miR-149-5p anti-proliferation and anti-oncogenic function in PCa cells, in Aim 2, we will define molecular mechanisms which negatively affects the maturation of miR-149-5p and in the aim 3, we will test the therapeutic and prognostic value of miR-149-5p. Significance: The study will provide a tumor-suppressor role of miR-149-5p in CRPC. The innovative research approaches the disease from a novel miRNA-mediated control of the androgen signaling and intratumoral sterol biosynthesis pathways in particular testosterone metabolism by directly co-targeting AR and SREBF1, and both are druggable targets in CRPC. This study has the potential to test for the first time co-targeting of primary PCa promoting transcription factors and a new paradigm for improved patient therapies by identifying the significant key regulators of androgen signaling and sterol biosynthesis pathways.

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Survival analysis and prognostic factors of the carcinoma of gallbladder.

DOI：
10.1186/s12957-022-02857-y
发表时间：
2022-12-20
期刊：
WORLD JOURNAL OF SURGICAL ONCOLOGY
影响因子：
3.2
作者：
Feroz, Zainab;Gautam, Priyanka;Tiwari, Sonia;Shukla, Girish C.;Kumar, Munish
通讯作者：
Kumar, Munish

Investigating the Role of Glutathione S- Transferase Genes, Histopathological and Molecular Subtypes, Gene-Gene Interaction and Its Susceptibility to Breast Carcinoma in Ethnic North- Indian Population.

DOI：
10.31557/apjcp.2022.23.10.3481
发表时间：
2022-10-01
期刊：
Asian Pacific journal of cancer prevention : APJCP
影响因子：
0
作者：
Gautam, Priyanka;Feroz, Zainab;Tiwari, Sonia;Vijayraghavalu, Sivakumar;Shukla, Girish C;Kumar, Munish
通讯作者：
Kumar, Munish

Differential Expression of Non-Coding RNAs in Stem Cell Development and Therapeutics of Bone Disorders.