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Toward Selective Androgen Deprivation by Targeting Androgen Activation of SRF

通过靶向 SRF 的雄激素激活来实现选择性雄激素剥夺

基本信息

批准号：
10322421
负责人：
Hannelore Heemers
金额：
$ 34.67万
依托单位：
CLEVELAND CLINIC LERNER COM-CWRU
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-06-19 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10322421
关键词：
ATAC-seq Affect Androgen Receptor Androgen Response Element Androgens Benign Biological Assay Biotin Bypass Castration Cell Survival Cell physiology Cessation of life ChIP-seq Chromatin Clinical Complex DNA Binding Development Disease Progression Disease remission Environment Event Foundations Funding Gene Expression Genes Genetic Genetic Transcription Goals Growth Human Impairment Knowledge Laboratories Lead Left Ligands Ligation Malignant - descriptor Malignant Neoplasms Malignant neoplasm of prostate Mass Spectrum Analysis Mediating Mission Modality Modeling Molecular Monomeric GTP-Binding Proteins Nucleic Acid Regulatory Sequences Oncogenes Outcome Output Patients Pharmacology Phenotype Phosphorylation Phosphotransferases Prostate Prostate Cancer therapy Protein Analysis Protein Kinase Proteome Public Health Receptor Signaling Regulation Research Resistance Role Sampling Serum Response Factor Signal Pathway Signal Transduction Testing Therapeutic Therapeutic Intervention Tissues United States National Institutes of Health Work Xenograft procedure activating transcription factor androgen deprivation therapy androgen sensitive base clinical application clinically relevant deprivation improved inhibitor innovation insight knock-down novel novel strategies novel therapeutic intervention novel therapeutics overexpression patient derived xenograft model prevent prostate cancer cell prostate cancer model prostate cancer progression receptor binding recruit response response biomarker targeted treatment transcription factor transcriptome transcriptome sequencing treatment strategy

项目摘要

Project summary/Abstract Despite the central role of androgen receptor (AR) in prostate cancer (CaP) progression, insights into the specific molecular mechanisms by which AR controls the cellular processes that drive CaP progression remain largely elusive. Lack of this knowledge is an important problem, because without it, development of novel therapeutic approaches that target specifically AR-dependent events underlying the lethal phenotype is unlikely. The long- term goal is to understand how the mechanism(s) by which AR controls clinically relevant gene expression in CaP cells can be manipulated for therapeutic intervention. The objective here is to determine the therapeutic potential of disrupting AR-responsive PKN1-SRF interactions. The central hypothesis is that targeting PKN1 will prevent CaP progression mediated by AR-responsive SRF action. This hypothesis is formulated based on preliminary work produced in the applicant's laboratory. The rationale for the proposed studies is that, once it is understood how AR regulation of SRF action in CaP occurs, select targeting of AR action that is relevant to disease progression will be possible. The central hypothesis is tested by pursuing 3 specific aims: 1) determine the role of PKN1 in the AR-responsive SRF transcriptional complex; 2) define the substrate for PKN1's kinase action in the AR-dependent SRF transcriptional complex; and 3) determine therapeutic potential of targeting AR- responsive PKN1-SRF interactions. Aim 1 will determine the impact of genetic or pharmacological inactivation of PKN1 on the composition and function of AR-dependent SRF complex at target genes using a combination of RNA-Seq, ChIP-Seq and ATAC-Seq assays. In Aim 2, state-of-the-art biotin-based proximity ligation assays and mass spectrometry in CaP models that express wild-type or kinase-dead PKN1 or in which PKN1 action is pharmacologically inhibited will define PKN1-dependent phosphorylation of SRF, the SRF transcriptional complex and its chromatin environment. Aim 3 will determine the therapeutic potential of inhibiting PKN1-SRF interactions in clinically relevant PDXs and fresh ex vivo explants of CaP tissue obtained from patients. Clinically applicable biomarkers of response to such treatment will be sought using gene expression and proximity ligation assays. The proposed research is innovative because it focuses on an entirely different approach to target AR action in CaP: unraveling and targeting an AR-dependent signaling pathway downstream of AR that controls the expression of genes that are relevant for CaP progression. This contribution is significant because is it the first step in a continuum of research that is expected to lead to the development of novel treatment modalities that target specifically AR-mediated gene expression that underlies the lethal CaP phenotype. With respect to expected outcomes, the proposed studies will identify the molecular mechanisms by which PKN1 introduces a therapeutic vulnerability in the AR-PKN1-SRF signaling cascade that gives rise to the aggressive CaP phenotype. These results will have an important positive impact because they will fundamentally advance knowledge about AR action in CaP, in general, and provide new targets for CaP therapy, specifically.

项目总结/文摘