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Targeting KDM4B, a novel alternative splicing regulator, in castration-resistant prostate cancer (CRPC)

靶向 KDM4B（一种新型选择性剪接调节因子）治疗去势抵抗性前列腺癌 (CRPC)

基本信息

批准号：
10116972
负责人：
Jer-Tsong Hsieh
金额：
$ 41.38万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-01-01 至 2022-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10116972
关键词：
3&apos Splice Site Address Alternative Splicing Androgen Antagonists Androgen Receptor Animal Model Antineoplastic Agents Binding Biological Assay Biological Availability Cancer Patient Characteristics Chemicals Chromatin Chromatin Structure Clinical Data Development Drug Kinetics Drug resistance Enzymes Epigenetic Process Exons FDA approved Generations Genes Genomic approach Goals Growth Hormones Human In Vitro Lead Ligand Binding Domain Link Malignant Neoplasms Malignant neoplasm of prostate Metabolic Metastatic Prostate Cancer Molecular Neoplasm Circulating Cells Oncogenic Pattern Pharmaceutical Chemistry Physiological Play Process Prognosis Property Protein Isoforms Proteins RNA Binding RNA Splicing Refractory Regulatory Element Resistance Role Spliceosomes Testing Therapeutic Trans-Activators Transgenic Mice Treatment Efficacy Variant androgen deprivation therapy base cancer cell cancer therapy castration resistant prostate cancer chromatin immunoprecipitation clinical candidate clinically relevant comparative design drug candidate effective therapy genome-wide high risk histone demethylase in vivo inhibitor/antagonist mRNA Precursor men next generation novel novel therapeutics overexpression pre-clinical prostate cancer cell prostate cancer cell line prostate cancer progression recruit standard care success targeted treatment therapy resistant tumorigenesis

项目摘要

Alternative splicing of pre-mRNA is a fundamental mechanism to generate protein diversity that is often deregulated in cancer cells, producing aberrant proteins that promote growth and survival. Growth of prostate cancer (PCa) is driven by the androgen receptor (AR) activities. The standard care for metastatic PCa is androgen-deprivation therapy (ADT). However, ADT inevitably leads to castration-resistant PCa (CRPC) that, while still relies on the AR activities, is no longer hormone-sensitive. Among the many mechanisms underlying CRPC, is the generation of constitutively active AR variants (AR-Vs) through alternative splicing. Of note is AR- V7, which may play a causal role in PCa progression and treatment resistance. Until now, no FDA-approved agent can target these AR-Vs. Recently, we identified a pro-oncogenic role for histone demethylase KDM4B in PCa and several chemical inhibitors of KDM4B. In our preliminary studies, we found that KDM4B is necessary and sufficient to promote AR-V7 expression. KDM4B binds RNA and interacts with many trans-acting factors and may regulate alternative splicing of AR at both the pre-mRNA and chromatin levels. In addition, KDM4B may have other genome-wide alternatively spliced targets that are hallmarks of cancer. High KDM4B expression in human PCa patients predicts poor prognosis and correlates with elevated AR-V7 expression. Based on these scientific premises, we hypothesize that KDM4B may be a gene-specific alternative splicing regulator that dictates an oncogenic splicing pattern in CRPC and that targeting this enzyme could inhibit CRPC and re-sensitize CRPC to current ADT. We propose three specific aims to test this hypothesis. Aim 1: To determine the molecular mechanisms by which KDM4B regulates alternative splicing of AR-Vs. KDM4B may promote alternative splicing by recruiting the spliceosome to the 3'-splice site of alternative exons via binding to splicing regulatory elements (SREs) and by changing the chromatin structures around alternatively spliced exons. We will identify these SREs and determine the chromatin landscape around alternatively spliced exons. Aim 2. To identify KDM4B-regulated genome-wide splice variants. Preliminary studies indicated that KDM4B may have additional alternatively spliced variants that are specific for PCa tumorigenesis. We will test this hypothesis by comparative profiling genome-wide KDM4B-targeted splice variants, their associated SREs and chromatin landscapes in both hormone-sensitive and refractory PCa cells. Aim 3. To generate a clinical candidate(s) through optimization of KDM4B inhibitors. Our data indicated that the KDM4B inhibitor B3 may serve as a strong lead compound for further optimization to generate a clinical candidate agent. We will optimize B3 through iterative rounds of medicinal chemistry design, synthesis and testing. The notion that KDM4B is an oncogenic regulator of alternative splicing is novel. Understanding mechanism of action of KDM4B and identifying potent KDM4B inhibitors with in vivo efficacy will have significant clinical impact on the development of new therapies for CRPC with active oncogenic alternatively spliced variants.

前mrna的选择性剪接是产生蛋白质多样性的基本机制