Targeting LSD1 in Neuroendocrine Prostate Cancer

靶向 LSD1 治疗神经内分泌前列腺癌

基本信息

批准号：
10045656
负责人：
Joshi James Alumkal
金额：
$ 35.1万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
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：
2014-09-11 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10045656
关键词：
Address Androgen Receptor Apoptosis Binding Biological Cancer Patient Cell Survival Cells ChIP-seq Chromatin Clinical Data Clinical Trials Complex Development Differentiated Gene Differentiation and Growth Dose Drug Combinations Epithelial Epithelium Frequencies Future Gene Activation Gene Expression Genes Growth HDAC1 gene HDAC2 gene Histone Acetylation Histone Deacetylase Histones Impairment Implant KDM1A gene Link Malignant Neoplasms Malignant neoplasm of prostate Measures Michigan Mus Neuroendocrine Therapy Neurosecretory Systems Outcome Study Pathway interactions Patients Pharmaceutical Preparations Phase Phase I Clinical Trials Phenotype Play Prostate Prostate Adenocarcinoma Prostate Cancer therapy Prostatic Epithelium Proteins Quality of life RNA Interference Repressor Proteins Role Testing Transcription Coactivator Treatment Efficacy Virulent Work abiraterone cancer survival effective therapy genetic corepressor histone demethylase in vivo inhibitor/antagonist men novel outcome prediction phase I trial pre-clinical prostate cancer cell prostate cancer cell line resistance mechanism response response biomarker sarcoma stem cells targeted agent targeted treatment transcription factor transcriptome sequencing tumor tumor growth

Address Androgen Receptor Apoptosis Binding Biological Cancer Patient Cell Survival Cells ChIP-seq Chromatin Clinical Data Clinical Trials Complex Development Differentiated Gene Differentiation and Growth Dose Drug Combinations Epithelial Epithelium Frequencies Future Gene Activation Gene Expression Genes Growth HDAC1 gene HDAC2 gene Histone Acetylation Histone Deacetylase Histones Impairment Implant KDM1A gene Link Malignant Neoplasms Malignant neoplasm of prostate Measures Michigan Mus Neuroendocrine Therapy Neurosecretory Systems Outcome Study Pathway interactions Patients Pharmaceutical Preparations Phase Phase I Clinical Trials Phenotype Play Prostate Prostate Adenocarcinoma Prostate Cancer therapy Prostatic Epithelium Proteins Quality of life RNA Interference Repressor Proteins Role Testing Transcription Coactivator Treatment Efficacy Virulent Work abiraterone cancer survival effective therapy genetic corepressor histone demethylase in vivo inhibitor/antagonist men novel outcome prediction phase I trial pre-clinical prostate cancer cell prostate cancer cell line resistance mechanism response response biomarker sarcoma stem cells targeted agent targeted treatment transcription factor transcriptome sequencing tumor tumor growth

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项目摘要

Project Summary/Abstract Neuroendocrine prostate cancer (NEPC) is the most virulent subtype, and the frequency of NEPC is increasing due to more widespread use of potent androgen receptor (AR)-targeting agents like abiraterone and enzalutamide (enza). Currently, there are no effective treatments for NEPC, and men with NEPC are commonly excluded from clinical trials due to NEPC’s aggressiveness, demonstrating an urgent need to develop more effective therapies for NEPC patients. Our supporting studies demonstrate NEPC tumors may be particularly reliant on the protein lysine specific demethylase 1 (LSD1) and that LSD1 inhibition is a promising strategy to treat NEPC. However, before LSD1 inhibitor trials may begin in NEPC patients, several critical questions must be answered that this proposal will address. LSD1 is a histone demethylase and regulator of differentiation in stem cells and cancer. Previously, we determined LSD1 cooperates with co-activators to primarily activate gene expression in prostate adenocarcinoma (adenoca) cells and that LSD1’s catalytic function was not critical. Importantly, our studies in NEPC demonstrate: LSD1 is even more highly expressed vs. adenoca; in NEPC, LSD1 primarily represses expression of genes linked with prostatic epithelial differentiation—not with its catalytic function but rather by cooperating with co-repressor proteins; NEPC cells are particularly susceptible to an allosteric LSD1 inhibitor that re-activates expression of prostatic epithelial differentiation genes and re-sensitizes AR+ NEPC cells to enza. We hypothesize that LSD1 promotes NEPC survival by repressing factors and pathways that promote epithelial differentiation and activating other factors and pathways that promote NEPC differentiation. LSD1 inhibition is a promising approach to block NEPC cell survival. The objectives of this proposal are to clarify mechanisms by which LSD1 promotes survival of NEPC so we may develop a novel, safe, and effective therapeutic strategy— LSD1 inhibition. Aim 1: Identify an LSD1 inhibitor gene response signature and determine mechanisms by which LSD1 blocks gene expression in NEPC. Aim 2: Treat NEPC tumors in vivo with LSD1 inhibition and determine the effect on tumor growth and differentiation. A predicted outcome of these studies is: clarification of how LSD1 promotes the lineage switch to NEPC tumors so we can target that switch, identification of LSD1 inhibition response biomarkers to determine the biologically optimal dose in future phase I trials, and development of rational LSD1 inhibitor drug combinations to maximize tumor control, quality of life, and survival for patients with NEPC tumors in the near-term.

项目摘要/摘要神经内分泌前列腺癌（NEPC）是最毒的亚型，NEPC的频率正在增加由于宽度更多地使用了潜在的雄激素受体（AR） - 靶向剂，例如阿比罗酮和恩扎拉塔米德（Enza）。目前，NEPC没有有效的治疗方法，而患有NEPC的男性则是由于NEPC的侵略性，通常被排除在临床试验之外，这表明迫切需要为NEPC患者开发更有效的疗法。我们的支持研究表明，NEPC肿瘤可能对蛋白质赖氨酸特异性去甲基酶1（LSD1）特别敏感，LSD1抑制是一个治疗NEPC的有希望的策略。但是，在NEPC患者可能开始LSD1抑制剂试验之前，有几名必须回答有关该提案将解决的关键问题。 LSD1是一种组蛋白脱甲基酶，是干细胞和癌症分化的调节剂。以前，我们确定的LSD1与共激活因子合作以初级激活前列腺中的基因表达腺癌（腺癌）细胞和LSD1的催化功能并不关键。重要的是，我们的研究 NEPC证明：LSD1与Adenoca更高度表达；在NEPC中，LSD1主要表示与前列腺上皮分化相关的基因的表达，而不是其催化功能，而是通过与共抑制蛋白合作； NEPC细胞特别容易受到变构LSD1抑制剂的影响这重新激活了前列腺上皮分化基因的表达和重新敏感性AR+ NEPC细胞的表达恩扎。我们假设LSD1通过反映促进上皮的因素和途径来促进NEPC的生存分化并激活促进NEPC分化的其他因素和途径。 LSD1抑制是阻止NEPC细胞存活的有希望的方法。该提案的目标是通过 LSD1促进了NEPC的生存，因此我们可以制定一种新颖，安全和有效的治疗策略 - LSD1抑制。 AIM 1：确定LSD1抑制剂基因响应签名并确定LSD1阻止的机制 NEPC中的基因表达。目标2：用LSD1抑制在体内治疗NEPC肿瘤，并确定对肿瘤生长和分化。这些研究的预测结果是：阐明LSD1如何促进谱系转换为NEPC肿瘤因此，我们可以针对该转换，鉴定LSD1抑制反应生物标志物以确定生物学上在未来的I期试验中的最佳剂量，并开发有理LSD1抑制剂药物组合以最大化 NEPC肿瘤患者的肿瘤控制，生活质量和生存率。