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

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.

项目概要/摘要神经内分泌前列腺癌（NEPC）是毒性最强的亚型，并且 NEPC 的发生频率正在增加由于阿比特龙等强效雄激素受体（AR）靶向药物的更广泛使用目前，NEPC 没有有效的治疗方法，患有 NEPC 的男性只能使用恩杂鲁胺 (enza)。由于 NEPC 的侵略性，通常被排除在临床试验之外，这表明迫切需要我们的支持研究表明 NEPC 肿瘤可能会开发出更有效的治疗方法。特别依赖于蛋白质赖氨酸特异性脱甲基酶 1 (LSD1)，并且 LSD1 抑制是一种然而，在 NEPC 患者中开始 LSD1 抑制剂试验之前，需要进行一些研究。必须回答该提案将解决的关键问题。 LSD1 是一种组蛋白去甲基化酶，也是干细胞和癌症分化的调节因子。确定LSD1与共激活剂合作主要激活前列腺中的基因表达重要的是，我们的研究表明，LSD1 的催化功能并不重要。 NEPC 证明：LSD1 在 NEPC 中比腺癌表达更高，LSD1 主要抑制与前列腺上皮分化相关的基因的表达——不是与其催化功能有关，而是通过与共阻遏蛋白合作；NEPC 细胞对变构 LSD1 抑制剂特别敏感；重新激活前列腺上皮分化基因的表达并使 AR+ NEPC 细胞重新敏感恩扎。我们发现 LSD1 通过抑制促进上皮细胞增殖的因子和途径来促进 NEPC 存活。分化并激活促进 NEPC 分化的其他因子和途径。阻止 NEPC 细胞存活的方法很有希望。该提案的目的是通过以下方式阐明机制。其中LSD1促进NEPC的存活，因此我们可以开发一种新颖、安全且有效的治疗策略—— LSD1 抑制。目标 1：识别 LSD1 抑制剂基因反应特征并确定 LSD1 阻断的机制 NEPC 中的基因表达。目标 2：用 LSD1 抑制体内治疗 NEPC 肿瘤，并确定对肿瘤生长和生长的影响。差异化。这些研究的预测结果是：阐明LSD1如何促进NEPC肿瘤的谱系转换因此我们可以针对该开关，识别 LSD1 抑制反应生物标志物来确定生物学未来 I 期试验的最佳剂量，以及开发合理的 LSD1 抑制剂药物组合以最大限度地提高 NEPC 肿瘤患者的近期肿瘤控制、生活质量和生存率。