Targeting LSD1 in Neuroendocrine Prostate Cancer

靶向 LSD1 治疗神经内分泌前列腺癌

• 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
• 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

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.

项目总结/摘要 神经内分泌前列腺癌（neuroendocrine prostate cancer，NEPC）是恶性程度最高的亚型，其发病率呈上升趋势 由于更广泛地使用有效的雄激素受体（AR）靶向剂，如阿比特龙， 恩杂鲁胺（恩扎）。目前，NEPC没有有效的治疗方法，NEPC患者 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患者开发更有效的治疗方法。我们的支持性研究表明NEPC肿瘤可能 特别依赖于蛋白质赖氨酸特异性脱甲基酶1（LSD 1），并且LSD 1抑制是一种 有希望的治疗NEPC的策略。然而，在NEPC患者中LSD 1抑制剂试验开始之前， 必须回答本提案将解决的关键问题。 LSD 1是一种组蛋白脱甲基酶，也是干细胞和癌症分化的调节因子。此前我们 确定的LSD 1与辅激活因子合作，主要激活前列腺中的基因表达 腺癌（adenoca）细胞，LSD 1的催化功能并不重要。重要的是，我们的研究 NEPC证明：LSD 1的表达甚至比腺苷更高;在NEPC中，LSD 1主要抑制 与前列腺上皮分化相关的基因表达-不是其催化功能，而是 与辅阻遏蛋白协同作用; NEPC细胞对变构LSD 1抑制剂特别敏感 重新激活前列腺上皮分化基因的表达，并重新使AR+ NEPC细胞对 恩扎。 我们假设LSD 1通过抑制促进上皮细胞增殖的因子和途径来促进NEPC存活。 分化和激活促进NEPC分化的其他因子和途径。LSD 1抑制是一种 阻断NEPC细胞存活的有希望的方法。这项建议的目的是澄清各种机制， LSD 1可以促进NEPC的存活，因此我们可以开发一种新的，安全有效的治疗策略- LSD 1抑制。 目标1：识别LSD 1抑制剂基因反应特征并确定LSD 1阻断的机制 NEPC中的基因表达。 目的2：用LSD 1抑制剂在体内治疗NEPC肿瘤，并确定对肿瘤生长的影响， 分化 这些研究的预测结果是：阐明LSD 1如何促进NEPC肿瘤的谱系转换 因此，我们可以靶向开关，鉴定LSD 1抑制反应生物标志物，以确定生物学上 未来I期试验的最佳剂量，以及开发合理的LSD 1抑制剂药物组合， 肿瘤控制、生活质量和NEPC肿瘤患者的近期生存率。