Mechanisms by which LSD1 Promotes Neuroendocrine Differentiation and Small Cell Lung Cancer

LSD1促进神经内分泌分化和小细胞肺癌的机制

• 批准号: 10584661
• 负责人: Matthew Gilbert Oser
• 金额: $ 46.31万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-06 至 2027-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10584661
• 关键词: 3' Untranslated Regions; ASCL1 gene; Binding; Binding Proteins; Biological; CRISPR/Cas technology; Cancer Patient; Cancer cell line; Cell Line; Chromatin; Clinical Trials; Clustered Regularly Interspaced Short Palindromic Repeats; Complex; Data; Engineering; Epigenetic Process; Foundations; Gene Expression; Genes; Genetic; Genetic study; Genetically Engineered Mouse; Goals; Immunocompetent; Immunologic Deficiency Syndromes; In Vitro; Induction of Apoptosis; KDM1A gene; Laboratories; Link; MAP Kinase Gene; MEK inhibition; Malignant Neoplasms; Messenger RNA; Minority; Modeling; Molecular; Mus; Neuroendocrine Cell; Neuroendocrine Tumors; Neurosecretory Systems; Pathway interactions; Patient Selection; Pre-Clinical Model; Principal Investigator; Proliferating; Repression; Research; Resistance; Testing; Therapeutic; Validation; Writing; derepression; experimental study; gene repression; genome-wide; genomic locus; histone demethylase; immunogenicity; in vivo; inhibitor; insight; loss of function; mouse model; mutant; neuroendocrine differentiation; neuroendocrine phenotype; novel; patient derived xenograft model; pre-clinical; predictive marker; screening; selective expression; small cell lung carcinoma; targeted treatment; treatment strategy; tumor; tumor initiation; tumorigenesis; ubiquitin ligase

PROJECT SUMMARY/ABSTRACT Small cell lung cancer (SCLC) is a high-grade neuroendocrine tumor currently without any approved targeted therapies. Inhibitors of the histone demethylase LSD1 are currently in clinical trials in SCLC inspired by strong preclinical data demonstrating that some SCLCs are highly and selectively sensitive to LSD1 inhibition. However, only a minority of SCLCs are highly sensitive to LSD1 inhibition, while most SCLCs are inherently resistant. The molecular basis for why some SCLCs are highly dependent on LSD1 is not understood. Understanding the causative mechanisms for why some SCLCs are highly sensitive to LSD1 inhibitors could identify predictive biomarkers to select patients more likely to respond to LSD1 inhibitors or identify rational combination strategies to make LSD1 inhibitors more effective. Using unbiased positive selection CRISPR/Cas9 loss of function screening with LSD1 inhibitors, we have uncovered novel causative mechanisms by which LSD1 inhibitors regulate SCLC, which include mechanisms by which LSD1 regulates neuroendocrine differentiation in SCLC, target genes that are bound and repressed by LSD1 and required for LSD1 inhibitor sensitivity, and also identified a rational combination strategy to overcome resistance to LSD1 inhibitors. The broad long-term objective of our proposal is to elucidate the molecular mechanisms by which LSD1 promotes SCLC tumorigenesis and neuroendocrine differentiation (aims 1 and 3), and test a rational combination strategy to make LSD1 inhibition more effective in SCLC (aim 2). To accomplish this, we will combine in vitro mechanistic approaches to rigorously dissect the mechanisms by which LSD1 drives SCLC proliferation and neuroendocrine differentiation with an in vivo autochthonous immunocompetent SCLC genetically-engineered mouse model (GEMM) that we developed using CRISPR/Cas9 that can be used to delete LSD1 at tumor initiation and study its function during SCLC tumorigenesis. Using these LSD1 isogenic SCLC GEMMs, we will interrogate how loss of LSD1 blocks neuroendocrine differentiation, promotes lineage plasticity, and increases tumor immunogenicity. Together, these studies will provide important biological insights into how SCLCs utilize LSD1 to drive tumorigenesis and neuroendocrine differentiation, which ultimately could lead to the identification of predictive biomarkers to select patients more likely to respond to LSD1 inhibitors. Lastly, this research could provide the preclinical foundation for a rational combination therapeutic strategy to make LSD1 inhibitors more effective for SCLC patients.

项目总结/摘要 小细胞肺癌（SCLC）是一种高度恶性的神经内分泌肿瘤，目前尚无任何批准的靶向治疗。 治疗组蛋白去甲基化酶LSD 1的抑制剂目前在SCLC的临床试验中受到强烈的刺激。 临床前数据表明，一些SCLC对LSD 1抑制高度和选择性敏感。然而，在这方面， 只有少数SCLC对LSD 1抑制高度敏感，而大多数SCLC是固有抗性的。的 为什么一些SCLC高度依赖LSD 1的分子基础尚不清楚。了解 一些SCLC对LSD 1抑制剂高度敏感的原因机制可以确定预测性 选择更可能对LSD 1抑制剂有反应的患者或确定合理的联合治疗策略的生物标志物 使LSD 1抑制剂更有效。 使用无偏阳性选择CRISPR/Cas9功能丧失筛选LSD 1抑制剂，我们 揭示了LSD 1抑制剂调节SCLC的新的致病机制，包括 LSD 1通过其调节SCLC中的神经内分泌分化，靶基因被LSD 1结合和抑制， LSD 1和LSD 1抑制剂敏感性所需，并确定了合理的组合策略，以克服 对LSD 1抑制剂的抗性。 我们建议的广泛的长期目标是阐明LSD 1的分子机制， 促进SCLC肿瘤发生和神经内分泌分化（目的1和3），并测试合理的组合 使LSD 1抑制在SCLC中更有效的策略（目的2）。为了实现这一点，我们将在体外联合收割机 严格剖析LSD 1驱动SCLC增殖的机制的机械方法， 用体内自体免疫活性SCLC基因工程进行神经内分泌分化 我们使用CRISPR/Cas9开发的小鼠模型（GEMM），可用于在肿瘤起始时删除LSD 1 研究其在小细胞肺癌发生发展中的作用。使用这些LSD 1同基因SCLC GEMM，我们将询问 LSD 1的缺失如何阻断神经内分泌分化，促进谱系可塑性，并增加肿瘤 免疫原性总之，这些研究将为SCLC如何利用LSD 1提供重要的生物学见解 来驱动肿瘤发生和神经内分泌分化，这最终可能导致识别 预测性生物标志物，以选择更可能对LSD 1抑制剂有反应的患者。最后，这项研究可以 为合理的联合治疗策略提供临床前基础，以使LSD 1抑制剂更多 对SCLC患者有效。