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

基本信息

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
项目类别：
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&apos 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

3&apos 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

展开

项目摘要

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.

项目摘要/摘要小细胞肺癌（SCLC）是一种高级神经内分泌肿瘤，目前没有任何批准的靶向疗法。组蛋白脱甲基酶LSD1的抑制剂目前正在SCLC中的临床试验中，灵感启发临床前数据表明，某些SCLC对LSD1抑制高度敏感。然而，只有少数SCLC对LSD1抑制高度敏感，而大多数SCLC固有地具有抗性。这为什么不了解某些SCLC高度依赖LSD1的分子基础。了解为何某些SCLC对LSD1抑制剂高度敏感的原因，可以识别预测性生物标志物选择患者更有可能对LSD1抑制剂做出反应或确定合理组合策略使LSD1抑制剂更有效。使用LSD1抑制剂使用公正的阳性选择CRISPR/CAS9功能筛查损失，我们有发现LSD1抑制剂调节SCLC的新型因果机制，其中包括机制通过该LSD1调节SCLC中的神经内分泌分化，靶基因被绑定和抑制 LSD1和LSD1抑制剂灵敏度所需对LSD1抑制剂的抗性。我们建议的长期长期目标是阐明LSD1的分子机制促进SCLC肿瘤发生和神经内分泌分化（目标1和3），并测试合理组合使LSD1抑制在SCLC中更有效的策略（AIM 2）。为此，我们将在体外结合严格剖析LSD1驱动SCLC增殖和神经内分泌与体内自动化免疫能力SCLC基因工程的分化我们使用CRISPR/CAS9开发的鼠标模型（GEMM），可用于在肿瘤启动时删除LSD1 并研究其在SCLC肿瘤发生过程中的功能。使用这些LSD1等基因SCLC GEMM，我们将询问 LSD1的丧失如何阻止神经内分泌分化，促进谱系可塑性并增加肿瘤免疫原性。这些研究将共同提供有关SCLC如何利用LSD1的重要生物学见解驱动肿瘤发生和神经内分泌分化，最终可能导致鉴定预测性生物标志物选择患者更有可能对LSD1抑制剂做出反应。最后，这项研究可能为合理组合治疗策略提供临床前的基础，以使LSD1抑制剂更多对SCLC患者有效。