Exploiting POU2F3 addiction in the tuft cell variant of small cell lung cancer

在小细胞肺癌簇细胞变体中利用 POU2F3 成瘾

• 批准号: 9980811
• 负责人: CHRISTOPHER VAKOC
• 金额: $ 43.92万
• 依托单位: COLD SPRING HARBOR LABORATORY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9980811
• 关键词: Affect; Avena sativa; Basic Science; Binding Sites; Biochemical; CRISPR screen; Cancer cell line; Cell Lineage; Cells; Cellular Morphology; Cessation of life; Characteristics; Chromatin; Clustered Regularly Interspaced Short Palindromic Repeats; Combined Modality Therapy; Complex; Data; Dependence; Disease; Drug Combinations; Elements; Enhancers; Epigenetic Process; Epithelial; Epithelium; Evolution; Exons; Exposure to; Gastrointestinal tract structure; Genes; Genetic; Genetic Screening; Genome; Genomic approach; Goals; Growth; Homologous Gene; Human; Insulin-Like-Growth Factor I Receptor; Lead; Libraries; Link; Lung; Lung Neuroendocrine Neoplasm; Maintenance; Malignant Neoplasms; Malignant neoplasm of lung; Maps; Mass Spectrum Analysis; Medicine; Methods; Mitotic; Molecular; Neuroendocrine Cell; Neurosecretory Systems; Newly Diagnosed; Phosphotransferases; Proteins; Publishing; Regulatory Element; Research; Research Proposals; Resistance; Respiratory System; Sampling; Scanning; Signal Transduction; Stains; Structure; Techniques; Technology; Therapeutic Intervention; Tumor Subtype; United States; Variant; Work; addiction; cancer cell; cell type; chemotherapy; clinical translation; cofactor; drug discovery; epigenomics; experimental study; functional genomics; genomic platform; inhibitor/antagonist; innovation; lung small cell carcinoma; novel; patient population; personalized medicine; preclinical study; programs; small molecule; targeted treatment; transcription factor; tumor

Project Summary Small cell lung cancer (SCLC) is the most aggressive form of lung cancer, which is associated with a high mitotic rate, early metastatic spread, and a rapid evolution of chemotherapy resistance. We recently discovered a novel form of SCLC that resembles the tuft cell lineage, which can be distinguished from the classical neuroendocrine form of this disease through immunohistochemical staining of POU2F3. Importantly, we have identified several molecular vulnerabilities that are specific to the variant form of this disease. In this research proposal, we seek to advance personalized therapies that exploit the unique lineage program present in the tuft cell variant of SCLC. Our innovative functional genomics strategy has already uncovered actionable dependencies that are unique to tuft cell variant of SCLC, such as the kinase IGF1R. In addition, we discovered a profound addiction of tuft cell variant SCLC tumors to POU2F3. Here we will investigate the molecular basis of POU2F3 addiction in SCLC, with the explicit intent to develop small molecules that interfere with POU2F3 function. The first Aim of this proposal will build upon the extensive epigenomic analyses we have performed in SCLC, which has defined a unique enhancer landscape sustained by POU2F3 in this disease. We will now employ two independent functional approaches to elucidate the critical POU2F3 binding sites/enhancers in the genome of SCLC cells, which will be leveraged to pinpoint the critical components of the tuft cell lineage circuit that might be targeted therapeutically. The second Aim will evaluate POU2F3 cofactors, which we have already nominated via an innovative ChIP-SICAP-mass spectrometry analysis of endogenous POU2F3 binding sites. We will perform CRISPR exon scanning and biochemical analysis of each cofactor to define the critical POU2F3:cofactor interactions that selectively support this malignancy. The final Aim of this proposal will employ functional genomics to devise drug combinations with the IGF1R inhibitor linsitinib that are rational and exploit synthetic- lethal genetic interactions. We will also employ our latest CRISPR innovation, homolog co-targeting CRISPR screens, to expose redundant kinase vulnerabilities that are linked with neuroendocrine versus tuft cell variants of SCLC. In summary, we estimate that the tuft cell-like variant is present in ~18% of SCLC cases, which corresponds to approximately 5,000 newly diagnosed SCLC cases and approximately 3,500 deaths in the United States alone each year. Hence, the proposed research could lead to a sustained impact that affects a large patient population for which novel medicines are desperately needed.

项目摘要 小细胞肺癌（SCLC）是肺癌的最具侵袭性的形式，其与高有丝分裂相关联。 率，早期转移扩散和化疗耐药性的快速演变。我们最近发现了一本小说 一种类似于簇状细胞谱系的SCLC形式，可与经典的神经内分泌细胞区分开来。 通过POU 2F 3的免疫组化染色，重要的是，我们已经确定了几个 这种疾病的变异形式所特有的分子脆弱性。在这项研究中，我们寻求 推进个体化治疗，利用SCLC的簇状细胞变体中存在的独特谱系程序。 我们创新的功能基因组学战略已经发现了独特的可操作的依赖关系， SCLC的簇细胞变体，例如激酶IGF 1 R。此外，我们发现了一个深刻的成瘾的簇细胞， 变异SCLC肿瘤与POU 2F 3。在这里，我们将研究POU 2F 3成瘾在小细胞肺癌的分子基础， 其明确意图是开发干扰POU 2F 3功能的小分子。第一个目的是 该提案将建立在我们在SCLC中进行的广泛的表观基因组分析的基础上，该分析已经定义了一个 POU 2F 3在这种疾病中持续的独特增强子景观。我们将雇佣两名独立的 阐明SCLC细胞基因组中关键POU 2F 3结合位点/增强子的功能方法， 这将被用来精确定位可能成为目标的簇细胞谱系电路的关键组件， 治疗上第二个Aim将评估POU 2F 3辅因子，我们已经通过一个 内源性POU 2F 3结合位点的创新ChIP-SICAP-质谱分析。我们将执行 CRISPR外显子扫描和每个辅因子的生化分析，以确定关键POU 2F 3：辅因子 选择性地支持这种恶性肿瘤的相互作用。本提案的最终目的将采用功能性 基因组学设计与IGF 1 R抑制剂linsitinib合理的药物组合，并利用合成的 致命的基因交互作用我们还将采用我们最新的CRISPR创新，同源物共靶向CRISPR 筛选，以暴露与神经内分泌和簇细胞变异相关的冗余激酶漏洞 关于SCLC总之，我们估计簇状细胞样变异存在于约18%的SCLC病例中， 相当于美国约5,000例新诊断的SCLC病例和约3,500例死亡 每年仅国家。因此，拟议的研究可能会产生持续的影响，影响到一个大的 迫切需要新型药物的患者群体。