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）是肺癌最具侵略性的形式，与高丝分裂有关 速率，早期转移扩散以及化学疗法抗性的快速演变。我们最近发现了一本小说 类似于簇细胞谱系的SCLC的形式，可以将其与经典神经内分泌区分开 通过POU2F3的免疫组织化学染色，这种疾病的形式。重要的是，我们已经确定了几个 特定于该疾病的变体形式的分子脆弱性。在这项研究建议中，我们寻求 促进个性化疗法，以利用SCLC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策略已经发现了可行的依赖性，这些依赖性是独特的 SCLC的Tuft细胞变体，例如激酶IGF1R。此外，我们发现了簇簇的深刻成瘾 变体SCLC肿瘤至POU2F3。在这里，我们将研究SCLC中POU2F3成瘾的分子基础， 具有显式的意图，以开发出干扰POU2F3功能的小分子。第一个目的 提案将基于我们在SCLC中进行的广泛的表观基因组分析，该分析定义了 POU2F3在该疾病中维持的独特增强剂景观。我们现在将雇用两个独立 阐明SCLC细胞基因组中关键POU2F3结合位点/增强子的功能方法， 它将被利用以查明可能针对的簇状细胞谱系电路的关键组件 在治疗上。第二个目标将评估POU2F3辅助因子，我们已经通过 内源性POU2F3结合位点的创新芯片 - 图形质谱分析。我们将表演 CRISPR外显子扫描和每个辅因子的生化分析，以定义关键POU2F3：辅因子 有选择地支持这种恶性肿瘤的互动。该提案的最终目标将采用功能 基因组学以将药物组合与IGF1R抑制剂linsitinib进行合理和利用合成 - 致命的遗传相互作用。我们还将采用我们最新的CRISPR创新，同源性共同靶向CRISPR 屏幕，以暴露与神经内分泌与簇细胞变体相关的冗余激酶漏洞 SCLC。总而言之，我们估计在约18％的SCLC病例中存在类似簇的细胞样变体 对应于大约5,000例新诊断的SCLC病例和大约3500例死亡 每年一个国家。因此，拟议的研究可能会导致持续的影响，从而影响大型 迫切需要新型药物的患者群体。