课题基金 / 基金详情

Targeting the transcriptional and epigenetic landscape in chemo-refractory Small-Cell Lung Cancer

Targeting the transcriptional and epigenetic landscape in chemo-refractory Small-Cell Lung Cancer
靶向化疗难治性小细胞肺癌的转录和表观遗传景观
批准号:
10174856
负责人:
NATHANAEL Schiander GRAY
金额:
$65.64万
依托单位国家:
美国
项目类别:
财政年份:
2017
资助国家:
美国
项目状态:
已结题
起止时间:
2017-06-09 至 2022-05-31

项目摘要

项目成果

NATHANAEL Schiander GRAY的其他基金

相关文献

中文摘要
翻译
摘要 小细胞肺癌(SCLC)具有侵袭性生长、基因组异质性和生长速度快等特点。 对化疗产生抗药性。小细胞肺癌患者经常表现出初步的临床反应 化疗包括临床标准的顺铂-依托泊苷方案的护理,但最终屈服于 化疗难治性疾病。最近的测序研究表明,小细胞肺癌是最高水平的 突变的癌症,但这些努力尚未确定化疗敏感和 化疗难治性疾病。使用不同化学库的无偏、高通量的蜂窝屏幕,我们 已经发现小细胞肺癌化疗敏感和化疗耐药的肿瘤细胞对抑制剂高度敏感 一般的转录装置。特别是,我们观察到小细胞肺癌肿瘤细胞对 THZ1,一种新发现的细胞周期蛋白依赖性激酶7(CDK7)的共价抑制物,它是细胞周期蛋白7的辅助因子 RNA聚合酶II(POL II)。我们发现,这种转录上的脆弱性部分是由精致的 关键的超级增强子(SE)驱动的小细胞肺癌癌基因对转录抑制的敏感性。因此,我们 假设在SE及其相关基因中发现的对其他转录CDK的抑制可能 提供更多的治疗途径。为此,我们开发了受结构启发的方法 针对不同转录CDK的共价抑制剂的设计。我们进一步假设 化疗与化疗的增强子图谱和基因表达谱的比较分析 难治性原发肿瘤将1)识别化疗难治性特有的转录和表观遗传特征 疾病,2)能够分组为临床上相关的亚型,以及3)识别转录和表观遗传学 化疗难治性疾病特有的依赖关系,可以使用转录CDK抑制剂来“下药”。 由于肿瘤癌基因表达的变化和化疗耐药性已被证明影响免疫 我们预计化疗难治性肿瘤也会表现出免疫细胞活化的变化。 和渗透。通过将我们的临床亚型分类扩展到肿瘤微环境,我们希望 找到符合小分子靶向的肿瘤和免疫细胞基因表达程序 增强肿瘤免疫监测能力的目标。最后,正如已知的许多转录CDK 转录调控调节对DNA损伤剂的反应的关键通路和 我们将研究转录CDK抑制剂是否也可能与其他 研究中的小细胞肺癌疗法。
英文摘要
Summary Small cell lung cancer (SCLC) is characterized by aggressive growth, genomic heterogeneity, and rapid development of resistance to chemotherapy. SCLC patients frequently demonstrate initial clinical response to chemotherapy, including the clinical standard of care cisplatin-etoposide regimen, but eventually succumb to chemo-refractory disease. Recent sequencing studies have demonstrated that SCLC is one of the most highly mutated cancers, but these efforts have yet to identify targetable `driver' mutations in both chemo-sensitive and chemo-refractory disease. Using an unbiased, high-throughput cellular screen of a diverse chemical library, we have identified that SCLC chemo-sensitive and chemo-refractory tumor cells are highly sensitive to inhibitors of the general transcription apparatus. In particular, we observed that SCLC tumor cells were highly sensitive to THZ1, a newly identified covalent inhibitor of cyclin-dependent kinase 7 (CDK7) that functions as a co-factor for RNA polymerase II (Pol II). We found that this transcriptional vulnerability is conferred, in part, by the exquisite sensitivity of key super-enhancer (SE) -driven SCLC oncogenes to transcriptional inhibition. We therefore hypothesize that the inhibition of other transcriptional CDKs found at SEs and their associated genes could provide additional therapeutic avenues. For this purpose we have developed structure-inspired approaches for the design of covalent inhibitors targeting various transcriptional CDKs. We further hypothesize that comparative analysis of enhancer landscapes and gene expression profiles from chemo-naïve and chemo- refractory primary tumors will 1) identify transcriptional and epigenetic features specific to chemo-refractory disease, 2) enable grouping into clinically relevant subtypes, and 3) identify transcriptional and epigenetic dependencies specific to chemo-refractory disease that can be `drugged' using transcriptional CDK inhibitors. As changes to tumor oncogene expression and chemo-resistance have been shown to impact the immune compartment, we anticipate that chemo-refractory tumors will also exhibit changes in immune cell activation and infiltration. By extending our classification of clinical subtypes to the tumor microenvironment, we hope to find both tumor and immune cell gene expression programs that amenable to small molecule targeting with the goal of enhancing tumor immune surveillance capabilities. Lastly, as many transcription CDKs are known to transcriptionally regulate key pathways that modulate the response to DNA-damaging agents and immunotherapies we will investigate whether transcriptional CDK inhibitors may also be combined with other investigational SCLC therapies.
期刊论文(1)
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会议论文
DOI: 10.1016/j.ccell.2020.12.003
发表时间: 2021-02-08
期刊: Cancer cell
影响因子: 50.3
作者: [Boija A, Klein IA, Young RA]
通讯作者: Young RA
Targeting CDK7 in CCNE1-amplified Ovarian Cancer
  • 批准号:
    10367792
  • 项目类别:
  • 资助金额:
    $72.71万
  • 财政年份:
    2022
  • 负责人:
    NATHANAEL Schiander GRAY
  • 依托单位:
Targeting CDK7 in CCNE1-amplified Ovarian Cancer
  • 批准号:
    10576332
  • 项目类别:
  • 资助金额:
    $68.47万
  • 财政年份:
    2022
  • 负责人:
    NATHANAEL Schiander GRAY
  • 依托单位:
Small molecule-induced degradation of dengue proteins as an antiviral strategy
  • 批准号:
    10472071
  • 项目类别:
  • 资助金额:
    $81.09万
  • 财政年份:
    2020
  • 负责人:
    NATHANAEL Schiander GRAY
  • 依托单位:
Small molecule-induced degradation of dengue proteins as an antiviral strategy
  • 批准号:
    10052821
  • 项目类别:
  • 资助金额:
    $82.98万
  • 财政年份:
    2020
  • 负责人:
    NATHANAEL Schiander GRAY
  • 依托单位: