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

基本信息

项目摘要

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.
总结

项目成果

期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Biomolecular Condensates and Cancer.
  • DOI:
    10.1016/j.ccell.2020.12.003
  • 发表时间:
    2021-02-08
  • 期刊:
  • 影响因子:
    50.3
  • 作者:
    Boija A;Klein IA;Young RA
  • 通讯作者:
    Young RA
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NATHANAEL Schiander GRAY其他文献

NATHANAEL Schiander GRAY的其他文献

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{{ truncateString('NATHANAEL Schiander GRAY', 18)}}的其他基金

Targeting CDK7 in CCNE1-amplified Ovarian Cancer
CCNE1 扩增的卵巢癌中靶向 CDK7
  • 批准号:
    10367792
  • 财政年份:
    2022
  • 资助金额:
    $ 65.64万
  • 项目类别:
Targeting CDK7 in CCNE1-amplified Ovarian Cancer
CCNE1 扩增的卵巢癌中靶向 CDK7
  • 批准号:
    10576332
  • 财政年份:
    2022
  • 资助金额:
    $ 65.64万
  • 项目类别:
Small molecule-induced degradation of dengue proteins as an antiviral strategy
小分子诱导的登革热蛋白降解作为抗病毒策略
  • 批准号:
    10472071
  • 财政年份:
    2020
  • 资助金额:
    $ 65.64万
  • 项目类别:
Small molecule-induced degradation of dengue proteins as an antiviral strategy
小分子诱导的登革热蛋白降解作为抗病毒策略
  • 批准号:
    10052821
  • 财政年份:
    2020
  • 资助金额:
    $ 65.64万
  • 项目类别:
Validating the Flavivirus Envelope Protein as an Antiviral Target
验证黄病毒包膜蛋白作为抗病毒靶点
  • 批准号:
    10338189
  • 财政年份:
    2020
  • 资助金额:
    $ 65.64万
  • 项目类别:
Validating the Flavivirus Envelope Protein as an Antiviral Target
验证黄病毒包膜蛋白作为抗病毒靶点
  • 批准号:
    10578759
  • 财政年份:
    2020
  • 资助金额:
    $ 65.64万
  • 项目类别:
Validating the Flavivirus Envelope Protein as an Antiviral Target
验证黄病毒包膜蛋白作为抗病毒靶点
  • 批准号:
    10413666
  • 财政年份:
    2020
  • 资助金额:
    $ 65.64万
  • 项目类别:
Small molecule-induced degradation of dengue proteins as an antiviral strategy
小分子诱导的登革热蛋白降解作为抗病毒策略
  • 批准号:
    10661608
  • 财政年份:
    2020
  • 资助金额:
    $ 65.64万
  • 项目类别:
Small molecule-induced degradation of dengue proteins as an antiviral strategy
小分子诱导的登革热蛋白降解作为抗病毒策略
  • 批准号:
    10429876
  • 财政年份:
    2020
  • 资助金额:
    $ 65.64万
  • 项目类别:
Development of covalent PIP4K2 inhibitors for the treatment of p53 deficient lung tumors
开发共价 PIP4K2 抑制剂用于治疗 p53 缺陷型肺部肿瘤
  • 批准号:
    8942703
  • 财政年份:
    2015
  • 资助金额:
    $ 65.64万
  • 项目类别:
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