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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

批准号：
10174856
负责人：
NATHANAEL Schiander GRAY
金额：
$ 65.64万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-06-09 至 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10174856
关键词：
Animal Model CTLA4 gene Cancer Model Cancer Patient Cell model Cells Chemoresistance Cisplatin Classification Clinical Clinical Research Cyclin-Dependent Kinase Inhibitor Cyclin-Dependent Kinases DNA Damage DNA Polymerase II DNA-Directed RNA Polymerase Dependence Development Drug usage Enhancers Epigenetic Process Etoposide Exhibits Gene Expression Gene Expression Profile Genes Genetic Transcription Genomics Goals Grouping Growth Heterogeneity Human Immune Immunologic Surveillance Immunotherapy Infiltration Institutes Investigation Investigational Therapies Maintenance Malignant Neoplasms Malignant neoplasm of lung Mus Mutate Mutation Oncogenes Pathway interactions Patients Pharmaceutical Chemistry Pharmacology Poly(ADP-ribose) Polymerases Primary Neoplasm Prognosis Refractory Refractory Disease Regimen Research Resistance development Structure Therapeutic Therapeutic Effect Translational Research Tumor-infiltrating immune cells Variant cancer therapy cell type chemotherapy clinical subtypes clinically relevant cofactor comparative design driver mutation epigenetic marker human model immune activation in vivo in vivo Model inhibitor/antagonist lung small cell carcinoma mouse model multidisciplinary neoplastic cell novel patient derived xenograft model pre-clinical programmed cell death protein 1 programs response small molecule small molecule libraries standard of care success synergism tumor tumor microenvironment tumor-immune system interactions

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.

概括小细胞肺癌 (SCLC) 的特点是侵袭性生长、基因组异质性和快速进展。对化疗产生耐药性。 SCLC 患者经常表现出初始临床反应化疗，包括临床护理标准顺铂-依托泊苷方案，但最终屈服于化疗难治性疾病。最近的测序研究表明，SCLC 是最受重视的疾病之一。突变的癌症，但这些努力尚未确定化疗敏感和化疗敏感的可靶向“驱动”突变化疗难治性疾病。使用对多样化化学库的公正、高通量细胞筛选，我们已经发现 SCLC 化疗敏感和化疗难治性肿瘤细胞对抑制剂高度敏感通用转录装置。特别是，我们观察到 SCLC 肿瘤细胞对 THZ1 是一种新发现的细胞周期蛋白依赖性激酶 7 (CDK7) 共价抑制剂，可作为辅助因子 RNA 聚合酶 II (Pol II)。我们发现这种转录脆弱性部分是由精致的关键超级增强子（SE）驱动的 SCLC 癌基因对转录抑制的敏感性。我们因此假设在 SE 及其相关基因中发现的其他转录 CDK 的抑制可以提供额外的治疗途径。为此，我们开发了受结构启发的方法针对各种转录 CDK 的共价抑制剂的设计。我们进一步假设对未经化疗和化疗的增强子景观和基因表达谱进行比较分析难治性原发性肿瘤将 1) 识别化疗难治性特有的转录和表观遗传特征疾病，2) 能够分为临床相关亚型，3) 识别转录和表观遗传化疗难治性疾病特有的依赖性，可以使用转录 CDK 抑制剂进行“药物治疗”。由于肿瘤癌基因表达和化疗耐药性的变化已被证明会影响免疫系统隔室中，我们预计化疗难治性肿瘤也将表现出免疫细胞激活的变化和渗透。通过将我们的临床亚型分类扩展到肿瘤微环境，我们希望找到适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视能力的目标。最后，众所周知，许多转录 CDK 转录调节关键途径，调节对 DNA 损伤剂的反应，对于免疫疗法，我们将研究转录 CDK 抑制剂是否也可以与其他药物联合使用研究性 SCLC 疗法。