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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.

总结