Project 3: Targeting transcriptional mechanisms of therapeutic resistance in non-small cell lung cancer.

项目 3：针对非小细胞肺癌治疗耐药的转录机制。

基本信息

批准号：
10231100
负责人：
MATTHEW L. MEYERSON
金额：
$ 34.82万
依托单位：
DANA-FARBER CANCER INST
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-05-11 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10231100
关键词：
Address Animal Model BRAF gene Cancer Model Cancer Patient Cancer cell line Cell Line Cell Survival Cell model Chemistry Clinical Clonal Evolution Complex Cyclin-Dependent Kinase Gene Cyclin-Dependent Kinase Inhibitor Cyclin-Dependent Kinases DNA Sequence Alteration Data Data Analyses Dependence Development Drug Targeting Drug resistance ERBB2 gene Enhancers Enzymes Epidermal Growth Factor Receptor Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Epigenetic Process Exhibits Fibroblast Growth Factor Receptors Genetic Genetic Transcription Genetically Engineered Mouse Genome Goals In Vitro Individual Informatics KRAS2 gene Lead MEKs Malignant Neoplasms Malignant neoplasm of lung Molecular Mutation Non-Small-Cell Lung Carcinoma Outcome Pathway interactions Patient-Focused Outcomes Pharmaceutical Preparations Pharmacology Phosphotransferases Population Process Property Protein Kinase Proteins Regulatory Element Residual state Resistance Resistance development Signal Transduction Specificity Structural Chemistry Structure Testing Therapeutic Time Transcript Transcription Elongation Transcription Initiation Transcription Process cancer cell cancer therapy clinical translation design genetic approach improved improved outcome in vivo inhibitor/antagonist kinase inhibitor member mouse model multidisciplinary mutant novel patient subsets prevent resistance mechanism response small molecule structural biology synergism targeted agent targeted cancer therapy targeted treatment therapeutic target therapy resistant tool transcription factor transcriptomics treatment response treatment strategy

项目摘要

The use of genomically targeted therapies has improved treatment response and clinical outcomes for molecularly defined subsets of patients with non-small cell lung cancers. While responses to these therapies can often be dramatic, they are rarely durable, and there is a significant need to improve the duration of response and delay or prevent treatment resistance. Studies from our group and others have characterized the properties of cancer cells which escape initial treatment with a targeted agent. Analyses of these data have revealed transcriptional and epigenetic adaptation as a requirement for the survival of cells that persist in the face of targeted therapy. Working with Core A (Chemistry) and Core B (Structure), we have obtained Preliminary Data suggesting that inhibitors of higher-order cyclin dependent kinases (CDKs), enzymes which perform key roles in transcriptional initiation and elongation, display potent synergy with targeted kinase inhibitors in a diverse array of NSCLC models both in vitro and in vivo. Specifically, we have identified THZ1, a covalent CDK7/12 inhibitor designed by Core A leader Dr. Gray, as a tool compound which synergizes with inhibitors of EGFR (Project 1), MEK (Project 2) as well as ALK, HER2, BRAF, FGFR and PI3K in genetically selected NSCLC models. In this project, we will advance our efforts in targeting transcriptional adaptation to targeted therapies by using genetic tools to define the key CDK/cyclin genes responsible for therapeutic synergy and using this information to design more selective CDK inhibitors and selective degraders with improved specificity and in vivo pharmacology as compared to THZ1. Further, we will use transcriptional and epigenetic analysis to define the mechanisms governing therapeutic synergy among targeted therapies and CDK inhibitors. This project will be amenable to clinical translation given the broad applicability of this approach and ongoing efforts to develop transcriptional CDK inhibitors for clinical use.

基因组靶向疗法的使用已改善治疗反应和临床结果非小细胞肺癌患者的分子定义的子集。而对这些疗法的反应通常可以是戏剧性的，它们很少耐用，并且有很大的需求来改善持续时间反应和延迟或防止治疗耐药性。我们小组和其他人的研究表征了癌细胞的特性，这些癌细胞逃脱了用靶向剂进行初始治疗的癌细胞。这些数据的分析揭示了转录和表观遗传适应，作为对持续存在的细胞存活的要求靶向治疗的面孔。使用核心A（化学）和核心B（结构），我们获得了初步数据，这表明高阶细胞周期蛋白依赖性激酶（CDK）的抑制剂，在转录中发挥关键作用的酶启动和伸长率，在各种NSCLC阵列中与靶向激酶抑制剂显示出有效的协同作用在体外和体内模型。具体而言，我们已经确定了THZ1，即设计的共价CDK7/12抑制剂核心领导者Gray博士，作为工具化合物，与EGFR的抑制剂协同（项目1），MEK （项目2）以及基因选择的NSCLC模型中的ALK，HER2，BRAF，FGFR和PI3K。在这个项目，我们将通过使用遗传来促进针对针对目标疗法的转录适应的努力定义负责治疗协同作用的关键CDK/细胞周期蛋白基因的工具，并将这些信息用于设计更有选择性的CDK抑制剂和具有提高特异性和体内的选择性降解器与THZ1相比，药理学。此外，我们将使用转录和表观遗传分析来定义靶向疗法和CDK抑制剂之间治疗协同作用的机制。这个项目将是鉴于这种方法的广泛适用性和不断发展的努力，可以适应临床翻译转录CDK抑制剂用于临床使用。