Transcriptional CDKs as therapeutic targets in MYC-dependent cancers

转录 CDK 作为 MYC 依赖性癌症的治疗靶点

• 批准号: 9106921
• 负责人: Rani E. George
• 金额: $ 40.77万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-03-07 至 2021-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9106921
• 关键词: Address; Affect; Amplifiers; Apoptosis; Binding Sites; CRISPR/Cas technology; Cell Cycle Progression; Cell Cycle Regulation; Cell Line; Cells; Chromatin Interaction Analysis by Paired-End Tag Sequencing; Chromosome Structures; Clinical; Cyclin-Dependent Kinases; Cytotoxic agent; Data; Dependence; Development; Drug Kinetics; Employee Strikes; Enhancers; Financial compensation; Genes; Genetic Transcription; Goals; Gray unit of radiation dose; Growth; Human; Life; Link; MYC Family Protein; MYCN gene; Malignant Neoplasms; Maps; Mediating; Modeling; Modification; Mus; Neuroblastoma; Normal tissue morphology; Oncogenes; Oncogenic; Patients; Phosphotransferases; Property; RNA Polymerase II; Regulation; Reporting; Research; Resistance; Role; Structure; Testing; Therapeutic; Toxic effect; Transcript; Transcription Elongation; Transcription Initiation; Transcriptional Regulation; Translating; Xenograft Model; analog; base; cancer cell; cohesin; design; genome-wide analysis; high risk; improved; inhibitor/antagonist; insight; meetings; neoplastic cell; neuroblastoma cell; novel; novel therapeutics; overexpression; prognostic; programs; promoter; prototype; public health relevance; resistance mechanism; response; targeted agent; therapeutic target; transcription factor; treatment strategy; tumorigenesis

 DESCRIPTION (provided by applicant): Many human cancers depend on deregulated and overexpressed MYC for their sustained growth and proliferation, yet pharmacological inhibition of this oncogenic transcription factor has proved daunting. Recent insights into how MYC promotes the cancer cell state suggests an avenue through which its oncogenic properties could be exploited therapeutically. When overexpressed, MYC acts as a global amplifier of transcription, leading to massively upregulated expression of all actively transcribed genes. Moreover, oncogenic MYC is transcriptionally regulated by large enhancer regions, or super-enhancers (SEs), that facilitate its high-level expression and are acutely sensitive to perturbation. Given the emerging status of oncogenic MYC as a SE-associated transcriptional amplifier, we sought to selectively target the mechanisms governing its transcriptional regulation. The transcription cycle of RNA polymerase II is governed by a group of cyclin-dependent kinases (CDKs), including CDKs 7-13, with critical roles in transcription initiation and elongation. We hypothesize that inhibition of CDK7, a CDK with primary roles in transcription regulation, selectively targets MYC-overexpressing cancer cells by interfering with enhancer-promoter control of gene transcription and thus MYC-driven global transcriptional amplification. In preliminary studies, we demonstrated striking activity and selectivity by THZ1, a novel prototype covalent CDK7 inhibitor, in MYCN-amplified neuroblastoma (NB) cells compared to those without MYCN amplification. This effect was associated with inhibition of global MYCN-dependent transcriptional amplification and preferentially reduced expression of SE-associated genes, especially MYCN, without toxicity to normal tissues. To validate CDK7 inhibition as a tractable therapeutic strategy against MYCN-amplified NB, we now address three pivotal research questions. Aim 1: Will newer THZ1 analogs with improved pharmacokinetics, in combination with targeted or standard cytotoxic agents, induce durable responses in MYCN-amplified NB? Aim 2: What is the basis for the selective lethality of CDK7 inhibition in MYCN-amplified NB cells? Aim 3: What are the mechanisms of resistance to THZ1? The results we generate are expected to yield important insights into approaches that could be used to inhibit amplified MYCN function in high-risk NB, and therefore may provide a compelling rationale for the treatment of other cancers with deregulated expression of MYC family proteins, which represents the long-term goal of our research.

 描述（由申请人提供）：许多人类癌症的持续生长和增殖依赖于失调和过度表达的 MYC，然而，最近对 MYC 如何促进癌细胞状态的见解已被证明是令人畏惧的。当过度表达时，其致癌特性可作为全局转录放大器，导致所有活跃转录基因的表达大幅上调。 MYC 受大增强子区域或超级增强子 (SE) 的转录调控，这些区域促进其高水平表达，并且对扰动极为敏感。鉴于致癌 MYC 作为 SE 相关转录放大器的新兴地位，我们试图选择性地对其进行调控。 RNA 聚合酶 II 的转录周期由一组细胞周期蛋白依赖性激酶 (CDK) 控制，包括具有关键作用的 CDK 7-13。我们率先抑制 CDK7（一种在转录调节中起主要作用的 CDK），通过干扰基因转录的增强子-启动子控制，从而选择性地靶向 MYC 过表达的癌细胞，从而初步实现 MYC 驱动的全局转录扩增。研究表明，与没有 MYCN 的细胞相比，THZ1（一种新型原型共价 CDK7 抑制剂）在 MYCN 扩增的神经母细胞瘤 (NB) 细胞中具有显着的活性和选择性这种效应与抑制全局 MYCN 依赖性转录扩增有关，并优先减少 SE 相关基因（尤其是 MYCN）的表达，且对正常组织没有毒性。现在解决三个关键的研究问题：具有改进的药代动力学的新型 THZ1 类似物与靶向或标准细胞毒性药物相结合，是否会在 MYCN 扩增中诱导持久反应。 NB？目标 2：MYCN 扩增的 NB 细胞中 CDK7 抑制的选择性致死作用的基础是什么？目标 3：THZ1 的耐药机制是什么？抑制高风险 NB 中扩增的 MYCN 功能，因此可能为通过 MYC 家族蛋白表达失调来治疗其他癌症提供令人信服的理由，这代表了我们的长期目标研究。