Targeting CDK7 in high-grade serous ovarian carcinoma

靶向 CDK7 治疗高级别浆液性卵巢癌

• 批准号: 10683737
• 负责人: Lin Zhang
• 金额: $ 43.44万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-05 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10683737
• 关键词: Affect; C-terminal; Cancer Etiology; Cell Cycle; Cell Death; Cell physiology; Cells; Cessation of life; Clinic; Clinical; Combined Modality Therapy; Communication; Cyclin-Dependent Kinase Inhibitor; Cyclin-Dependent Kinases; Cyclins; DNA Damage; DNA Repair; DNA Sequence Alteration; Dependence; Diagnosis; Dose; Drug resistance; Dysmyelopoietic Syndromes; Enhancers; Essential Genes; FDA approved; Gene Expression; Genes; Genetic Transcription; Goals; Impairment; Malignant Epithelial Cell; Malignant Female Reproductive System Neoplasm; Malignant Neoplasms; Malignant neoplasm of ovary; Medical; Molecular; Molecular Biology; Mutation; Nature; Oncology; Ovarian Serous Adenocarcinoma; Pathway interactions; Patients; Pharmaceutical Preparations; Phosphorylation; Platinum; Poly(ADP-ribose) Polymerase Inhibitor; Pre-Clinical Model; RNA Polymerase II; RNA Processing; Recurrence; Relapse; Reporting; Repression; Resistance; Resources; Revlimid; Solid Neoplasm; Testing; Therapeutic; Transcript; Translational Research; United States; Woman; addiction; analog; cancer cell; cancer genome; cancer therapy; cancer type; chemotherapy; chromosome 5q loss; clinical development; early phase clinical trial; fusion gene; gene repression; homologous recombination; in vivo Model; inhibitor; lenalidomide; mortality; mutant; new therapeutic target; novel strategies; patient population; preclinical study; programs; response; structural biology; targeted treatment; taxane; translational medicine; translational potential; treatment response; treatment strategy; tumor

PROJECT SUMMARY Ovarian cancer remains the most lethal gynecologic malignancy and the fifth most frequent cause of cancer- related mortality in women in the United States. Advanced-stage high-grade serous ovarian carcinoma (HGSOC) is the most commonly diagnosed subtype and constitutes the majority of ovarian cancer deaths. Despite a high response rate to initial platinum-taxane chemotherapy, patients with HGSOC frequently relapse and become increasingly resistant to platinum analogues. PARP inhibitors have been recently approved to treat HGSOC; however, the greatest clinical benefit from PARPi monotherapy has been mainly observed in tumors with homologous recombination (HR) deficiency. Therefore, there is an urgent unmet medical need to develop alternative therapeutic strategies for patients with HGSOC. Given that the transcriptional program is remarkably dysregulated in cancer, resulting in cancer dependency on specific components of the transcriptional program (termed “transcriptional addiction”), targeting transcriptional CDKs is emerging as a new strategy for cancer treatment. Among the transcriptional CDKs, CDK7 shows the most significant copy number loss (dominantly hemizygous) across multiple cancer types with the highest deletion score in HGSOC. Importantly, HGSOC cells with hemizygous loss of CDK7 are highly sensitive to CDK7i treatment. Additionally, CDK7 loss is correlated with increased sensitivities to DNA damaging drugs such as PARPi and platinum. Inhibition of CDK7 preferentially represses the expression of genes in the DNA damage repair pathways and impairs the activity of HR. Therefore, we hypothesize that hemizygous loss of CDK7 is a targetable vulnerability in HGSOC, and that CDK7i alone or in combination with DNA damaging agents is a novel strategy to treat patients with HGSOC. Low-dose CDK7i treatment can preferentially repress a group of HGSOC-associated genes that are driven by super enhancers, serving as an effective and tolerable treatment for a select population of patients with HGSOC. The central goal of this application is to study the mechanistic basis and translational potential of CDK7-targeted therapy in HGSOC. We have assembled a team of collaborators with added expertise and resources to test the above hypothesis through three specific aims. Specific Aim 1. Evaluate whether hemizygous loss of CDK7 is a targetable vulnerability in HGSOC. Specific Aim 2. Characterize the molecular mechanisms of low-dose CDK7i treatment in DNA damage response. Specific Aim 3. Evaluate CDK7i in combination with FDA-approved therapies in preclinical models of HGSOC. Our proposed studies may provide strong rationale for clinical development of CDK7 inhibitors for ovarian cancer treatment.

项目摘要 卵巢癌仍然是最致命的妇科恶性肿瘤，是癌症最常见的第五个原因 - 美国妇女的相关死亡率。高级高级浆液卵巢癌（HGSOC） 是最常见的亚型，构成大多数卵巢癌死亡。尽管很高 对初始铂taxane化学疗法的反应率，HGSOC患者经常缓解并成为 对铂类似物的抗药性越来越多。 PARP抑制剂最近已被批准治疗HGSOC； 然而，PARPI单药治疗的最大临床益处主要是在患有 同源重组（HR）缺陷。因此，紧急未满足的医疗需要发展 HGSOC患者的替代理论策略。鉴于转录程序非常明显 癌症失调，导致癌症依赖转录程序的特定组成部分 （称为“转录成瘾”），靶向转录CDK是癌症的新策略 治疗。在转录CDK中，CDK7显示了最重要的拷贝数损失（主要是 半合基）在多种癌症类型中，HGSOC的缺失评分最高。重要的是，HGSOC细胞 CDK7的半细胞损失对CDK7I治疗高度敏感。此外，CDK7损失与 对DNA破坏药物的敏感性增加，例如PARPI和铂。优先抑制CDK7 抑制基因在DNA损伤修复途径中的表达，并损害HR的活性。所以， 我们假设CDK7的半正合损失是HGSOC中的一个目标脆弱性，并且仅CDK7I或 结合DNA损伤剂是治疗HGSOC患者的新型策略。低剂量CDK7I 治疗最好反映一组由超级增强子驱动的HGSOC相关基因 对于精选的HGSOC患者，可作为有效且可耐受的治疗方法。中心目标 该应用的是研究CDK7靶向治疗的机械基础和翻译潜力 HGSOC。我们已经组建了一个具有更多专业知识和资源的合作者团队，以测试上述 通过三个特定目标的假设。具体目标1。评估CDK7的半合基因损失是否为 HGSOC中的可目标漏洞。特定目标2。表征低剂量CDK7I的分子机制 DNA损伤反应的治疗。特定目的3。与FDA批准的评估CDK7I评估 HGSOC的临床前模型中的疗法。我们提出的研究可能为临床提供强大的理由 开发用于卵巢癌治疗的CDK7抑制剂。