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.

项目概要 卵巢癌仍然是最致命的妇科恶性肿瘤，也是第五大最常见的癌症原因 美国女性的相关死亡率。晚期高级别浆液性卵巢癌 (HGSOC) 是最常诊断的亚型，占卵巢癌死亡的大部分。尽管具有高 HGSOC 患者对初始铂类紫杉烷化疗的反应率较低，经常复发并成为 对铂类似物的抵抗力越来越强。 PARP抑制剂最近被批准用于治疗HGSOC； 然而，PARPi 单一疗法的最大临床益处主要在患有以下疾病的肿瘤中观察到： 同源重组（HR）缺陷。因此，迫切需要开发未满足的医疗需求 HGSOC 患者的替代治疗策略。鉴于转录程序非常出色 癌症失调，导致癌症对转录程序特定成分的依赖 （称为“转录成瘾”），靶向转录 CDK 正在成为一种新的癌症策略 治疗。在转录 CDK 中，CDK7 显示最显着的拷贝数丢失（主要是 半合子）跨越多种癌症类型，在 HGSOC 中缺失得分最高。重要的是，HGSOC 电池 CDK7 半合子缺失的患者对 CDK7i 治疗高度敏感。此外，CDK7 损失与 对 PARPi 和铂等 DNA 损伤药物的敏感性增加。优先抑制CDK7 抑制 DNA 损伤修复途径中基因的表达并损害 HR 的活性。所以， 我们假设 CDK7 的半合子丢失是 HGSOC 中的一个可针对的漏洞，并且 CDK7i 单独或 与 DNA 损伤剂联合使用是治疗 HGSOC 患者的一种新策略。低剂量CDK7i 治疗可以优先抑制一组由超级增强子驱动的 HGSOC 相关基因， 对于特定的 HGSOC 患者群体来说，这是一种有效且可耐受的治疗方法。中心目标 该应用的目的是研究 CDK7 靶向治疗的机制基础和转化潜力 HGSOC。我们组建了一个具有更多专业知识和资源的合作者团队来测试上述内容 通过三个具体目标的假设。具体目标 1. 评估 CDK7 的半合子缺失是否是一种 HGSOC 中的可针对漏洞。具体目标 2. 表征低剂量 CDK7i 的分子机制 DNA损伤反应的治疗。具体目标 3. 结合 FDA 批准的 CDK7i 进行评估 HGSOC 临床前模型的治疗。我们提出的研究可能为临床提供强有力的理论依据 开发用于卵巢癌治疗的CDK7抑制剂。