Targeting CDK7 in high-grade serous ovarian carcinoma

项目摘要 卵巢癌仍然是最致命的妇科恶性肿瘤和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，构成了卵巢癌死亡的大多数。尽管高 尽管HGSOC患者对初始铂-紫杉烷化疗的反应率很低，但HGSOC患者经常复发， 对铂类似物的耐药性越来越强。PARP抑制剂最近已被批准用于治疗HGSOC; 然而，PARPi单药治疗的最大临床益处主要在以下肿瘤中观察到： 同源重组（HR）缺陷。因此，有一个迫切的未满足的医疗需求， HGSOC患者的替代治疗策略。鉴于转录程序是非常重要的， 在癌症中失调，导致癌症依赖于转录程序的特定组分 （称为“转录成瘾”），靶向转录CDKs正在成为治疗癌症的新策略 治疗在转录CDK中，CDK 7显示出最显著的拷贝数损失（占主导地位 半合子），在HGSOC中具有最高的缺失评分。重要的是，HGSOC细胞 具有CDK 7半合子缺失的患者对CDK 7i治疗高度敏感。此外，CDK 7丢失与以下因素相关： 对DNA损伤药物如PARPi和铂的敏感性增加。CDK 7优先抑制 抑制DNA损伤修复途径中基因的表达并损害HR的活性。因此， 我们假设CDK 7的半合子缺失是HGSOC中的一个靶向脆弱性，并且CDK 7i单独或 与DNA损伤剂组合是治疗HGSOC患者的新策略。低剂量CDK 7i 治疗可以优先抑制一组由超级增强子驱动的HGSOC相关基因， 作为HGSOC患者选择人群的有效和可耐受治疗。中心目标 本申请的目的是研究CDK 7靶向治疗的机制基础和翻译潜力， HGSOC。我们已经组建了一个团队的合作者增加了专业知识和资源来测试上述内容 通过三个具体目标的假设。具体目标1。评估CDK 7的半合子丢失是否是 HGSOC中有针对性的漏洞。具体目标2。表征低剂量CDK 7i的分子机制 DNA损伤反应。具体目标3。评估CDK 7i与FDA批准的 HGSOC临床前模型中的治疗。我们提出的研究可能为临床应用提供强有力的依据。 用于卵巢癌治疗的CDK 7抑制剂的开发。

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.