Targeting CDK7 in high-grade serous ovarian carcinoma

项目总结 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。 美国妇女的相关死亡率。晚期高级别浆液性卵巢癌 是最常见的诊断亚型，构成了卵巢癌死亡的大部分。尽管有很高的 铂-紫杉烷初始化疗的有效率，HGSOC患者经常复发并成为 对铂类似物的抵抗力越来越强。PARP抑制剂最近已被批准用于治疗HGSOC； 然而，PARPI单一疗法的最大临床益处主要是在患有 同源重组(HR)缺陷。因此，迫切需要发展尚未得到满足的医疗需求。 HGSOC患者的替代治疗策略。考虑到转录程序显著地 癌症中的失调，导致癌症对转录程序的特定成分的依赖 (称为“转录成瘾”)，靶向转录CDK正在成为治疗癌症的一种新策略 治疗。在转录CDK中，CDK7表现出最显著的拷贝数丢失(主要是 HGSOC中缺失分数最高的多种癌症类型。重要的是，HGSOC细胞 CDK7半合子缺失对CDK7i治疗高度敏感。此外，CDK7的丢失与 对PARPI和铂等破坏DNA的药物的敏感性增加。CDK7的优先抑制作用 抑制DNA损伤修复途径中基因的表达，损害HR的活性。因此， 我们假设CDK7的半合子丢失是HGSOC中的一个靶向漏洞，并且CDK7i单独或 联合DNA损伤剂是治疗HGSOC患者的一种新策略。小剂量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， 作为一种对特定人群的HGSOC患者有效且可耐受的治疗。中心目标 这一应用的目的是研究CDK7靶向治疗的机制基础和翻译潜力。 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来测试以上内容 通过三个具体目标提出假设。具体目的1.评估CDK7基因半合子缺失是否是一种 HGSOC中的目标漏洞。特定目的2.研究小剂量CDK7i的分子机制 DNA损伤反应中的治疗。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。我们建议的研究可能会为临床提供强有力的理论基础 CDK7抑制剂治疗卵巢癌的研究进展。

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.