Targeting CDK7 in CCNE1-amplified Ovarian Cancer

CCNE1 扩增的卵巢癌中靶向 CDK7

基本信息

批准号：
10367792
负责人：
NATHANAEL Schiander GRAY
金额：
$ 72.71万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-02-17 至 2027-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10367792
关键词：
Biological Availability Biological Markers CCNE1 gene Cancer Science Cancer cell line Cell Cycle Cell Death Cell Line Cellular biology Chemicals Clinical Cyclin-Dependent Kinases Cytotoxic Chemotherapy Data Dependence Development Disease Drug Exposure Drug Kinetics Exhibits Generations Genetic Genomics Goals Half-Life Hour Human Knowledge Lead Malignant - descriptor Malignant Neoplasms Malignant neoplasm of ovary Medical Molecular Target Mus Oral Outcome Ovarian Ovarian Serous Adenocarcinoma Patients Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacology Phosphotransferases Plasma Platinum Poly(ADP-ribose) Polymerases Property Proteomics Rattus Research Resistance Sampling Series Specificity Structure Systems Biology Tumor-Derived Xenograft procedure analog arm base cancer cell cancer genetics chemotherapy druggable target efficacy study experimental study improved in vivo in vivo evaluation inhibitor knock-down lead candidate medical schools mouse model multidisciplinary neoplastic cell novel novel strategies novel therapeutics overexpression patient derived xenograft model pre-clinical preclinical development preclinical evaluation resistance mechanism response scaffold small molecule synergism targeted treatment therapy resistant transcriptome sequencing treatment strategy tumor

项目摘要

Project Abstract. High-grade serous ovarian carcinoma (HGS-OvCa) is the most malignant form of ovarian cancer. Among the most aggressive HGS-OvCa tumors are those that harbor genomic amplification and overexpression of CCNE1, the gene that encodes for cyclin E1, a key cell cycle regulator. This challenging HGS-OvCa subset carries poor outcomes after standard cytotoxic chemotherapy, and is associated with high proliferative rate, rapid development of platinum resistance, and de novo resistance to poly ADP (ribose) polymerase inhibitors. Despite intense efforts, targeted therapies for the treatment of CCNE1-amplified HGS-OvCa remain elusive, in part, due to the paucity of druggable molecular targets. As such there remains an urgent unmet medical need for the development of new therapies for CCNE1-amplified HGS-OvCa and other cancers marked by CCNE1 overexpression. Promising preclinical evidence demonstrates that knockdown or inhibition of cyclin-dependent kinase (CDK2), the catalytic kinase partner of cyclin E1, selectively kills CCNE1-amplified ovarian cancer cell lines, highlighting a potential dependency associated with CCNE1 amplification. However, efforts to directly target CDK2 with pharmacological agents have been plagued by difficulties in achieving specificity for CDK2. We recently employed an alternative strategy of selectively inhibiting CDK7, a key upstream activator of CDK2, to achieve selective killing of CCNE1-amplified ovarian cancer cells. In proof-of-principle studies, YKL-5-124, a new CDK7 inhibitor with superior selectivity over existing inhibitors of its kind, led to pronounced tumor shrinkage in a human xenograft mouse models of CCNE1-amplified HGS-OvCa. The primary goal of the proposed research is to expand on our preliminary findings by elucidating the underlying principles governing CCNE1-amplified HGS-OvCa sensitivity to CDK7 inhibition. This knowledge will then be leveraged to guide further preclinical inquiry into targeting CDK7 in CCNE1-amplified HGS-OvCa. Herein we propose to identify (1) HGS-OvCa cancer cells and genetic backgrounds that are sensitive to YKL-5-124; (2) biomarkers that correlate with drug response; and (3) combination strategies that augment or expand drug response (Aim 1). While YKL-5-124 displays potent in vivo activity in mice, we will continue to optimize these CDK7 inhibitors for improved pharmacokinetics to further the preclinical development of this chemical series (Aim 2). Lastly, we will evaluate YKL-5-124 (or a further in vivo optimized analog) in mouse models of CCNE1-amplified and non-amplified HGS- OvCa (Aim 3). To accomplish these goals we have assembled a multi-disciplinary team with expertise in medicinal chemistry (Nathanael Gray, Stanford); cell and systems biology (Caitlin Mills and Peter Sorger, Harvard Medical School); mouse models in ovarian cancer (Panagiotis Konstantinopoulos, DFCI); and translational and clinical ovarian research (Ursula Matulonis, DFCI). This research describes a new approach to selectively target CCNE1-overexpressing tumors and identifies novel small-molecules that will enable the preclinical evaluation of this strategy for the treatment of CCNE1-amplified HGS-OvCa.

项目摘要。高级别浆液性卵巢癌 (HGS-OvCa) 是卵巢癌中最恶性的一种形式。其中最具侵袭性的 HGS-OvCa 肿瘤是那些具有基因组扩增和 CCNE1 过度表达的肿瘤，编码细胞周期蛋白 E1（一种关键的细胞周期调节因子）的基因。这个具有挑战性的 HGS-OvCa 子集携带较差标准细胞毒性化疗后的结果，并且与高增殖率、快速铂耐药性的发展，以及对聚 ADP（核糖）聚合酶抑制剂的从头耐药性。尽管经过不懈的努力，治疗 CCNE1 扩增的 HGS-OvCa 的靶向疗法仍然难以捉摸，部分原因是缺乏可成药的分子靶点。因此，仍然存在未得到满足的迫切医疗需求开发针对 CCNE1 扩增的 HGS-OvCa 和 CCNE1 标记的其他癌症的新疗法过度表达。有希望的临床前证据表明，细胞周期蛋白依赖性细胞的敲低或抑制激酶 (CDK2) 是细胞周期蛋白 E1 的催化激酶伴侣，选择性杀死 CCNE1 扩增的卵巢癌细胞线，突出显示与 CCNE1 扩增相关的潜在依赖性。然而，努力直接用药物靶向 CDK2 一直受到难以实现 CDK2 特异性的困扰。我们最近采用了选择性抑制 CDK7（CDK2 的关键上游激活剂）的替代策略，实现对CCNE1扩增的卵巢癌细胞的选择性杀伤。在原理验证研究中，YKL-5-124 新型 CDK7 抑制剂比现有同类抑制剂具有更高的选择性，可显着缩小肿瘤在 CCNE1 扩增的 HGS-OvCa 的人类异种移植小鼠模型中。拟议研究的主要目标是通过阐明管理 CCNE1 放大的基本原则来扩展我们的初步发现 HGS-OvCa 对 CDK7 抑制的敏感性。然后将利用这些知识来指导进一步的临床前研究对 CCNE1 扩增的 HGS-OvCa 中靶向 CDK7 的调查。在此我们建议识别 (1) HGS-OvCa 对 YKL-5-124 敏感的癌细胞和遗传背景； (2)与药物相关的生物标志物回复; (3) 增强或扩大药物反应的组合策略（目标 1）。而YKL-5-124 在小鼠中显示出有效的体内活性，我们将继续优化这些 CDK7 抑制剂以改善药代动力学，以进一步推进该化学系列的临床前开发（目标 2）。最后我们来评价一下 CCNE1 扩增和非扩增 HGS 小鼠模型中的 YKL-5-124（或进一步体内优化的类似物） OvCa（目标 3）。为了实现这些目标，我们组建了一支具有专业知识的多学科团队药物化学（Nathanael Gray，斯坦福大学）；细胞和系统生物学（Caitlin Mills 和 Peter Sorger，哈佛医学院）；卵巢癌小鼠模型（Panagiotis Konstantinopoulos，DFCI）；和转化和临床卵巢研究（Ursula Matulonis，DFCI）。这项研究描述了一种新方法选择性地靶向 CCNE1 过表达的肿瘤，并鉴定出新的小分子，使对这种治疗 CCNE1 扩增的 HGS-OvCa 策略的临床前评估。