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。高级浆液卵巢癌（HGS-OVCA）是卵巢癌最恶性的形式。在最激进的HGS-ovca肿瘤是携带基因组扩增和CCNE1过表达的肿瘤。编码Cyclin E1的基因，一种钥匙细胞周期调节剂。这个具有挑战性的HGS-ovca子集使很差标准细胞毒性化疗后的结局，并与高增生速率相关，快速铂耐药性的发展和对聚ADP（核糖）聚合酶抑制剂的抗性。尽管激烈的努力，针对CCNE1放大HGS-OVCA治疗的针对疗法，部分原因是由于可药物分子靶标的缺乏。因此，对开发用于CCNE1扩增的HGS-OVCA和其他CCNE1的癌症的新疗法过表达。有希望的临床前证明，敲低或抑制细胞周期蛋白依赖性激酶（CDK2）是细胞周期蛋白E1的催化激酶伴侣，有选择地杀死CCNE1扩增的卵巢癌细胞线，突出了与CCNE1扩增相关的潜在依赖性。但是，直接努力具有药理学剂的靶标CDK2在达到CDK2的特异性方面的困难困扰着。最近，我们采用了选择性抑制CDK7的替代策略，CDK7是CDK2的关键上游激活剂，为了选择性杀死CCNE1扩增的卵巢癌细胞。在原则研究中，YKL-5-124，A 新的CDK7抑制剂比现有抑制剂具有较高选择性，导致明显的肿瘤收缩在CCNE1扩增的HGS-OVCA的人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在CCNE1放大的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）增加或扩大药物反应的组合策略（目标1）。而YKL-5-124 在小鼠中显示有效的体内活性，我们将继续优化这些CDK7抑制剂以改进药代动力学进一步促进该化学系列的临床前开发（AIM 2）。最后，我们将评估 YKL-5-124（或CCNE1扩增和未扩增HGS-的小鼠模型中的进一步优化类似物） OVCA（目标3）。为了实现这些目标，我们组装了一个具有专业知识的多学科团队药物化学（Nathanael Gray，Stanford）；细胞和系统生物学（Caitlin Mills和Peter Sorger，哈佛医学院）；卵巢癌的小鼠模型（Panagiotis konstantinopoulos，dfci）；和翻译和临床卵巢研究（Ursula Matulonis，DFCI）。这项研究描述了一种新的方法有选择地靶向CCNE1过表达肿瘤，并识别新型的小分子，以实现对CCNE1扩增的HGS-OVCA治疗此策略的临床前评估。