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Targeting CDK7 in high-grade serous ovarian carcinoma

靶向 CDK7 治疗高级别浆液性卵巢癌

基本信息

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
项目类别：
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

项目摘要

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.

项目总结