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Synthetic lethality by targeting the core senescent mechanism in lung cancer.

针对肺癌核心衰老机制的综合致死率。

基本信息

批准号：
10368019
负责人：
XIAO-FAN WANG
金额：
$ 48.09万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-02-01 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10368019
关键词：
Adverse effects Adverse event Anticoagulants Apoptosis Aromatase Inhibitors Attenuated Automobile Driving Binding Bypass CDK4 gene Cancer Etiology Cancer Patient Cancer Relapse Cancer cell line Cell Aging Cell Cycle Arrest Cell Cycle Regulation Cell Proliferation Cells Cessation of life Clinical Clinical Trials Combined Modality Therapy Cyclin-Dependent Kinase Inhibitor Cyclin-Dependent Kinases Diagnosis Disease Disease Progression ERBB2 gene Endothelial Cells Endothelium Epithelial Cells Estrogen receptor positive FDA approved G1 Phase Genetic Screening Goals Growth Human In Vitro In complete remission Intervention Left Letrozole Leukopenia Lung Malignant neoplasm of lung Mediating Medical Metabolic Metastatic breast cancer Molecular Names Neutropenia Non-Small-Cell Lung Carcinoma Nonmetastatic PAR-1 Receptor Pathway interactions Patient-Focused Outcomes Patients Pharmaceutical Preparations Pharmacology Phase II Clinical Trials Physical Function Progression-Free Survivals Protein C Radiation Recurrence Research Resistance Resistance development Role Serine Protease Signal Pathway Signal Transduction Solid Neoplasm Stable Disease Stimulus Survival Rate Testing Therapeutic Therapeutic Effect Thrombin Thrombomodulin Toxic effect Treatment Efficacy Work base cancer therapy chemotherapy improved in vivo inhibitor innovation interest lung cancer cell malignant breast neoplasm neoplastic cell new therapeutic target novel partial response preclinical efficacy preclinical trial programs receptor response senescence side effect targeted treatment transcriptome tumor microenvironment tumor progression tumorigenesis tumorigenic

项目摘要

Abstract Lung cancer is the most common cause of cancer-related deaths worldwide. Non-small cell lung cancer (NSCLC) accounts for 85% of all lung cancer cases and is generally diagnosed at advanced stages, requiring multimodal therapy involving radiation, chemotherapy, and targeted therapies. Despite these medical interventions, the five- year survival rates of NSCLC patients are less than 5%, highlighting the need for innovative and more effective strategies to treat NSCLC. Dysregulation of cyclin-dependent kinases (CDKs), such as CDK4 and CDK6, occurs in 70% of NSCLC patients and results in aberrant cellular proliferation and tumorigenesis. Palbociclib (PD-03329, trade name Ibrance) is the first cyclin dependent kinase 4 and 6 inhibitor to be approved for breast cancer and is currently investigated as a monotherapy for other solid tumors, including NSCLC. While palbociclib has shown initial improvements in progression-free survival in a phase II clinical trial for recurrent or metastatic NSCLC patients, over half of patients either experience adverse effects or develop resistance and disease progression after eight weeks of treatment. Palbociclib achieves its therapeutic effect by arresting cells in G1 phase and promoting an irreversible cell cycle arrest known as cellular senescence. Senescence was initially thought to suppress tumorigenesis; however, growing evidence has suggested that senescent cells can paradoxically promote tumorigenesis and cancer relapse by altering the surrounding tumor microenvironment. The use of senolytic therapies to promote synthetic lethality may bypass the negative side effects of senescence and enhance the efficacy of palbociclib by either driving palbociclib-treated cells towards apoptosis rather than senescence. Through genetic screening, we identified thrombomodulin (THBD), a potent anticoagulant endothelial receptor, as a novel senolytic target for palbociclib-induced senescence. THBD-mediated signaling was upregulated during palbociclib-induced senescence in NSCLC cancer cell lines and served as a critical regulator of NSCLC cell fate and survival, as inhibition of THBD signaling in NSCLC cells attenuated senescence and promoted apoptosis. Importantly, inhibiting the activity of THBD downstream signaling by an FDA-approved drug caused senescent NSCLC cells to apoptose under treatment of palbociclib. Built on these findings, we propose two specific aims to fully investigate the mechanism by which THBD signaling mediates the senescent program induced by palbociclib and validate this pathway as a target to induce synthetic lethality in palbociclib- treated NSCLC cells both in vitro and in vivo for combinational therapy with the ultimate goal to develop preclinical and clinical trials to improve overall NSCLC patient outcome.

摘要