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：
10090580
负责人：
Qijing Li
金额：
$ 49.06万
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/10090580
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 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 Modeling 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 Proliferating 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/antagonist 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.

抽象的肺癌是全球与癌症相关死亡的最常见原因。非小细胞肺癌（NSCLC）占所有肺癌病例的85％，通常在高级阶段被诊断出，需要多模式涉及放疗，化学疗法和靶向疗法的疗法。尽管采取了这些医疗干预措施，但 NSCLC患者的年份存活率不到5％，强调了对创新和更有效的需求治疗NSCLC的策略。发生细胞周期蛋白依赖性激酶（CDK）的失调，例如CDK4和CDK6 在70％的NSCLC患者中，会导致异常的细胞增殖和肿瘤发生。 palbociclib（PD-03329，商业名称Ibrance）是第一个依赖细胞周期蛋白的激酶4和6抑制剂，该抑制剂被批准用于乳腺癌和目前被研究为包括NSCLC在内的其他实体瘤的单一疗法。而palbociclib已显示在复发或转移性NSCLC的II期临床试验中，无进展生存的初步改善患者，超过一半的患者会出现不良反应或发展抗药性和疾病进展经过八周的治疗。 palbociclib通过在G1期间阻止细胞和促进不可逆的细胞周期停滞，称为细胞衰老。衰老最初被认为是抑制肿瘤发生；但是，越来越多的证据表明，衰老细胞可以自相矛盾通过改变周围的肿瘤微环境来促进肿瘤发生和癌症复发。使用促进合成致死性的鼻溶性疗法可能会绕过衰老的负面影响和通过将Palbociclib处理的细胞驱动到凋亡而不是衰老。通过遗传筛查，我们确定了血栓形成蛋白（THBD），这是一种有效的抗凝剂内皮受体，是palbociclib引起的衰老的新型鼻溶剂。 THBD介导的信号传导在palbociclib诱导的NSCLC癌细胞系衰老期间被上调，并作为关键 NSCLC细胞命运和存活的调节剂，因为NSCLC细胞中THBD信号的抑制作用减弱了衰老并促进凋亡。重要的是，抑制FDA批准的THBD下游信号的活性药物导致衰老的NSCLC细胞在palbociclib治疗下凋亡。基于这些发现，我们提出了两个特定的目的，以充分研究THBD信号介导衰变的机制 Palbociclib引起的程序并验证该途径是诱导palbociclib-的合成致死性的目标在体外和体内处理的NSCLC细胞，用于结合疗法与发展的最终目标临床前和临床试验可改善NSCLC患者的总体结果。