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：
10558746
负责人：
XIAO-FAN WANG
金额：
$ 47.84万
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/10558746
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 PAR-1 Receptor Pathway interactions Patient-Focused Outcomes Patients Pharmaceutical Preparations Phase II Clinical Trials Physical Function Progression-Free Survivals Protein C Radiation Recurrence Recurrent disease 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 cancer therapy chemotherapy improved in vivo inhibitor innovation interest lung cancer cell malignant breast neoplasm neoplastic cell new therapeutic target novel partial response pharmacologic preclinical efficacy preclinical trial programs receptor response senescence side effect targeted treatment transcriptomic profiling 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.

抽象的肺癌是全世界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%，通常诊断时已处于晚期，需要多模式治疗治疗包括放疗、化疗和靶向治疗。尽管采取了这些医疗干预措施，五 NSCLC 患者的年生存率低于 5%，凸显了创新和更有效的治疗方法的必要性治疗 NSCLC 的策略。细胞周期蛋白依赖性激酶 (CDK)（例如 CDK4 和 CDK6）发生失调 70% 的 NSCLC 患者发生异常细胞增殖和肿瘤发生。 Palbociclib（PD-03329，商品名 Ibrance）是第一个被批准用于乳腺癌和细胞周期蛋白依赖性激酶 4 和 6 抑制剂目前正在研究作为其他实体瘤（包括非小细胞肺癌）的单一疗法。虽然 palbociclib 已显示复发性或转移性非小细胞肺癌 II 期临床试验中无进展生存期的初步改善患者中，超过一半的患者要么出现不良反应，要么出现耐药性和疾病进展治疗八周后。 Palbociclib 通过将细胞阻滞在 G1 期来达到治疗效果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；然而，越来越多的证据表明，衰老细胞可能会自相矛盾地通过改变周围肿瘤微环境促进肿瘤发生和癌症复发。使用促进合成致死性的衰老疗法可能会绕过衰老和衰老的负面副作用通过驱动 palbociclib 治疗的细胞凋亡而不是增强 palbociclib 的功效衰老。通过基因筛查，我们发现了血栓调节蛋白（THBD），一种有效的抗凝剂内皮受体，作为帕博西尼诱导衰老的新型衰老靶点。 THBD 介导的信号传导在 NSCLC 癌细胞系中 palbociclib 诱导的衰老过程中上调，并作为关键 NSCLC 细胞命运和存活的调节因子，抑制 NSCLC 细胞中的 THBD 信号传导可减轻衰老并促进细胞凋亡。重要的是，通过 FDA 批准的药物抑制 THBD 下游信号传导的活性在 palbociclib 治疗下，该药物导致衰老的 NSCLC 细胞凋亡。基于这些发现，我们提出两个具体目标来充分研究 THBD 信号介导衰老的机制 palbociclib 诱导的程序并验证该途径作为诱导 palbociclib 合成致死的目标在体外和体内处理 NSCLC 细胞进行联合治疗，最终目标是开发临床前和临床试验，以改善 NSCLC 患者的总体预后。