Interruption of cholesterol metabolism and replication stress response in cancer therapy

癌症治疗中胆固醇代谢和复制应激反应的中断

基本信息

批准号：
10044013
负责人：
Junran Zhang
金额：
$ 40.11万
依托单位：
OHIO STATE 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：
2020-09-01 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10044013
关键词：
ATR checkpoint Adenocarcinoma Cell Affect Antifungal Agents Atlases Biochemical Biological Biological Assay CHEK1 gene Cancer Etiology Cancer Patient Cell Cycle Checkpoint Cell Death Cell Line Cell Proliferation Cell Survival Cells Cessation of life Cholesterol Cholesterol Homeostasis Clinical Trials Correlation Studies DNA DNA Damage DNA Double Strand Break DNA Repair DNA replication fork Data Development Disease Drug Targeting Enzyme Inhibition Enzymes FDA approved Fiber Genes Goals Human Immunotherapy Incidence Interruption Lead Liquid Chromatography Lung Adenocarcinoma Lung Neoplasms Malignant Neoplasms Malignant neoplasm of lung Metabolic Metabolism Non-Small-Cell Lung Carcinoma Oncogenes Oncogenic Oncology Patients Pharmaceutical Preparations Pharmacologic Substance Phosphotransferases Process Protein Inhibition Proteins Reactive Oxygen Species Reporting Signal Transduction Single-Stranded DNA Squalene Squamous cell carcinoma Stress Testing The Cancer Genome Atlas Therapeutic Intervention Time Xenograft procedure antitumor effect ataxia telangiectasia mutated protein base biological adaptation to stress cancer cell cancer therapy cholesterol biosynthesis epoxidase genome-wide improved in vitro Assay in vivo inhibitor/antagonist knock-down liquid dynamics loss of function mortality mouse model novel novel strategies novel therapeutic intervention outcome forecast overexpression replication stress response small hairpin RNA tandem mass spectrometry targeted cancer therapy targeted treatment therapy resistant transcription factor treatment strategy tumor tumor growth

项目摘要

Project Summary: Lung cancer is the most common malignancy worldwide, both in incidence and mortality. Unfortunately, this disease is often driven by activating oncogenes that are either not amenable to direct therapeutic intervention or when targeted therapies are available treatment resistance invariably develops, thus highlighting the urgent need for the development of novel treatment strategies. Metabolic reprogramming is a hallmark of cancer and is a pharmaceutical target for cancer therapy. SQLE, a key enzyme required for cholesterol synthesis, is frequently overexpressed in lung cancer and is associated with poor prognosis. Excitingly, our recent genome-wide loss of function screen discovered that SQLE reduction caused enhanced sensitivity to an inhibitor targeting CHK1, a key DNA damage response (DDR)/replication stress (RS) response protein that is required for cell survival and proliferation under RS. Our preliminary data suggest that SQLE inhibition by shRNA knockdown causes RS and activates ATR/CHK1 signaling. Thus, the goal of this application is to determine whether high SQLE-expressing lung cancer can be specifically targeted by the combined inhibition of SQLE and CHK1 or its upstream factor ATR. Because the inhibition of proteins required for cholesterol biosynthesis leads to decreased dNTP and increased reactive oxygen species (ROS) (i.e., two common mechanisms for RS ), we hypothesize that SQLE inhibition leads to increased RS by deregulation of dNTP and/or ROS, triggering the ATR/CHK1 axis for survival. Thus, co-administration of an SQLE inhibitor and an ATR or CHK1 inhibitor could synergistically suppress tumor growth of lung cancer. Specific Aim 1 will delineate whether SQLE inhibition-induced RS is associated with perturbation of the dNTP pool and increased ROS, using liquid chromatography-tandem mass spectrometry, DNA fiber assays and biochemical/cell biological approaches. Specific Aim 2 will assess the antitumor effects of the combined inhibition of SQLE and RS response proteins using in vitro assays and cell line-based and patient-derived xenograft (PDX) mouse models of lung cancer. If successful, our studies will have a significant impact on improving the survival of lung cancer patients by identifying novel therapeutic approaches.

项目摘要：肺癌是全球最常见的恶性肿瘤，无论是发病率还是死亡率。不幸的是，这种疾病通常是通过激活的致癌物来驱动的治疗干预或靶向疗法可用时，耐药性总是会发展出来，因此强调迫切需要制定新的治疗策略。代谢重编程是癌症的标志，是癌症治疗的药物靶标。 SQLE，需要的关键酶胆固醇合成，经常在肺癌中过表达，并且预后不良。令人兴奋的是，我们最近全基因组的功能屏幕屏幕发现SQLE降低引起了增强对靶向CHK1的抑制剂的敏感性，关键的DNA损伤响应（DDR）/复制应力（RS）响应 rs下细胞存活和增殖所需的蛋白质。我们的初步数据表明SQLE SHRNA敲低抑制作用会导致Rs并激活ATR/CHK1信号。因此，目标的目标应用是确定是否可以由 SQLE和CHK1或其上游因子ATR的组合抑制作用。因为需要抑制蛋白质对于胆固醇生物合成会导致DNTP降低和活性氧增加（ROS）（即两个我们的常见机制），我们假设SQLE抑制作用导致rs通过放松调节而增加 DNTP和/或ROS，触发ATR/CHK1轴的生存。因此，平方抑制剂的共同给药和 ATR或CHK1抑制剂可以协同抑制肺癌的肿瘤生长。具体目标1将描述SQLE抑制引起的RS是否与DNTP库的扰动有关并增加 ROS，使用液相色谱串联质谱法，DNA纤维测定和生化/细胞生物学方法。具体目标2将评估SQLE综合抑制和使用体外测定和基于细胞系和患者衍生的异种移植（PDX）小鼠的RS反应蛋白肺癌的模型。如果成功，我们的研究将对改善肺的生存产生重大影响癌症患者通过鉴定新的治疗方法。