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Targeting cholesterol metabolism and replication stress response in cancer therapy

癌症治疗中针对胆固醇代谢和复制应激反应

基本信息

批准号：
10548830
负责人：
Junran Zhang
金额：
$ 34.97万
依托单位：
OHIO STATE UNIVERSITY
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：
2021-02-01 至 2026-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10548830
关键词：
ATM function Address Affect Antifungal Agents Biological Biological Assay CHEK1 gene CRISPR/Cas technology Ca(2+)-Calmodulin Dependent Protein Kinase Cancer Etiology Cancer Patient Cell Death Cell Line Cell Survival Cells Cessation of life Cholesterol Cholesterol Homeostasis Clinical Clinical Trials Complex Cytogenetics DNA DNA Damage DNA Repair DNA Repair Disorder DNA biosynthesis DNA replication fork Data Defect Disease Drug Targeting Endoplasmic Reticulum Enzymes Event FDA approved Fiber Fura-2 Goals Human Immunotherapy Impairment In Vitro Interruption Lead Malignant Neoplasms Malignant neoplasm of lung Mediating Movement Non-Small-Cell Lung Carcinoma Oncogenic Pathway interactions Phosphoric Monoester Hydrolases Phosphotransferases Prognosis Proteins Reporter Reporting Role Signal Transduction Squalene Techniques Testing Woman anticancer research antitumor effect ataxia telangiectasia mutated protein biological adaptation to stress cancer cell cancer diagnosis cancer therapy cell growth cholesterol biosynthesis cholesterol control efficacy evaluation endoplasmic reticulum stress epoxidase genome-wide homologous recombination improved in vitro Assay inhibitor innovation knock-down live cell imaging loss of function lung cancer cell men mouse model multimodality neoplastic cell novel novel strategies novel therapeutic intervention overexpression patient derived xenograft model pharmacologic prevent protein expression ratiometric repaired replication stress response screening small hairpin RNA synergism synthetic lethal interaction targeted treatment therapy resistant treatment strategy tumor growth

项目摘要

Project Summary: Lung cancer is the leading cause of cancer deaths in both men and women. Non-small cell lung cancer (NSCLC) accounts for large majority of lung cancer diagnoses, and novel treatment strategies for this disease are urgently needed. ATR and its downstream effector CHK1 are key component of replication stress (RS) response that specifically deal with the stalled replication forks during DNA replication and are critical for cell survival under RS. Inhibitors targeting ATR and CHK1 are currently being tested in clinical trials. However, only limited efficacy has been observed when those agents are combined with standard therapy. Identifying the new synergistic conditions that render cells sensitive to ATR/CHK1 inhibitors will be key to improving the efficacy of these agents. Squalene epoxidase (SQLE), an enzyme controlling cholesterol biosynthesis by converting squalene to oxidosqualene in endoplasmic reticulum (ER), is frequently overexpressed in human cancers, including lung cancer. High expression of SQLE is associated with poor prognosis. Our recent genome-wide loss of function screen discovered that SQLE reduction led to enhanced sensitivity to a CHK1 inhibitor. Thus, the goal of this application is to determine whether SQLE inhibition sensitizes NSCLC cells to ATR and CHK1 inhibitors and whether high SQLE-expressing NSCLC cancer can be specifically targeted by the combined inhibition of SQLE and ATR/CHK1. Our preliminary data suggest that SQLE inhibition by shRNA knockdown causes RS and activates ATR/CHK1 activation. In addition, SQLE inhibition lead to increased protein expression of WIP1, a phosphatase that suppress the activity of ATM, a master DNA damage response protein controlling DNA repair. We hypothesize that SQLE inhibition leads to increased RS by suppressing DNA repair, rendering cells sensitive to ATR and CHK1 inhibition. Thus, co-administration of an SQLE inhibitor and an ATR or CHK1 inhibitor could synergistically suppress tumor growth. To test our hypothesis, three Specific Aims are proposed. Specific Aim 1 will interrogate the mechanism by which SQLE inhibition leads to increased WIP1 expression. Specific Aim 2 will determine whether SQLE inhibition leads to increased RS by impairing DNA repair, particularly homologous recombination, a major repair pathway that prevents and antagonizes RS. Specific Aim 3 will assess the efficacy of combined SQLE inhibition and ATR/CHK1 inhibition in suppressing tumor cell growth using in vitro assays as well as cell line-based and patient-derived xenograft (PDX) models of NSCLC. If successful, our studies will reveal a new synthetic lethal interaction between inhibition of SQLE and ATR/CHK1 and will have a significant impact on improving the survival of lung cancer patients by identifying novel therapeutic approaches.

项目总结: