权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Targeting RIP3-mediated Necroptosis for Chemosensitization

针对 RIP3 介导的坏死性凋亡进行化疗增敏

基本信息

批准号：
9251788
负责人：
Yong Lin
金额：
$ 23.71万
依托单位：
LOVELACE BIOMEDICAL & ENVIRONMENTAL RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-01 至 2019-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9251788
关键词：
Antineoplastic Agents Apoptosis Biopsy Cancer Etiology Cancer Patient Cell Death Cell Death Induction Cell Line Cells Cessation of life Chemosensitization Chemotherapy-Oncologic Procedure Cisplatin Clinical DNA Methylation Deoxycytidine Epigenetic Process Foundations Genetic Transcription Goals Human Hypermethylation Immunity Immunohistochemistry Impairment In Vitro Inflammation Lung Neoplasms Malignant neoplasm of lung Mediating Messenger RNA Methylation Modification Non-Small-Cell Lung Carcinoma Nude Mice Operative Surgical Procedures Pathway interactions Patient Selection Patients Physiological Platinum Post-Transcriptional Regulation Progression-Free Survivals Proteins RIPK3 gene Repression Resistance Reverse Transcriptase Polymerase Chain Reaction Role Sampling Solid Testing Therapeutic Tissues Translations Xenograft procedure anticancer activity base bisulfite cancer cell chemotherapy chromatin immunoprecipitation design epigenetic regulation histone modification improved in vivo killings knock-down mRNA Expression neoplastic cell overexpression promoter public health relevance response response biomarker restoration standard of care translational study tumor

项目摘要

DESCRIPTION (provided by applicant): Chemotherapy is usually ineffective for lung cancer due to chemoresistance. The anticancer activity of chemotherapeutics is mainly through the killing of cancer cells. Tremendous efforts on apoptosis resistance-related mechanisms have moderately improved lung cancer chemotherapy, suggesting other mechanisms are critical in chemoresistance. Recent studies suggest that therapeutics can induce RIP3- mediated necroptosis to kill tumor cells that are resistant to apoptosis. However, cancer cells may develop necroptosis-evading capacities. Our preliminary studies found: (1) RIP3 expression is suppressed in 22% of human lung cancer tissues; (2) RIP3 promoter hypermethylation is associated with RIP3 suppression; (3) restoring RIP3 expression significantly increased sensitivity of lung cancer cells to cisplatin; (4) forced RIP3 expression enhanced cisplatin-induced necroptosis; and (5) sensitizing necroptosis increased chemosensitivity. Thus, we hypothesize that the necroptosis pathway is impaired in some human lung cancers and sensitizing necroptosis will improve chemotherapy efficacy and overcome chemoresistance in these lung cancers. The hypothesis will be tested in three specific aims: (1) To determine if sensitizing necroptosis overcomes chemoresistance in lung cancer cells; (2) To determine if epigenetic and post- transcriptional regulation of RIP3 underlies the mechanisms of necroptosis suppression-associated chemoresistance in human lung cancer; and (3) To determine if RIP3 re-expression sensitizes necroptosis and overcomes chemoresistance in human NSCLC xenografts in nude mice. The goal of this application is to obtain more supportive evidence validating the role of necroptosis in lung cancer's clinical response to first-line chemotherapy and chemoresistance. Positive results from this project will be a solid foundation for an R01 application with comprehensive mechanistic and translational studies for improving the efficacy of chemotherapy against lung cancer.

描述（申请人提供）：由于化疗耐药，化疗通常对肺癌无效。化疗药物的抗癌活性主要是通过杀死癌细胞来实现的。对细胞凋亡抵抗相关机制的巨大努力已经适度改善了肺癌化疗，这表明其他机制在化疗抵抗中也至关重要。最近的研究表明，治疗方法可以诱导 RIP3 介导的坏死性凋亡，从而杀死对细胞凋亡有抵抗力的肿瘤细胞。然而，癌细胞可能会产生逃避坏死性凋亡的能力。我们的初步研究发现：（1）RIP3的表达在22%的人类肺癌组织中被抑制； (2) RIP3启动子高甲基化与RIP3抑制相关； (3)恢复RIP3表达显着增加肺癌细胞对顺铂的敏感性； (4)强制RIP3表达增强顺铂诱导的坏死性凋亡； (5) 致敏坏死性凋亡增加化疗敏感性。因此，我们假设坏死性凋亡途径在某些人类肺癌中受损，而使坏死性凋亡敏感将提高化疗效果并克服这些肺癌的化疗耐药性。该假设将在三个具体目标上进行检验：（1）确定致敏性坏死性凋亡是否克服了肺癌细胞的化疗耐药性； (2) 确定RIP3的表观遗传和转录后调控是否是人肺癌坏死性凋亡抑制相关化疗耐药机制的基础； (3) 确定 RIP3 重新表达是否会敏化坏死性凋亡并克服裸鼠人 NSCLC 异种移植物的化疗耐药性。本申请的目的是获得更多支持性证据，验证坏死性凋亡在肺癌对一线化疗和化疗耐药的临床反应中的作用。该项目的积极结果将为 R01 的应用奠定坚实的基础，通过全面的机制和转化研究来提高肺癌化疗的疗效。