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Functional Networks for Persister Cell Sensitivities

持久细胞敏感性的功能网络

基本信息

批准号：
9520153
负责人：
MICHAEL T MCMANUS
金额：
$ 55.18万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-01 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9520153
关键词：
Antioxidants BRAF gene Bioavailable Breast Cancer Model Breast Melanoma Cancer Patient Cancer cell line Cell Death Cell Fraction Cell Line Cell Survival Cells Cessation of life Characteristics Chemicals Clinic Clinical Clustered Regularly Interspaced Short Palindromic Repeats Development Disabled Persons Disease Drug resistance ERBB2 gene Epithelial Cells Gene Expression Generations Genes Genetic Glutathione Goals Human Immunocompetent Implant Intervention Iron Knock-out Knockout Mice Lipid Peroxides Lipids Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of ovary Mammalian Cell Maps Masks Measurement Measures Mediating Melanoma Cell Methods Modeling Molecular NADP Neoplasm Metastasis Normal tissue morphology Pathway interactions Pharmaceutical Preparations Pharmacotherapy Proliferating Reactive Oxygen Species Recurrence Relapse Residual Cancers Residual state Role Signal Pathway Signal Transduction Testing Therapeutic Toxic effect Translations Tumor Volume Work Xenograft procedure acquired drug resistance cancer cell cancer recurrence cancer type cell type cofactor combinatorial dosage experimental study gene interaction genetic approach in vivo inhibitor/antagonist insight leukemia malignant breast neoplasm melanoma mouse model neoplastic cell novel novel strategies prevent programs small molecule synergism targeted treatment therapeutic target tool tumor whole genome

项目摘要

Project Summary In this proposal we aim to characterize and identify mechanisms for the persister cell state. Specifically, we have found that cancer persister cells are specifically and potently sensitive to ferroptosis, a newly discovered non-apoptotic cell death program which involves toxic buildup of lipid hydroperoxides. Ferroptotic death can be induced by chemical or genetic inhibition of GPX4, the primary human antioxidant which scavenges lipid peroxides. We have found that drug naïve parental cancer cells and nontransformed human epithelial cells are insensitive to ferroptosis and propose to elucidate the molecular basis for persister cell sensitivity to ferroptosis. This will be accomplished via cellular and molecular approaches including high throughput genetic interaction screens. In Aim 1, we plan to evaluate the generality of our observations in breast cancer persister cells in other cancer types including melanoma, ovarian and lung cancer. We will determine mechanisms for why persisters are potently and specifically sensitive to ferroptosis, while their parental cancer cells are insensitive. This will be accomplished by measurement of anti- and pro-oxidant cellular metabolites and cofactors (e.g. glutathione and iron), differentially peroxidated lipids upon GPX4 inhibition, ROS signaling pathways and other mechanistic analyses. These experiments will provide a framework for genetic interaction studies described in Aim 3. In Aim 2, we will also establish the role for GPX4 in persister cell survival and acquired drug resistance in cancer cell xenografts, PDXs and syngeneic immunocompetent mouse models of breast cancer and melanoma by inducing ferroptosis in persisters in vivo. Preventing tumor recurrence by inducing ferroptosis in persister cells in vivo will be a significant result to promote further work towards clinical intervention targeting GPX4. We will also focus on our efforts to identify the genetic interactions behind the persister state and its sensitivity to ferroptosis. In Aim 3 we will build on our existing efforts to develop a platform for conducting persister gene interaction maps (EMAPs). This is will help us identify the relationship between our screen hits, with the hope of identifying synergies among the genes and small molecules. In addition it may help us discover new synergistic interactions with druggable genes. We have already accomplished a pilot level EMAP analysis to establish feasibility, and here we propose to expand the scope to the whole genome. The mechanisms underlying cancer persister cells have not been thoroughly explored and this proposal will identify genes and disease relevance. Our accomplishments will yield the first persister cell state genetic interaction map and pave the way to identify polytherapies for translation to the clinic.

项目总结