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Project 2: Targeting differentiation-linked redox sensitivity in melanoma

项目 2：针对黑色素瘤中分化相关的氧化还原敏感性

基本信息

批准号：
10261397
负责人：
THOMAS G GRAEBER
金额：
$ 51.79万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
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：
2020-09-11 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10261397
关键词：
Address Antitumor Response Apoptosis Automobile Driving BRAF gene Biological Models Biometry Buffers CTLA4 gene Caring Cell Death Cell Death Process Cell Line Cells Classification Clinical Clinical Trials Collaborations Combined Modality Therapy Complement Data Data Set Drug Targeting Epigenetic Process Genetic Transcription Genomics Goals Human Immune checkpoint inhibitor Immune system Immunotherapy Inflammation Interferons Iron Knowledge Link Lipids MAP3K1 gene MEKs Mediating Melanins Melanoma Cell Metabolism Metastatic Melanoma Modality Modeling Modernization Mutate Neural Crest Oxidation-Reduction Oxidative Stress PD-1/PD-L1 Patients Pharmaceutical Preparations Pharmacogenomics Pharmacology Phosphotransferases Pre-Clinical Model Process Production Proto-Oncogene Proteins B-raf Publications Publishing Regulation Research Personnel Resistance Role Route Sampling Signal Transduction Stress Structure Sum Testing Therapeutic Undifferentiated Validation Variant anti-PD-1/PD-L1 base cancer cell cytokine efficacy testing experience experimental study genetic approach immune checkpoint blockade immunogenic inhibitor/antagonist insight iron metabolism kinase inhibitor lipid metabolism lipidomics melanocyte melanoma metabolomics mouse model new therapeutic target patient derived xenograft model pre-clinical prevent programs resistance mechanism standard of care statistics targeted treatment therapy resistant treatment strategy tumor two-dimensional

项目摘要

PROJECT 2 ABSTRACT Melanoma treatment has had instrumental advances in two modern modalities: immunotherapy and targeted kinase inhibitor treatments. Nevertheless, there is a crucial clinical need to address dedifferentiation as a resistance mechanism to modern melanoma therapies. Notably, dedifferentiation is a documented cross- resistance mechanism that impacts both of the new expanding standards of care: BRAF and MEK kinase inhibitor therapies, and immunotherapies such as immune checkpoint blockade (e.g. anti-PD-1/PD-L1). Our discovery of a new dedifferentiation-associated sensitivity to iron-dependent oxidative stress (ferroptosis), provides a new angle from which to complement current standard of care therapies for melanoma. In our studies, sensitivity to ferroptosis is an Achilles heel for dedifferentiated cells independent of whether they were dedifferentiated at baseline, or induced to dedifferentiate by BRAF and MEK inhibitor therapy or by immunotherapy associated cytokines. Thus, using preclinical models, we will further pursue this orthogonal sensitivity to prevent the dedifferentiation escape route. Our discovery and proposed experiments brings the programmed cell death process of ferroptosis into the field of melanoma and melanocytes. We will investigate how the redox stress protection mechanisms specific to redox-regulated melanin production in melanocytes interact with iron metabolism, ferritinophagy and ferroptosis in melanoma cells. Studies in the melanoma and melanocyte context will help advance our knowledge of this relatively recently discovered cell death mechanism. We will test the efficacy of combining ferroptosis induction with either kinase inhibitor therapy, or checkpoint inhibitor immunotherapy using preclinical models. We will interrogate human samples from clinical trials to assess the immunotherapy contexts in which dedifferentiation presents the highest clinical challenge and opportunity. Our discovery of dedifferentiation-linked ferroptosis sensitivity was the result of an integrative genomics and pharmacogenomics approach. We will continue to expand our framework of the regulation of melanoma dedifferentiation using integrative genomics to delineate transcription and epigenetic regulatory programs. To expand upon the multiple links between metabolism, redox buffering, differentiation, and ferroptosis, we will incorporate metabolomics and lipidomics in our discovery and mechanistic delineation approaches. Our goal in these aims is to mechanistically understand and enhance the therapeutic approach of targeting the melanoma dedifferentiation resistance escape route.

项目二摘要