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：
10443860
负责人：
THOMAS G GRAEBER
金额：
$ 50.76万
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/10443860
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 inhibitor therapy 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2摘要黑色素瘤治疗在两种现代方式中具有工具性进步：免疫疗法并针对性激酶抑制剂治疗。然而，仍有至关重要的临床需要解决去分化作为一个现代黑色素瘤疗法的抗性机制。值得注意的是，去分化是有记录的交叉影响两种新扩展护理标准的电阻机制：BRAF和MEK激酶抑制剂疗法和免疫疗法，例如免疫检查点阻滞（例如抗PD-1/PD-L1）。我们的发现对铁依赖性氧化应激（铁毒性）的新的去分化相关敏感性，提供了一种新的从中可以补充黑色素瘤当前护理疗法标准的角度。在我们的研究中，对铁凋亡是用于去分化细胞的致命弱点，独立于在基线，或诱导通过BRAF和MEK抑制剂疗法推导或与免疫疗法相关的细胞因子。因此，使用临床前模型，我们将进一步追求这种正交敏感性，以防止去分化逃生路线。我们的发现和提出的实验将铁凋亡的程序性细胞死亡过程带入了现场黑色素瘤和黑色素细胞。我们将研究如何特有的氧化还原应力保护机制黑色素细胞中的氧化还原调节的黑色素产生与铁代谢，铁蛋白噬菌体和铁铁蛋白相互作用在黑色素瘤细胞中。黑色素瘤和黑色素细胞环境中的研究将有助于提高我们对此的了解相对最近发现的细胞死亡机制。我们将测试结合铁铁诱导的功效使用临床前模型使用激酶抑制剂治疗或检查点抑制剂免疫疗法。我们将从临床试验中询问人类样本，以评估免疫疗法的情况下进行去分化提出最高的临床挑战和机会。我们发现与去分化连接的铁铁作用敏感性是综合基因组学和药物基因组学方法的结果。我们将继续扩大使用综合基因组学划定黑色素瘤去分化的调节框架转录和表观遗传调节计划。扩展新陈代谢之间的多个联系，氧化还原缓冲，差异化和铁毒性，我们将在我们的发现中纳入代谢组学和脂质组学机械描述方法。我们在这些目标中的目标是机械理解和增强靶向黑色素瘤去分化抗性逃脱途径的治疗方法。