Project 2: Targeting differentiation-linked redox sensitivity in melanoma

项目2摘要 黑色素瘤的治疗在两种现代方式方面取得了重要进展：免疫治疗和靶向治疗。 激酶抑制剂治疗。然而，有一个关键的临床需要来解决去分化作为一种 现代黑色素瘤治疗的耐药机制。值得注意的是，去分化是一种有记录的交叉 影响两种新的CARE扩展标准的耐药机制：BRAF和MEK激酶抑制剂 治疗和免疫疗法，如免疫检查点阻断(如抗PD-1/PD-L1)。我们的发现 一种与去分化相关的对铁依赖的氧化应激(铁性下垂)的新敏感性，提供了一种新的 从这个角度来补充目前黑色素瘤的护理治疗标准。在我们的研究中，对 铁下垂是去分化细胞的阿喀琉斯之踵，与它们是否在 基线，或通过BRAF和MEK抑制剂治疗或联合免疫治疗诱导去分化 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 去分化逃逸途径。 我们的发现和提出的实验将铁下垂的程序性细胞死亡过程带入了这个领域 黑色素瘤和黑素细胞。我们将调查特定的氧化还原压力保护机制是如何 黑素细胞氧化还原调节的黑色素生成与铁代谢、吞铁蛋白和铁下垂的相互作用 在黑色素瘤细胞中。对黑色素瘤和黑素细胞背景的研究将有助于促进我们对此的了解 相对较新发现的细胞死亡机制。我们将测试联合铁性下垂诱导的疗效。 使用临床前模型进行激酶抑制剂治疗或检查点抑制免疫治疗。我们会 询问临床试验中的人体样本以评估去分化的免疫治疗环境 带来了最高的临床挑战和机遇。我们发现的脱分化相关的铁性下垂 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 用整合基因组学来扩展我们对黑色素瘤去分化调控的框架 转录和表观遗传调控程序。为了进一步阐述新陈代谢、氧化还原 缓冲、分化和铁下垂，我们将把代谢组学和脂类组学结合到我们的发现和 机械化的描述方法。我们在这些目标中的目标是机械地理解和提高 针对黑色素瘤去分化耐药逃逸途径的治疗途径。

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.