Project 2: Targeting differentiation-linked redox sensitivity in melanoma

项目2摘要 黑色素瘤治疗在两种现代模式方面取得了重要进展：免疫疗法和靶向治疗。 激酶抑制剂治疗。然而，有一个关键的临床需要解决去分化作为一种治疗方法。 对现代黑色素瘤疗法的抵抗机制。值得注意的是，去分化是一个有记录的交叉- 耐药机制影响两种新的扩展护理标准：BRAF和MEK激酶抑制剂 治疗和免疫治疗，如免疫检查点阻断（如抗PD-1/PD-L1）。我们发现 一种新的去分化相关的铁依赖性氧化应激（铁凋亡）的敏感性，提供了一个新的 从这个角度来补充目前的标准治疗黑色素瘤。在我们的研究中， 铁凋亡是去分化细胞的致命弱点，与它们是否在 基线或通过BRAF和MEK抑制剂治疗或通过免疫治疗相关诱导去分化 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凋亡的程序性细胞死亡过程带入该领域 黑色素瘤和黑素细胞的我们将研究如何氧化还原应激保护机制，具体到 黑素细胞中氧化还原调节的黑素生成与铁代谢、铁蛋白吞噬和铁凋亡相互作用 在黑色素瘤细胞中。黑色素瘤和黑素细胞的研究将有助于我们进一步了解这一点 最近发现的细胞死亡机制。我们将测试结合铁凋亡诱导 激酶抑制剂疗法或使用临床前模型的检查点抑制剂免疫疗法。我们将 询问来自临床试验的人类样本，以评估免疫治疗背景，其中去分化 提出了最高的临床挑战和机遇。我们发现去分化相关的铁凋亡 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 利用整合基因组学扩展我们的黑色素瘤去分化调控框架， 转录和表观遗传调控程序。为了扩展新陈代谢、氧化还原 缓冲，分化和铁凋亡，我们将在我们的发现中纳入代谢组学和脂质组学， 机械描绘方法。我们在这些目标中的目标是机械地理解和增强 靶向黑色素瘤去分化抗性逃逸途径的治疗方法。

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.