Project 2. Harnessing Epigenetic Regulation of Endogenous Retroelements in Melanoma

项目2：项目概要 尽管在治疗晚期黑色素瘤方面取得了显著进展，但预后仍然可变。具体地说， 几乎所有的转移性黑色素瘤患者随着时间的推移对靶向治疗产生耐药性，而大约 一半对免疫疗法没有反应。这些挑战凸显了开发新型治疗药物的迫切需要。 干预措施，改善目前的治疗，并开发生物标志物预测反应。新出现的证据 表明表观遗传调节因子KDM 5 B和SETDB 1作为治疗靶点和内源性逆转录因子， (REs)作为免疫治疗反应的生物标志物。我们的长期目标是将我们的研究成果 黑色素瘤进展到临床的机制。本项目的目标是剖析 KDM 5 B和SETDB 1缺失诱导抗肿瘤免疫的细胞机制，开发生物标志物， 预测对免疫检查点抑制剂的反应，并评估耗尽KDM 5 B的治疗潜力 黑色素瘤我们的中心假设是KDM 5 B和SETDB 1靶向去抑制表达， 启动强大的抗黑色素瘤免疫反应，并且retroelements可以 用来预测对免疫疗法的反应这一假设也得到了先前研究的支持 作为我们自己从患者来源的黑色素瘤和临床前黑色素瘤模型中获得的初步数据。的理由 更好地理解KDM 5 B和SETDB 1如何抑制黑色素瘤生长和抗肿瘤免疫 这些反应将导致新的和创新的方法来治疗黑色素瘤。这些假设将在 三个具体目的：1）研究KDM 5 B和SETDB 1缺失诱导的免疫应答机制; 2)评估耗尽KDM 5 B在黑色素瘤中的治疗潜力; 3）评估KDM 5 B抑制的RE 和SETDB 1作为人黑素瘤的预测性生物标志物。拟议的研究在概念上，技术上， 和临床创新，因为它的目的是检查KDM 5 B消耗的治疗潜力，使用“第一次”， 类”KDM 5 B降解剂，并评估RE水平作为新的预测生物标志物， 免疫疗法这些研究的结果可能会影响黑素瘤患者的治疗， 增加我们对调节抗肿瘤免疫反应的因素的理解。

PROJECT 2: PROJECT SUMMARY Despite remarkable progress in treating advanced melanoma, the prognosis remains variable. Specifically, nearly all metastatic melanoma patients develop resistance to targeted therapy with time, while approximately half do not respond to immunotherapy. These challenges highlight an urgent need to develop novel therapeutic interventions, improve current treatments, and develop biomarkers that predict response. Emerging evidence suggests that epigenetic regulators KDM5B and SETDB1 as therapeutic targets and endogenous retroelements (REs) as biomarkers of response to immunotherapies. Our long-term goal is to translate our findings of novel mechanisms involved in melanoma progression to the clinic. The objectives of this project are to dissect the cellular mechanisms by which KDM5B and SETDB1 loss induce anti-tumor immunity, develop biomarkers to predict response to immune checkpoint inhibitors, and to evaluate the therapeutic potential of depleting KDM5B in melanoma. Our central hypotheses are that KDM5B and SETDB1 targeting de-repress the expression of retroelements to initiate robust anti-melanoma immune responses, and retroelements can be harnessed to predict response to immunotherapy. The hypothesis is supported by previous studies as well as our own preliminary data from patient-derived melanomas and preclinical melanoma models. The rationale is that better understanding of how KDM5B and SETDB1 suppress melanoma growth and anti-tumor immune responses will result in new and innovative approaches to treat melanoma. The hypotheses will be tested in three Specific Aims: 1) Dissect the mechanisms of immune responses induced by KDM5B and SETDB1 loss; 2) Evaluate the therapeutic potential of depleting KDM5B in melanoma; 3) Evaluate REs suppressed by KDM5B and SETDB1 as predictive biomarkers in human melanoma. The proposed research is conceptually, technically, and clinically innovative, because it aims to examine the therapeutic potential of KDM5B depletion using “first in class” KDM5B degraders, and to evaluate RE levels as novel predictive biomarker for response to immunotherapy. The results from these studies could impact the treatment of patients with melanoma and increase our understanding of the factors that regulate anti-tumor immune responses.