Project 3: KDM5 Histone Demethylases in Melanoma Growth and Tumor Immunity

项目3：项目概要 尽管最近取得了显著进展，但晚期黑色素瘤患者的预后仍然很差。具体地说， 原发性和获得性耐药性通常会发展为靶向治疗，只有一部分患者有反应 免疫疗法这些挑战突出了迫切需要开发新的治疗方法，改善治疗效果， 目前针对黑色素瘤的治疗方法，并开发预测反应的生物标志物。新出现的证据 表明表观遗传调节因子KDM 5 B是黑色素瘤治疗的有吸引力的靶标和生物标志物。 长期目标是将我们发现的黑色素瘤形成的新机制转化为 进展到诊所。本项目的目的是评估靶向治疗的潜力， 黑色素瘤中的KDM 5组蛋白脱甲基酶，并开发生物标志物以预测对PD-1通路的反应 阻断和组合的KDM 5抑制/免疫疗法。我们的中心假设是KDM 5靶向 导致直接的抗肿瘤作用和通过将免疫学上的“冷”肿瘤转化为 “热”肿瘤，更容易被淋巴细胞浸润并对免疫检查点做出反应 封锁初步数据表明，这种效应可能是由STING途径介导的。的假设 是由以前的研究，以及我们自己的初步数据，从病人来源的黑色素瘤和 临床前黑素瘤模型。基本原理是更好地理解KDM 5组蛋白去甲基化酶的功能 在黑色素瘤生长和抗肿瘤免疫反应将导致新的和创新的方法来治疗 黑素瘤将在两个特定目的中检验假设：1）评价靶向治疗的潜力 KDM 5在黑色素瘤中的作用; 2）评估KDM 5 B作为人黑色素瘤中的生物标志物。拟议的研究是 概念上和理论上的创新，因为它旨在确定KDM 5抑制是否可以转化为 黑色素瘤从免疫学“冷”到“热”状态，并评估肿瘤KDM 5 B水平作为新的生物标志物 治疗黑色素瘤这些研究的结果可能会影响黑色素瘤患者的治疗， 我们对调节抗肿瘤免疫反应的因素的理解。

PROJECT 3: PROJECT SUMMARY Despite remarkable recent progress, prognosis for patients with advanced melanoma remains poor. Specifically, primary and acquired drug resistance often develops for targeted therapy, and only a subset of patients respond to immunotherapy. These challenges highlight an urgent need to develop novel therapeutic methods, improve current treatments against melanoma, and develop biomarkers that predict response. Emerging evidence suggests that the epigenetic regulator KDM5B is an attractive target and biomarker for melanoma treatment. The long-term goal is to translate our findings of novel mechanisms involved in melanoma formation and progression to the clinic. The objective of this project is to evaluate the therapeutic potential of targeting the KDM5 histone demethylases in melanoma and to develop biomarkers to predict response to PD-1 pathway blockade and combined KDM5 inhibition/immunotherapy. Our central hypothesis is that KDM5 targeting results in direct anti-tumor effects and indirect effects by converting immunologically “cold” tumors into “hot” tumors, which are more likely to be infiltrated by lymphocytes and to respond to immune checkpoint blockade. Preliminary data suggests that this effect may be mediated by the STING pathway. 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 KDM5 histone demethylase function in melanoma growth and anti-tumor immune responses will result in new and innovative approaches to treat melanoma. The hypotheses will be tested in two Specific Aims: 1) Evaluate the therapeutic potential of targeting KDM5 in melanoma; 2) Evaluate KDM5B as a biomarker in human melanoma. The proposed research is conceptually and translationally innovative, because it aims to determine whether KDM5 inhibition can convert melanomas from an immunologically “cold” to “hot” state, and to evaluate tumor KDM5B level as a new biomarker for melanoma. 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.