Identifying novel therapies targeting Merkel cell carcinoma and tumor microenvironment

摘要 1默克尔细胞癌MCC是一种经常致命的皮肤癌，发病率增加，治疗很少 2个选项。晚期MCC令人沮丧的五年生存率不到18%，死亡率为3倍 3高于黑色素瘤。尽管免疫检查点抑制剂(ICI)已成为晚期患者的标准护理 4MCC，50%的MCC患者不符合ICIS标准，大多数接受治疗的患者产生耐药性。 5重要的是，这些患者没有其他治疗方法。鉴于这一紧迫的临床需求，我们的长期- 6学期目标是确定可用于增强ICI疗效和克服ICI耐药性的新疗法， 7或作为不符合ICIS资格的MCC患者的替代治疗。利用MCC细胞系 本实验室建立的高通量剂量-反应药物筛选430个临床相关药物 9个激酶抑制剂，我们鉴定出一类PI3K/HDAC抑制剂非美比诺斯特，它具有强大的抗MCC作用 10项活动。这项建议的目的是确定非美比妥单独和联合治疗的疗效。 11与ICIS结合，解决抗MCC作用的内在和外在机制。中环 12假说认为非美比妥通过靶向PI3K和HDAC表观遗传学抑制MCC的生长和进展 13条途径，并通过增强MCC中的抗肿瘤免疫使肿瘤细胞对ICIS增敏 14.微环境。我们将通过利用系统级的方法来验证这一假设， 15个单细胞分辨率的分子和成像分析，以全面研究MCC的功能复杂性 我们的临床相关动物模型中的16个生态系统代表了最接近的人类MCC临床前模型- 17免疫微环境。这个异常强大的生物平台将使我们能够研究 18非美比妥单药联合应用对肿瘤及肿瘤-免疫相互作用的影响 19免疫治疗，以及发现对TME介导的抵抗和反应的新见解。建议数 这项研究意义重大，因为该项目的成功完成将为新的治疗方法奠定基础 21 MCC的范例，克服或绕过目前治疗选择的限制，并提供见解 22进入免疫耐药将适用于人类癌症，并改善患者的预后。

ABSTRACT 1 Merkel cell carcinoma MCC is an often-lethal skin cancer with increasing incidence and few treatment 2 options. The dismal five-year survival rate of advanced MCC is less than 18% and the mortality rate is 3-times 3 higher than melanoma. Although immune checkpoint inhibitors (ICI) have become standard of care in advanced 4 MCC, 50% of all MCC patients are ineligible for ICIs and resistance develops in the majority of treated patients. 5 Importantly, there is no therapeutic alternative for these patients. Given this urgent clinical demand, our long- 6 term goal is to identify novel therapies which can be used to augment ICI efficacy and overcome ICI resistance, 7 or to serve as alternative treatments for MCC patients who are ineligible for ICIs. Utilizing MCC cell lines 8 established in our laboratory and high throughput dose-response drug screening of 430 clinically relevant 9 kinase inhibitors, we identified fimepinostat, the first-in-class PI3K/HDAC inhibitor, with potent anti-MCC 10 activities. The objective of this proposal is to determine therapeutic efficacy of fimepinostat alone and in 11 combination with ICIs, and resolve intrinsic and extrinsic mechanisms of anti-MCC activities. The central 12 hypothesis is that fimepinostat inhibits MCC growth and progression by targeting PI3K and HDAC epigenetic 13 pathways, and by sensitizing tumor cells to ICIs through augmentation of antitumor immunity in the MCC 14 microenvironment. We will test this hypothesis by utilizing systems-level approaches integrating cellular, 15 molecular and imaging analyses in single cell resolution to fully study the functional complexity of the MCC 16 ecosystem in our clinically relevant animal model representing the closest preclinical models of human MCC- 17 immune microenvironment. This singularly powerful biological platform will enable us to study direct effects of 18 fimepinostat on tumors and tumor-immune interactions as a monotherapy and in combination with 19 immunotherapy, as well as uncover new insights into TME-mediated resistance and response. The proposed 20 research is significant because successful completion of the project will lay foundation for a new treatment 21 paradigm for MCC, overcoming or circumventing current limitations in therapeutic options, and lending insights 22 into immune resistance will be applicable across human cancers and improve patient outcomes.