Identifying novel therapies targeting Merkel cell carcinoma and tumor microenvironment

摘要 1默克尔细胞癌MCC是一种常见的致死性皮肤癌，发病率不断上升，治疗很少 2个选项。晚期MCC的5年生存率低于18%，死亡率为3倍 比黑色素瘤高3倍。尽管免疫检查点抑制剂（ICI）已成为晚期癌症患者的标准治疗， 4 MCC，50%的MCC患者不适合接受ICI，大多数接受治疗的患者出现耐药性。 5重要的是，这些患者没有治疗替代方案。鉴于这一迫切的临床需求，我们的长期- 6项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ICI条件的MCC患者的替代治疗。利用MCC细胞系 我们实验室建立了8个与高通量剂量反应药物筛选相关的430个临床 9激酶抑制剂，我们确定了fimepinostat，第一类PI 3 K/HDAC抑制剂，具有有效的抗MCC 10活动该提议的目的是确定单独的非美匹司他和与非美匹司他联合使用的治疗功效。 11与ICIs的组合，并解决抗MCC活性的内在和外在机制。中央 12假设是fimepinostat通过靶向PI 3 K和HDAC表观遗传抑制MCC生长和进展 13种途径，并通过增强MCC中的抗肿瘤免疫使肿瘤细胞对ICI敏感 14微环境我们将通过利用系统级方法来测试这一假设， 15个单细胞分辨率的分子和成像分析，以充分研究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。这个非常强大的生物平台将使我们能够研究 18 fimepinostat作为单一疗法和与 19免疫疗法，以及揭示TME介导的抗性和反应的新见解。拟议 20研究意义重大，因为项目的成功完成将为新的治疗方法奠定基础 MCC的21个范例，克服或规避治疗选择的当前限制，并提供见解 22进入免疫抵抗将适用于人类癌症和改善患者的结果。

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.