Identifying novel therapies targeting Merkel cell carcinoma and tumor microenvironment

确定针对默克尔细胞癌和肿瘤微环境的新疗法

基本信息

批准号：
10665544
负责人：
Ling Gao
金额：
$ 37.93万
依托单位：
SOUTHERN CALIFORNIA INST FOR RES/EDUC
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-14 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10665544
关键词：
Animal Model Antibodies Attenuated Bioinformatics Biological Biological Markers Biological Models Cancer Model Case Study Cell Line Cell Survival Cells Clinical Dose Drug Screening Ecosystem Epigenetic Process Exhibits Foundations Genetic Engineering Goals Growth Histone Deacetylation Human Image Immune Immune checkpoint inhibitor Immune system Immunocompetent Immunodeficient Mouse Immunotherapy In Vitro Incidence Laboratories Malignant Epithelial Cell Malignant Neoplasms Mediating Merkel cell carcinoma Molecular Molecular Analysis Mus Pathway interactions Patient-Focused Outcomes Patients Pharmaceutical Preparations Phosphatidylinositide 3-Kinase Inhibitor Phosphotransferases Positioning Attribute Pre-Clinical Model Protocols documentation Reporting Research Resistance Resistance development Resolution Skin Cancer Solid Solid Neoplasm Survival Rate System T-Lymphocyte Testing Therapeutic Treatment Efficacy Tumor Immunity Tumor-Derived United States Food and Drug Administration Work Xenograft Model Xenograft procedure advanced disease alternative treatment antitumor effect chemokine clinically relevant comorbidity drug candidate established cell line high-throughput drug screening human model humanized mouse immune cell infiltrate immune resistance improved in vivo inhibitor innovation insight kinase inhibitor melanoma mortality mouse model neoplastic cell neuroendocrine cancer new therapeutic target novel novel therapeutics pembrolizumab potential biomarker programmed cell death protein 1 reconstitution response single-cell RNA sequencing standard of care success targeted treatment therapeutic target therapy resistant tool translational potential treatment response tumor tumor growth tumor microenvironment tumor xenograft tumor-immune system interactions

项目摘要

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.

抽象的 1 默克尔细胞癌 MCC 是一种常常致命的皮肤癌，发病率不断增加，且治疗方法很少 2 个选项。晚期MCC的五年生存率惨淡不足18%，死亡率是其3倍比黑色素瘤高3倍。尽管免疫检查点抑制剂（ICI）已成为晚期患者的标准治疗 4 MCC，所有 MCC 患者中 50% 不适合 ICI，并且大多数接受治疗的患者会产生耐药性。 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，我们长期 6 个学期的目标是确定可用于增强 ICI 疗效并克服 ICI 耐药性的新疗法， 7 或作为不符合 ICI 资格的 MCC 患者的替代治疗。利用 MCC 细胞系我们实验室建立了8个与临床相关的430个高通量剂量反应药物筛选在 9 种激酶抑制剂中，我们鉴定出非美匹司他，这是一流的 PI3K/HDAC 抑制剂，具有有效的抗 MCC 作用 10 项活动。该提案的目的是确定单独使用非美匹司他和单独使用非美匹司他的治疗效果 11 与 ICI 组合，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 PI3K 和 HDAC 表观遗传抑制 MCC 生长和进展 13 条途径，并通过增强 MCC 中的抗肿瘤免疫力使肿瘤细胞对 ICI 敏感 14.微环境。我们将通过利用集成细胞、 15 项单细胞分辨率的分子和成像分析，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 芬匹司他作为单一疗法和联合疗法对肿瘤和肿瘤免疫相互作用的影响 19 免疫疗法，以及揭示 TME 介导的耐药性和反应的新见解。拟议的 20 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 MCC 的 21 个范例，克服或规避当前治疗选择的局限性，并提供见解 22 免疫抵抗将适用于人类癌症并改善患者的治疗结果。