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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.

摘要