HTS for the discovery of activators of NK cell cytotoxicity

HTS 用于发现 NK 细胞毒性激活剂

基本信息

批准号：
10372203
负责人：
David Wald
金额：
$ 43.09万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10372203
关键词：
Acute Myelocytic Leukemia Address Adverse event Antigens Biological Biological Assay Cancer Etiology Cancer Patient Cancer cell line Cell Surface Receptors Cellular immunotherapy Cessation of life Chemicals Clinical Clinical Trials Collection Cytolysis Development Dose Enhancers Epithelial ovarian cancer Future Hematologic Neoplasms Immunodeficient Mouse Immunotherapy In Vitro Lead Libraries Ligands Lymphocyte Lymphocyte Subset Malignant Neoplasms Malignant neoplasm of ovary Measures Mediator of activation protein Molecular NK Cell Activation NK cell therapy Natural Killer Cells Normal Cell Patients Phenotype Property Public Health Refractory Refractory Disease Relapse Series Solid Neoplasm System Testing Therapeutic Woman Work base cancer cell cancer therapy cell killing circulating leukemia cell clinical efficacy cytotoxic cytotoxicity human cancer mouse model human model improved in vivo insight metastatic colorectal neoplastic cell novel receptor safety testing small molecule success

项目摘要

Abstract Natural killer (NK) cells are lymphocytes that are capable of killing malignant cells without antigen-specific receptor recognition. Due to this property, NK cells have been utilized for adoptive immune cell therapy for a variety of malignancies. Despite limited success for hematologic malignancies, the therapeutic potential of NK cell therapy for cancer has been limited by the insufficient cytotoxic activity of NK cells particularly for solid tumors. Due to the ability of NK cells to specifically target cancer cells and avoid killing of normal cells, we hypothesize that enhancing the cytotoxic activity of NK cells can lead to enhanced efficacy of NK cell therapies for cancer. As the molecular mediators regulating NK cell cytotoxic activity are still not fully characterized, we will conduct a small molecule high throughput compound library screen to identify novel mediators of NK cell cytotoxic activity. The purpose of this work is to identify small molecules that can be further developed for therapeutic purposes as well as to reveal important probes to elucidate mechanistic insights into NK cell activity that may enable future targeted approaches. In the first aim, we will identify compounds that enhance NK cell killing of ovarian cancer cells through a HTS of a diverse 300k small molecule collection. In the second aim, the primary hits will be tested in a series of secondary assays to identify the most promising hits. The most promising hits will then undergo biological characterization in vitro and in vivo. It is hoped that this work will lead to the identification of promising approaches to improve NK cell therapy for cancer patients.

抽象的天然杀伤（NK）细胞是淋巴细胞，能够杀死不具有抗原特异性的恶性细胞受体识别。由于该特性，NK细胞已被用于过养免疫细胞治疗。各种恶性肿瘤。尽管血液系统恶性肿瘤的成功有限，但NK的治疗潜力癌症的细胞疗法受到NK细胞的细胞毒性活性不足的限制，特别是针对固体肿瘤。由于NK细胞具有特异性靶向癌细胞并避免杀死正常细胞的能力，我们假设增强NK细胞的细胞毒性活性可以提高NK细胞疗法的功效用于癌症。由于调节NK细胞细胞毒性活性的分子介质仍未完全表征，我们将进行小分子高吞吐量复合库屏幕，以识别NK细胞的新型介体细胞毒性活性。这项工作的目的是确定可以进一步开发的小分子治疗目的以及揭示重要的探针，以阐明机械洞察到NK细胞可能使未来有针对性的方法的活动。在第一个目标中，我们将确定化合物通过300K小分子收集的HTS增强NK细胞杀死卵巢癌细胞。在第二个目标中，主要命中将在一系列辅助测定中进行测试，以识别最多有希望的热门歌曲。然后，最有希望的命中将在体外和体内进行生物学表征。它希望这项工作将导致鉴定有前途的改善NK细胞疗法的方法适用于癌症患者。