Discovery and characterization of exceptionally specific surface oncoprotein LIPI in Ewing Sarcoma

尤文肉瘤中异常特异性表面癌蛋白 LIPI 的发现和表征

• 批准号: 10721942
• 负责人: Irfan Ahmed Asangani
• 金额: $ 18.99万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-06 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10721942
• 关键词: Affect; Antibodies; Antibody-drug conjugates; Binding; Biological Markers; Biological Process; Biology; CRISPR/Cas technology; Cancer Center; Cancer Vaccines; Cancer cell line; Cell Line; Cell Surface Proteins; Cell Survival; Cell Therapy; Cell physiology; Cell surface; Cells; ChIP-seq; Chickens; Child; Chimeric Proteins; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; Collaborations; Coupled; Data; Data Set; Dependence; Development; Disease; Disease Progression; Drug Targeting; EWS-FLI1 fusion protein; EWSR1 gene; Enhancers; Ensure; Ewings sarcoma; FLI1 gene; Foundations; Gene Expression; Genes; Genetic Transcription; Genotype; Germany; Growth; Human; Hydrolase; Immune system; Immunohistochemistry; Immunotherapeutic agent; Immunotherapy; In Vitro; Invaded; Knock-out; Laboratories; Lipase; Lipids; Malignant Neoplasms; Maps; Mediating; Membrane; Metastatic Ewing' s Sarcoma; Microsatellite Repeats; Modeling; Monoclonal Antibodies; Mus; Natural Killer Cells; Neoplasm Metastasis; Normal tissue morphology; Oncogenes; Oncogenic; Oncoproteins; Outcome; Pathology; Patients; Pattern; Pennsylvania; Phenotype; Phospholipase; Physicians; Physiology; Prognostic Marker; Proliferating; Proteins; Proteomics; Reagent; Recurrence; Regulation; Research; Role; Scientist; Signal Pathway; Signal Transduction; Specimen; Surface; Surface Antigens; Survival Rate; T-Lymphocyte; The Cancer Genome Atlas; Therapeutic; Tissue Microarray; Tissues; Transcriptional Regulation; Transmembrane Domain; Tumor Antigens; University Hospitals; Upstream Enhancer; Work; Xenograft Model; Zebrafish; cancer type; chimeric antigen receptor T cells; clinically relevant; clinically significant; design; drug discovery; epigenetic silencing; extracellular; genetic signature; in vivo; lysophosphatidic acid; member; new therapeutic target; novel; novel therapeutic intervention; novel therapeutics; overexpression; prion-like; professor; programs; receptor; sarcoma; success; transcription factor; transcriptome; transcriptomics; tumor growth; vaccine-induced antibodies; young adult

Project Summary Children and young adults with metastatic Ewing sarcoma driven by oncogenic fusion transcription factor EWS- FLI1 continue to have poor outcomes. Immunotherapies using T cells, NK cells, cancer vaccines, and monoclonal antibodies are being considered for Ewing sarcoma, especially for recurrent patients. The identification of human tumor-associated antigens (TAAs) recognized by the immune system is crucial for immunotherapy. Through integration of Ewing sarcoma cell line gene expression, ChIP-seq, and normal and cancer tissue gene expression from the Genotype-Tissue Expression (GTEx), and the TCGA project, we have identified LIPI as a highly specific tumor antigen and a potential oncogene that relies on the transcriptional activity of EWS-FLI1 in Ewing sarcoma. LIPI (Lipase member I (EC:3.1.1.-) is an evolutionarily conserved protein predicted to poses a transmembrane domain and extracellular lipid hydrolase domain. The biological function of LIPI is not known but the enzymatic activity of LIPI is expected to produce lysophosphatidic acid (LPA) that potently affects several biological functions including proliferation, cell survival, and metastasis of tumor cells. We hypothesize that the LIPI is a unique biomarker and an oncogene that is expressed exclusively in Ewing sarcoma and is a potential target for cell based therapy. To our knowledge, this proposal represents the first study evaluating the role of LIPI in cellular physiology and in particular Ewing sarcoma progression and metastasis. The two specific aims of the projects are: Specific Aim 1: To elucidate the regulation and role of cell surface LIPI in Ewing sarcoma Specific Aim 2: To investigate the role of LIPI in Ewing sarcoma growth/metastasis. Following the successful completion of the proposed aims in this application, we will have evaluated the potential of LIPI as a Ewing sarcoma specific surface oncoprotein, and will have a long-term impact by establishing the strong foundation for the development of LIPI-directed immunotherapeutics against Ewing sarcoma.

项目摘要 致癌融合转录因子EWS驱动的儿童和年轻人转移性尤文肉瘤- FLI 1的结果仍然很差。使用T细胞、NK细胞、癌症疫苗和 单克隆抗体被考虑用于尤文肉瘤，特别是用于复发患者。的 鉴定免疫系统识别的人肿瘤相关抗原（TAA）对于 免疫疗法。通过整合尤文肉瘤细胞系基因表达、ChIP-seq以及正常和 癌症组织基因表达的基因型-组织表达（GTEx），和TCGA项目，我们有 LIPI是一种高度特异性的肿瘤抗原，也是一种依赖于转录活性的潜在致癌基因 EWS-FLI 1在尤文肉瘤中的表达。LIPI（脂肪酶成员I（EC：3.1.1.-）是一种进化上保守的蛋白质 预测其构成跨膜结构域和胞外脂质水解酶结构域。的生物学功能 LIPI是未知的，但预期LIPI的酶活性产生溶血磷脂酸（LPA）， 有效地影响几种生物学功能，包括肿瘤细胞的增殖、细胞存活和转移。 我们假设LIPI是一种独特的生物标志物，也是一种只在尤文氏细胞中表达的癌基因。 肉瘤，并且是基于细胞的治疗的潜在靶点。据我们所知，这项建议是第一个 一项评价LIPI在细胞生理学，特别是尤文肉瘤进展中作用的研究， 转移这些项目的两个具体目标是： 具体目的1：阐明尤文肉瘤细胞表面LIPI的调控及其作用 具体目标2：研究LIPI在尤文肉瘤生长/转移中的作用。 在成功完成本申请中提出的目标后，我们将评估 LIPI作为尤文肉瘤特异性表面癌蛋白，并将通过建立 为开发针对尤文肉瘤的LIPI导向的免疫治疗剂奠定了坚实的基础。