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.

项目概要 患有由致癌融合转录因子 EWS-驱动的转移性尤文肉瘤的儿童和年轻人 FLI1 的结果仍然不佳。使用 T 细胞、NK 细胞、癌症疫苗和 单克隆抗体正在考虑用于治疗尤文肉瘤，特别是对于复发患者。这 识别被免疫系统识别的人类肿瘤相关抗原（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 通过基因型-组织表达 (GTEx) 和 TCGA 项目，我们可以了解癌症组织基因表达 鉴定 LIPI 是一种高度特异性的肿瘤抗原和依赖于转录活性的潜在癌基因 尤文肉瘤中的 EWS-FLI1。 LIPI（脂肪酶成员 I (EC:3.1.1.-)）是一种进化上保守的蛋白质 预测构成跨膜结构域和细胞外脂质水解酶结构域。的生物学功能 LIPI 尚不清楚，但 LIPI 的酶活性预计会产生溶血磷脂酸 (LPA)， 有效影响多种生物学功能，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和仅在尤文中表达的癌基因 肉瘤，是细胞治疗的潜在靶点。据我们所知，该提案是第一个 研究评估 LIPI 在细胞生理学中的作用，特别是尤文肉瘤进展和 转移。该项目的两个具体目标是： 具体目标1：阐明细胞表面LIPI在尤文肉瘤中的调控和作用 具体目标 2：研究 LIPI 在尤文肉瘤生长/转移中的作用。 成功完成本申请中提出的目标后，我们将评估潜在的 LIPI 作为尤文肉瘤特异性表面癌蛋白，并将通过建立 为针对尤文肉瘤的 LIPI 定向免疫疗法的开发奠定了坚实的基础。