Defining Protein Signature of Vascular Invasion in Hepatoblastoma

定义肝母细胞瘤血管侵袭的蛋白质特征

• 批准号: 10606870
• 负责人: Andy Espinoza
• 金额: $ 7.83万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-24 至 2024-10-23
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10606870
• 关键词: Address; Adjuvant Therapy; Area; Basement membrane; Biological Assay; Biological Markers; Biology; Biopsy; Biopsy Specimen; Blood; Blood Vessels; Cancer Center; Cell Line; Cells; Cellular Structures; Child; Cisplatin; Clinical; Clinical Trials; Data; Development; Diagnostic; Disease; Drug Targeting; Epithelium; Exhibits; Formalin; Foundations; Freezing; Future; Gene Expression; Gene Expression Profile; Genes; Growth; Hepatic; Hepatoblastoma; Histologic; Histopathology; IL6 gene; Immunohistochemistry; In Vitro; International; Invaded; Knowledge; Laboratories; Liver neoplasms; Malignant Childhood Neoplasm; Malignant neoplasm of liver; Matrix Metalloproteinases; Measures; Mesenchymal; Molecular; Neoplasm Metastasis; Operative Surgical Procedures; Outcome; Paraffin Embedding; Pathway interactions; Patient-Focused Outcomes; Patients; Phenotype; Pre-Clinical Model; Primary Neoplasm; Proteins; Registries; Relapse; Reporting; Research; Research Technics; Risk; Role; STAT3 gene; Sampling; Scientist; Signal Transduction; Specimen; Standardization; Stromal Cells; Surgeon; Survival Rate; Technology Assessment; Testing; Thrombus; Tissues; Treatment Protocols; Tumor Cell Invasion; Validation; Work; Xenograft Model; Xenograft procedure; aggressive therapy; biomarker panel; biomarker signature; cancer cell; career; cell growth; chemotherapy; cohort; design; disorder risk; drug development; effective therapy; experimental study; fetal; gain of function; genetic signature; high risk; imaging study; improved; improved outcome; in vivo; inhibitor; innovation; knowledge translation; loss of function; migration; mouse model; multiplexed imaging; neoplastic cell; novel; novel marker; patient derived xenograft model; patient stratification; pre-clinical; preclinical study; predictive modeling; predictive signature; prevent; protein expression; risk prediction; risk stratification; specific biomarkers; standard of care; targeted treatment; therapeutic target; tool; transcriptome sequencing; tumor

PROJECT SUMMARY Hepatoblastoma (HB) is the most common liver cancer seen in children and has a poor overall survival in patients that present with vascular invasion (VI). Standard of care treatments with additional chemotherapy and surgical treatment have been developed, but despite this aggressive treatment, the survival rate remains <50%. Furthermore, our group recently reported that HB patients with microvascular invasion (micro-VI) had worse overall survival rates than those without micro-VI. Despite the understanding that VI is the precursor to multifocal disease and metastasis, little is known about the mechanisms that enable VI in HB, nor are there any targeted therapies to address this mechanism of disease. Therefore, to create effective therapies, further understanding of the biomarkers and biology of VI in HB is critically needed. Our prior work identified the JAK/STAT3 pathway as being significantly upregulated in the tumor thrombus of patients with high-risk HB and VI. In addition, downstream targets of the JAK/STAT3 pathway were upregulated in a patient-derived xenograft model of high-risk HB, and STAT3 inhibition in our patient-derived cell lines countered HB cell growth and invasion. Based on the rigor of our and other’s prior research, we hypothesize that HB tumors with VI exhibit unique expression signatures that involve JAK/STAT3 signal activation, which can inform the development of VI-targeted therapies. To address this, our first aim (Aim 1) will be to investigate changes in protein expression between HB cells in the primary tumor and those involved in VI to identify a VI-specific protein signature using innovative Phenocycler analysis. This signature will then be validated in a cohort of FFPE patient tissues as a novel biomarker panel to identify patients at risk for VI, as well as pathway targets for future drug development. Then in Aim 2, we will study the role of JAK/STAT3 in VI. Our laboratory has shown that JAK/STAT3 plays a role in enabling cancer cells to invade the blood, emphasizing the role that JAK/STAT3 may have in HB metastasis and VI. Using gain- and loss-of-function assays, we will prove the necessity and sufficiency of STAT3 function to drive HB tumor cell invasion. We will then test targeted JAK/STAT3 pathway inhibitors in vitro and in vivo using two of our unique high-risk patient derived xenograft models as a validation tool. Taken together, these aims will result in new prediction models and preclinical data to inform future clinical trials for high-risk HB patients with VI. Completion of this project will also provide me with a foundation in novel research techniques and help develop my scientific acumen so that I can build a successful career as a surgeon- scientist.

项目摘要 肝母细胞瘤（HB）是儿童中最常见的肝癌， 有血管侵犯的患者（VI）。标准治疗加化疗， 手术治疗已经发展，但尽管这种积极的治疗，生存率仍然是 <50%。此外，我们的小组最近报告说，HB患者微血管浸润（微VI）， 总体生存率比没有微VI的患者更低。尽管人们认为VI是 由于多灶性疾病和转移，对HB中VI的机制知之甚少， 任何靶向治疗来解决这种疾病的机制。因此，为了创造有效的疗法，进一步 迫切需要了解HB中VI的生物标志物和生物学。我们之前的工作确定了 JAK/STAT 3通路在高风险HB患者的癌栓中显著上调， 六.此外，JAK/STAT 3通路的下游靶点在患者来源的异种移植物中上调。 高风险HB模型，并且我们的患者来源的细胞系中的STAT 3抑制抑制了HB细胞生长， 入侵基于我们和其他人先前研究的严谨性，我们假设伴有VI的HB肿瘤表现出 涉及JAK/STAT 3信号激活的独特表达特征，这可以告知 VI靶向治疗。为了解决这个问题，我们的第一个目标（目标1）将是研究蛋白质表达的变化 在原发性肿瘤中的HB细胞和VI中涉及的HB细胞之间，使用 创新Phenocycler分析。然后，将在FFPE患者组织的队列中验证该签名， 新的生物标志物面板，以确定患者的风险VI，以及未来的药物开发的途径目标。 目的2：研究JAK/STAT 3在VI中的作用。我们的实验室已经表明JAK/STAT 3在细胞内起着重要的作用。 在使癌细胞侵入血液中的作用，强调JAK/STAT 3可能在HB中的作用 转移和VI.使用获得和丧失功能的分析，我们将证明的必要性和充分性， STAT 3功能驱动HB肿瘤细胞侵袭。然后，我们将测试靶向JAK/STAT 3通路抑制剂， 使用我们两种独特的高风险患者来源的异种移植物模型作为验证工具进行体外和体内研究。采取 总之，这些目标将产生新的预测模型和临床前数据，为未来的临床试验提供信息， 高危乙肝患者VI.这个项目的完成也将为我提供一个小说研究的基础 技术和帮助发展我的科学敏锐性，使我能够建立一个成功的职业生涯作为一个外科医生- 科学家