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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要肝母细胞瘤 (HB) 是儿童中最常见的肝癌，其总生存率较差出现血管侵犯的患者 (VI) 接受额外化疗和标准护理治疗。已经开发出手术治疗方法，但尽管采取了这种积极的治疗方法，存活率仍然很高此外，我们小组最近报道，HB 患者存在微血管侵犯（micro-VI）。总体生存率比没有微 VI 的人更差，尽管我们知道 VI 是先兆。多灶性疾病和转移，对于 HB 中发生 VI 的机制知之甚少，也不存在因此，要进一步创造有效的疗法。我们之前的工作确定了 HB 中 VI 的生物标志物和生物学特性。 JAK/STAT3 通路在高危 HB 患者的肿瘤血栓中显着上调 VI. 此外，JAK/STAT3 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，并且在我们的患者来源的细胞系中抑制 STAT3 可抑制 HB 细胞的生长和基于我们和其他人之前的研究的严谨性，我们捕获了具有 VI 表现的 HB 肿瘤。涉及 JAK/STAT3 信号激活的独特表达特征，可以为以下疾病的发展提供信息为了解决这个问题，我们的首要目标（目标 1）是研究蛋白质表达的变化。在原发肿瘤中的 HB 细胞和参与 VI 的细胞之间进行比较，以使用以下方法识别 VI 特异性蛋白质特征：创新的 Phenocycler 分析随后将在一组 FFPE 患者组织中进行验证。新型生物标志物组可识别有 VI 风险的患者，以及未来药物开发的途径目标。然后在目标2中，我们将研究JAK/STAT3在VI中的作用。我们的实验室已经证明JAK/STAT3发挥着重要作用。使癌细胞侵入血液的作用，强调 JAK/STAT3 在 HB 中可能发挥的作用转移和VI。利用功能获得和丧失，我们将证明检测的必要性和充分性。然后我们将测试靶向 JAK/STAT3 通路抑制剂的 STAT3 驱动 HB 肿瘤细胞侵袭的功能。使用我们两个独特的高风险患者衍生异种移植模型作为验证工具进行体外和体内试验。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完成这个项目也将为我的新研究奠定基础。技术并帮助培养我的科学敏锐度，以便我能够作为一名外科医生建立成功的职业生涯- 科学家。