Defining Protein Signature of Vascular Invasion in Hepatoblastoma

项目总结 肝母细胞瘤(HB)是儿童最常见的肝癌，其总体存活率较低。 出现血管侵犯的患者(VI)。标准护理治疗，包括额外的化疗和 手术治疗已经被开发出来，但尽管这种积极的治疗方法，存活率仍然存在。 &lt；50%。此外，我们的小组最近报告了有微血管侵犯(Micro-VI)的乙肝患者有 总体存活率比未使用Micro-VI的患者差。尽管人们认识到VI是 多灶性疾病和转移，对HB中使VI的机制知之甚少，也不存在 任何针对这一疾病机制的靶向治疗。因此，为了创造有效的治疗方法，进一步 了解HB中VI的生物标志物和生物学特性是非常必要的。我们之前的工作确定了 JAK/STAT3通路在高危Hb和HB患者癌栓中显著上调 此外，JAK/STAT3通路的下游靶点在患者来源的异种移植中上调 高危HB的模型，以及我们患者来源的细胞系中STAT3的抑制抑制了HB细胞的生长和 入侵。根据我们和其他人之前的严格研究，我们假设伴有VI的HB肿瘤表现出 涉及JAK/STAT3信号激活的独特表达签名，可以通知 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 在原发肿瘤中的HB细胞和参与VI的那些细胞之间进行比较以识别VI特异的蛋白质信号 创新的苯环分析。然后，该签名将在FFPE患者组织队列中作为一种 新的生物标记物小组，以确定VI的风险患者，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在VI中扮演着 在使癌细胞侵入血液中的作用，强调JAK/STAT3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 STAT3具有驱动HB肿瘤细胞侵袭的功能。然后，我们将测试靶向JAK/STAT3途径抑制剂 使用我们两个独特的高危患者来源的异种移植模型作为验证工具，进行体外和体内实验。已被占用 这些目标加在一起，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 这个项目的完成也将为我的新研究提供一个基础 技术，并帮助发展我的科学敏锐性，这样我就可以建立一个成功的外科医生职业生涯- 科学家。

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.