PEA15 IN DEVELOPMENT OF LIVER CANCER AND ITS THERAPEUTIC IMPLICATION

PEA15 在肝癌发展中的作用及其治疗意义

• 批准号: 10329953
• 负责人: Ju-Seog Lee
• 金额: $ 35.06万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-06 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10329953
• 关键词: Ablation; Accounting; Aftercare; Angiogenesis Inhibitors; Antineoplastic Agents; Antisense Oligonucleotides; Apoptosis; Automobile Driving; BAY 54-9085; Biological Assay; Cancer Center; Cancer Etiology; Cell model; Cell physiology; Cessation of life; Clinical; Data; Development; Disease; Disease Pathway; Disease Progression; Down-Regulation; Drug Targeting; Epigenetic Process; Excision; Failure; Gene Expression Profiling; Genetic; Genome; Goals; Growth; HIF1A gene; Incidence; Knowledge; Malignant Epithelial Cell; Malignant Neoplasms; Malignant neoplasm of liver; Malignant neoplasm of lung; Malignant neoplasm of pancreas; Malignant neoplasm of urinary bladder; Mediating; Mediator of activation protein; Mesenchymal; Molecular; Mutagenesis; Oncogenic; Outcome; Pathogenesis; Pathway interactions; Patient Care; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Phase III Clinical Trials; Phenotype; Pilot Projects; Primary carcinoma of the liver cells; Prognosis; Proteins; Proteomics; Public Health; Regulation; Research; Resistance; Role; Survival Rate; Testing; Therapeutic; Time; Transplantation; Treatment Efficacy; United States; VEGFC gene; Virulent; Work; angiogenesis; base; cancer therapy; cancer type; care costs; cell growth; curative treatments; design; drug efficacy; experimental study; genomic data; glucose metabolism; hepatocellular carcinoma cell line; human data; improved; inhibitor; kinase inhibitor; liver development; malignant breast neoplasm; molecular subtypes; mortality; mouse model; novel; novel strategies; novel therapeutic intervention; overexpression; patient derived xenograft model; predictive marker; prognostic; public health relevance; response; standard of care; targeted agent; therapeutic target; therapeutically effective; treatment strategy; tumor; tumor growth

Summary and Abstract HCC is one of the most common cancers worldwide, accounting for an estimated 600,000 deaths annually. The incidence of HCC has increased in the United States over the past 25 years and the incidence of and mortality rate for HCC are expected to double over the next 10 to 20 years. The increased incidence rate is exacerbated by high mortality rate of HCC. The overall five-year survival rates of patients with HCC in the United States are around 16%, making HCC the most lethal cancer type after pancreatic cancer. Despite its importance, HCC is understudied compared to other major lethal cancers, and hence, our knowledge of the genetic or epigenetic alterations associated with the initiation, progression, and clinical outcomes of HCC is still fragmentary. Furthermore, there is only a limited arsenal of treatment options for HCC as less than one-third of patients with HCC are eligible for potentially curative treatments such as resection, transplantation, or percutaneous ablation. Sorafenib, a multi-kinase inhibitor with antiangiogenic and anti-proliferative effects, has been shown to improve survival in these patients, and has become the standard of care in advanced HCC. However, unfortunately, benefit of sorafenib treatment appears to be marginal extending only 2.8 months of overall survival and a dismal response rate of only 2%, highlighting the urgent need for new targeted agents or finding new ways to overcome resistant to sorafenib. By analyzing proteomic and genomic data from human HCC, we uncovered three molecularly and clinically distinct proteomic subtype of HCC. Analysis with integrated proteomic data with genomic data further showed that PEA15 is highly amplified in HCC genome and its amplification and expression are significantly associated with poor prognosis. Its amplification is not limited to HCC as amplified in bladder cancer, lung cancer, and breast cancer. We demonstrated that PEA15 is up-regulated in vast majority of HCC cell lines and it is essential for proliferation and survival of HCC cells. We further demonstrated that PEA15 promotes invasion of cancer. Our study also showed HCC cells with high PEA15 expression is accountable for angiogenesis. In proposed study, we aim to (1) determine roles of PEA15 in HCC developments. (2) determine roles of PEA15 in angiogenesis. (3) determine if PEA15 is good therapeutic targets for treatment of HCC. If successful, this will open up new opportunity for development of novel therapeutic approaches for poor prognostic patients with HCC. Furthermore, knowledge obtained from this study can be used in other cancer type (i.e. bladder cancer, lung cancer, and breast cancer) in which PEA15 is highly amplified and associated with survival.

摘要和摘要 HCC是全球最常见的癌症之一，估计每年有60万人死亡。 在过去25年中，美国的HCC发病率增加了，并且 HCC的死亡率预计将在未来10到20年内翻一番。发病率增加 高死亡率的HCC加剧。 HCC患者的总体五年生存率 美国约为16％，使HCC成为胰腺癌后最致命的癌症类型。 尽管它很重要，但与其他主要的致命癌相比，HCC被研究研究了，因此我们 了解与起始，进展和临床相关的遗传或表观遗传改变 HCC的结果仍然是零散的。此外，只有有限的治疗选择库 HCC不到三分之一的HCC患者有资格进行潜在治疗治疗，例如 切除，移植或经皮消融。索拉非尼，一种具有抗血管生成的多激酶抑制剂 和抗增殖作用已被证明可以提高这些患者的生存率，并已成为 高级HCC的护理标准。但是，不幸的是，索拉非尼治疗的好处似乎是 边际仅延长2.8个月的总生存期，而惨淡的响应率仅为2％ 迫切需要新的目标代理商或寻找新的方法来克服对索拉非尼的抗药性。 通过分析人类HCC的蛋白质组学和基因组数据，我们发现了三个分子和 HCC的临床上不同的蛋白质组学亚型。与基因组数据的集成蛋白质组学数据分析 进一步表明，PEA15在HCC基因组中高度扩增，其扩增和表达是 与预后不良显着相关。它的扩增不仅限于膀胱扩增的HCC 癌症，肺癌和乳腺癌。我们证明了PEA15在绝大多数 HCC细胞系，这对于HCC细胞的增殖和存活至关重要。我们进一步证明了 PEA15促进癌症的入侵。我们的研究还表明，PEA15表达高的HCC细胞是 对血管生成负责。 在拟议的研究中，我们的目标是（1）确定PEA15在HCC开发中的作用。 （2）确定 PEA15在血管生成中的作用。 （3）确定PEA15是否是治疗的良好治疗靶标 HCC。如果成功，这将为开发新型治疗方法开发新的机会 HCC的预后患者不良。此外，从这项研究中获得的知识可用于其他 癌症类型（即膀胱癌，肺癌和乳腺癌），其中PEA15高度扩增，并且 与生存有关。