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.

内容和摘要 HCC是世界上最常见的癌症之一，估计每年有60万人死亡。 在过去的25年中，HCC的发病率在美国有所增加， HCC的死亡率预计在未来10至20年内将翻一番。增加的发病率 HCC的高死亡率加剧了这一问题。肝癌患者的总体5年生存率 美国约为16%，使HCC成为仅次于胰腺癌的最致命的癌症类型。 尽管它的重要性，肝癌是研究不足相比，其他主要的致命癌症，因此，我们的研究， 与疾病的发生、进展和临床相关的遗传或表观遗传改变的知识 HCC的预后仍不完整。此外，只有有限的治疗选择， 只有不到三分之一的HCC患者有资格接受潜在的治愈性治疗， 切除、移植或经皮消融。索拉非尼，一种具有抗血管生成作用的多激酶抑制剂 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 晚期HCC的标准治疗。然而，不幸的是，索拉非尼治疗的益处似乎 总生存期仅延长2.8个月，缓解率仅为2%， 迫切需要新的靶向药物或寻找新的方法来克服索拉非尼的耐药性。 通过分析人类HCC的蛋白质组和基因组数据，我们发现了三种分子和 临床上不同的HCC蛋白质组亚型。整合蛋白质组数据和基因组数据进行分析 进一步表明PEA15在HCC基因组中高度扩增，并且其扩增和表达与HCC基因组中的表达相关。 与预后不良显著相关。它的扩增并不局限于肝癌，如在膀胱中扩增 癌症、肺癌和乳腺癌。我们证明PEA15在绝大多数的肿瘤细胞中上调， 肝癌细胞系，它是必不可少的肝癌细胞的增殖和生存。我们进一步证明， PEA15促进癌症的侵袭。我们的研究还表明，PEA15高表达的HCC细胞， 负责血管生成。 在这项研究中，我们的目标是（1）确定PEA15在HCC发展中的作用。(2)确定 PEA15在血管生成中的作用。(3)确定PEA15是否是治疗以下疾病的良好治疗靶点： HCC。如果成功，这将为开发新的治疗方法开辟新的机会。 预后不良的HCC患者。此外，从这项研究中获得的知识可以用于其他领域。 PEA15高度扩增的癌症类型（即膀胱癌、肺癌和乳腺癌）， 与生存有关。