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

基本信息

批准号：
10554410
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
项目类别：
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/10554410
关键词：
Ablation Accountability 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 Collaborations Data Development Disease Disease Pathway Disease Progression Down-Regulation Drug Targeting Eligibility Determination Epigenetic Process Excision Failure Gene Expression Profiling Genetic Genome Goals Growth HIF1A gene Incidence Invaded 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 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 Proliferating Proteins Proteomics Public Health Regulation Research Resistance Role Survival Rate Testing Therapeutic Time Transplantation Treatment Efficacy United States VEGFC gene Vascular Endothelial Growth Factor C Virulent Work angiogenesis cancer therapy cancer type cell growth cost curative treatments design drug efficacy efficacy evaluation experimental study genomic data glucose metabolism hepatocellular carcinoma cell line human data improved 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 understudied cancer

项目摘要

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.

总结与摘要 HCC 是全世界最常见的癌症之一，估计每年导致 60 万人死亡。过去 25 年来，美国 HCC 的发病率有所增加，并且预计未来 10 至 20 年内，肝癌的死亡率将翻一番。发病率增加 HCC 的高死亡率加剧了这种情况。我国肝癌患者的总体五年生存率美国约为 16%，使 HCC 成为继胰腺癌之后最致命的癌症类型。尽管 HCC 很重要，但与其他主要致命癌症相比，它的研究还不够充分，因此，我们的研究与起始、进展和临床相关的遗传或表观遗传改变的知识 HCC 的结果仍然是零散的。此外，治疗方案的选择也很有限。 HCC，因为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，例如切除、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 的护理标准。然而，不幸的是，索拉非尼治疗的益处似乎是总生存期仅延长 2.8 个月，且缓解率仅为 2%，这凸显了迫切需要新的靶向药物或寻找新的方法来克服对索拉非尼的耐药性。通过分析人类肝癌的蛋白质组和基因组数据，我们发现了三个分子和临床上不同的 HCC 蛋白质组亚型。蛋白质组数据与基因组数据的综合分析进一步表明，PEA15在HCC基因组中高度扩增，其扩增和表达量与不良预后显着相关。它的扩增并不局限于在膀胱中扩增的 HCC 癌症、肺癌和乳腺癌。我们证明 PEA15 在绝大多数 HCC 细胞系，它对于 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。在拟议的研究中，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肝癌。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，从本研究中获得的知识可用于其他领域 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。