Novel Targeted Combinatorial Therapy for Hepatocellular Carcinoma

肝细胞癌的新型靶向组合疗法

基本信息

批准号：
10299601
负责人：
PAUL B FISHER
金额：
$ 49.44万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-12-01 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10299601
关键词：
Animal Model Astrocytes Automobile Driving BAY 54-9085 Binding Proteins Cancer Etiology Cell membrane Cessation of life Clinical Clinical Trials Databases Dependence Development Diethylnitrosamine EGFR Protein Overexpression Epidermal Growth Factor Receptor Evaluation FDA approved Genes Growth Hepatocarcinogenesis Hepatocyte Human Immunocompetent In Vitro Investigational Therapies Knock-out Knockout Mice Knowledge Malignant Epithelial Cell Malignant Neoplasms Mediating Membrane Methodology Molecular Molecular Analysis Monitor Mus Neoplasm Metastasis Nude Mice Oncogenes Oncogenic Pathogenesis Patients Pharmaceutical Preparations Phase I/II Clinical Trial Phenotype Play Pre-Clinical Model Preventive Primary carcinoma of the liver cells Property Proteins Protocols documentation RNA Interference Therapy Research Role Scaffolding Protein Seminal Signal Transduction Small Interfering RNA System Testing The Cancer Genome Atlas Therapeutic Therapeutic Uses Transgenic Mice Transgenic Organisms Translations Treatment Efficacy Unresectable Work Xenograft procedure advanced disease angiogenesis c-myc Genes clinical application combinatorial effective therapy expectation in vivo Model inhibitor innovation insight liver cancer model melanoma mouse model nanoparticle delivery novel overexpression patient derived xenograft model small molecule inhibitor syndecan targeted treatment therapeutically effective trafficking tumorigenic

项目摘要

Hepatocellular carcinoma (HCC), the fifth most common cancer and the second most common cause of cancer-related deaths worldwide, has no effective treatment for advanced disease. The present proposal focuses on two interacting oncogenes, AEG-1 and MDA-9, promoting HCC development and progression. Our studies over the last decade has firmly established that AEG-1 functions as a bona fide oncogene for HCC and we have developed the methodology of targeted nanoplexes delivering AEG-1 siRNA (PAMAM- AEG-1si) that markedly inhibits orthotopic human HCC xenografts in nude mice. We now document that MDA-9 is overexpressed in human HCC patients and MDA-9 plays an important role in regulating invasion and angiogenesis induced by HCC cells. TCGA database analysis reveals that AEG-1 and MDA-9 genes are co-amplified in human HCC patients. We identify a novel interaction between AEG-1 and MDA-9 in cell membrane of human HCC cells and demonstrate that they cooperate to promote HCC. We have now developed a novel, specific small molecule inhibitor of MDA-9 (PDZ1i), displaying excellent PK and ADME properties, which significantly reduces invasion by human HCC cells, and markedly inhibits human HCC xenografts in combination with sorafenib, an FDA-approved drug for unresectable HCC. PDZ1i also shows added inhibitory effect on the growth of xenografts of human HCC cells in which AEG-1 has been knocked out. The long-term objective of the present proposal is to develop effective targeted therapies for HCC that will provide significant survival benefit to HCC patients. Our immediate objective is to stringently evaluate PDZ1i and PAMAM-AEG-1si, and PDZ1i and sorafenib combinatorial therapies in immunocompetent mouse models of HCC, and decipher the molecular mechanism(s) by which AEG-1 and MDA-9 cooperate to promote HCC. All these components are innovative and have high mechanistic and translational significance. Sorafenib is routinely used for HCC treatment and combination of sorafenib and PDZ1i, if proven successful in our proposed animal models, has the potential to be fast-tracked for evaluation in Phase I/II clinical trials. For AEG-1 siRNA we have specifically chosen a nanoparticle delivery system which is already FDA approved, and note that RNAi therapy is showing promise in current HCC clinical trials, in the expectation of effective and rapid translation of results of PDZ1i and PAMAM-AEG-1si combinatorial therapy to practice. Successful completion of our research holds promise for establishing an effective therapeutic protocol for advanced HCC that will help significantly prolong the lives of scores of HCC patients.

肝细胞癌（HCC），第五大常见的癌症，第二大常见的原因全球与癌症相关的死亡没有有效治疗晚期疾病。目前的提议专注于两个相互作用的Oncogenes AEG-1和MDA-9，促进了HCC的发展和进展。在过去的十年中，我们的研究牢固地确定AEG-1是真正的癌基因 HCC和我们已经开发了具有AEG-1 siRNA的靶向纳米旋转的方法（PAMAM- AEG-1SI）明显抑制裸鼠的原位人HCC异种移植物。我们现在记录了 MDA-9在人类HCC患者中过表达，MDA-9在调节入侵中起着重要作用 HCC细胞诱导的血管生成。 TCGA数据库分析表明AEG-1和MDA-9基因在人类HCC患者中共扩散。我们确定了细胞中AEG-1和MDA-9之间的新型相互作用人类HCC细胞的膜并证明它们合作以促进HCC。我们现在有开发了一种新型的MDA-9（PDZ1I）的新型小分子抑制剂，显示出极好的PK和ADME 性质，可显着降低人类HCC细胞的侵袭，并显着抑制人类HCC 异种移植物与索拉非尼（Sorafenib）结合使用，索拉非尼（Sorafenib）是一种无法切除的HCC的FDA批准药物。 PDZ1I也显示对已敲击AEG-1的人类HCC细胞的异种移植物的生长增加了抑制作用出去。本提案的长期目标是为HCC开发有效的靶向疗法将为HCC患者提供显着的生存益处。我们的直接目标是严格评估 PDZ1I和PAMAM-AEG-1SI，PDZ1I和索拉非尼组合疗法 HCC的小鼠模型，并破译了AEG-1和MDA-9合作的分子机制促进HCC。所有这些组件都是创新的，具有高机械和翻译意义。索拉非尼通常将索拉非尼和pdz1i的HCC治疗和组合用于HCC治疗和组合在我们提出的动物模型中被证明是成功的，有可能快速跟踪以进行评估 I/II期临床试验。对于AEG-1 siRNA，我们已特别选择了纳米粒子输送系统这已经获得FDA批准，并注意RNAi疗法在当前的HCC临床中显示出希望试验期望有效，快速地翻译PDZ1I和PAMAM-AEG-1SI的结果组合疗法进行实践。成功完成我们的研究有望建立高级HCC的有效治疗方案，这将有助于大大延长分数的寿命 HCC患者。