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：
10063980
负责人：
PAUL B FISHER
金额：
$ 50.45万
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/10063980
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/antagonist innovation insight 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)，第五大常见癌症，也是第二大常见原因全球范围内与癌症相关的死亡人数较多，目前尚无针对晚期疾病的有效治疗方法。目前的建议重点关注两个相互作用的癌基因 AEG-1 和 MDA-9，促进 HCC 的发生和进展。我们过去十年的研究已经证实 AEG-1 是一种真正的癌基因 HCC 和我们开发了靶向纳米复合物递送 AEG-1 siRNA (PAMAM- AEG-1si) 显着抑制裸鼠原位人类 HCC 异种移植物。我们现在记录一下 MDA-9在人类HCC患者中过度表达且MDA-9在调节侵袭中发挥重要作用以及 HCC 细胞诱导的血管生成。 TCGA 数据库分析揭示 AEG-1 和 MDA-9 基因在人类 HCC 患者中共同扩增。我们在细胞中发现了 AEG-1 和 MDA-9 之间的新相互作用人类肝癌细胞膜，并证明它们合作促进肝癌。我们现在有开发了一种新型特异性MDA-9小分子抑制剂（PDZ1i），表现出优异的PK和ADME 特性，显着减少人肝癌细胞的侵袭，并显着抑制人肝癌异种移植与索拉非尼联合使用，索拉非尼是 FDA 批准的用于治疗不可切除的 HCC 的药物。 PDZ1i 还显示对 AEG-1 被敲除的人 HCC 细胞异种移植物的生长具有额外的抑制作用出去。本提案的长期目标是开发有效的 HCC 靶向疗法，将为 HCC 患者带来显着的生存获益。我们当前的目标是严格评估 PDZ1i 和 PAMAM-AEG-1si 以及 PDZ1i 和索拉非尼联合治疗免疫功能正常 HCC 小鼠模型，并破译 AEG-1 和 MDA-9 合作的分子机制促进肝癌。所有这些组件都是创新的，具有很高的机械性和转化性意义。索拉非尼常规用于 HCC 治疗，并且索拉非尼和 PDZ1i 联合使用，如果在我们提出的动物模型中被证明是成功的，有可能在以下方面进行快速评估 I/II 期临床试验。对于 AEG-1 siRNA，我们专门选择了纳米颗粒递送系统已获得 FDA 批准，并注意到 RNAi 疗法在当前 HCC 临床中显示出希望试验，期望 PDZ1i 和 PAMAM-AEG-1si 的结果得到有效和快速的转化组合疗法进行实践。我们的研究的成功完成有望建立一个晚期 HCC 的有效治疗方案将有助于显着延长数十例患者的生命肝癌患者。