Novel Targeted Combinatorial Therapy for Hepatocellular Carcinoma

肝细胞癌的新型靶向组合疗法

• 批准号: 10521269
• 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
• 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/10521269
• 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; Invaded; Investigational Therapies; Knock-out; Knockout Mice; Knowledge; Malignant Epithelial Cell; Malignant Neoplasms; Mediating; Membrane; Methodology; Molecular; 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; nano; nanoparticle delivery; novel; overexpression; patient derived xenograft model; small molecule inhibitor; syndecan; targeted treatment; therapeutically effective; trafficking; tumorigenic

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.

肝细胞癌是第五大常见癌症，也是第二大常见病因。 在世界范围内，与癌症相关的死亡人数很多，但对晚期疾病没有有效的治疗方法。目前的建议 关注两个相互作用的癌基因，AEG-1和MDA-9，促进肝细胞癌的发生和发展。 我们在过去十年的研究已经确定，AEG-1是一种真正的致癌基因 我们开发了靶向纳米网络递送AEG-1 siRNA(PAMAM-1)的方法。 AEG-1si)，显著抑制裸鼠原位人肝癌移植瘤。我们现在将其记录下来 丙二醛-9在人肝细胞癌患者中的过度表达及其在侵袭调节中的重要作用 以及肝癌细胞诱导的血管生成。TCGA数据库分析显示AEG-1和MDA-9基因 在人类肝细胞癌患者中共扩增。我们在细胞中发现AEG-1和MDA-9之间的一种新的相互作用 人肝细胞癌细胞膜，并证明它们协同促进肝细胞癌。我们现在有了 开发了一种新型的、特异的MDA-9小分子抑制剂(PDZ1i)，表现出良好的PK和ADME 可显著减少人肝癌细胞的侵袭，并显著抑制人肝癌 异种移植联合索拉非尼，一种FDA批准的治疗不能切除的肝癌的药物。PDZ1i还显示了 AEG-1基因敲除对人肝癌细胞移植瘤生长的附加抑制作用 出去。本提案的长期目标是为肝细胞癌开发有效的靶向治疗方法 将为肝细胞癌患者提供显著的生存益处。我们的近期目标是严格评估 PDZ1i和PAMAM-AEG-1si及PDZ1i和索拉非尼联合治疗免疫活性 小鼠肝癌模型，并破译AEG-1和MDA9协同作用的分子机制(S) 以促进肝细胞癌。所有这些部件都是创新的，具有很高的机械性和平移性 意义。索拉非尼常规用于肝癌的治疗以及索拉非尼和PDZ1i的联合治疗。 在我们建议的动物模型中被证明是成功的，有可能被快速跟踪以在 I/II期临床试验。对于AEG-1 siRNA，我们特别选择了纳米颗粒递送系统 这已经是FDA批准的，并注意到RNAi治疗在当前的肝癌临床上显示出希望 试验，以期有效和快速地翻译PDZ1i和PamAM-AEG-1si的结果 结合疗法来实践。我们研究的成功完成有望建立一个 治疗晚期肝癌的有效治疗方案将有助于显著延长数十名 肝细胞癌患者。