Novel Targeted Combinatorial Therapy for Hepatocellular Carcinoma

肝细胞癌的新型靶向组合疗法

• 批准号: 10737864
• 负责人: PAUL B FISHER
• 金额: $ 6.7万
• 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/10737864
• 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（HCC）是第五大常见癌症和第二大常见病因。 全球癌症相关死亡人数最多，但对晚期疾病尚无有效治疗方法。现时的建议 关注两个相互作用的癌基因AEG-1和MDA-9，促进HCC的发展和进展。 我们在过去十年的研究已经确定AEG-1作为一个真正的癌基因， 我们已经开发了递送AEG-1 siRNA的靶向纳米复合物（PAMAM-1）的方法。 AEG-1 si），其显著抑制裸鼠中的原位人HCC异种移植物。我们现在记录， MDA-9在人HCC患者中过表达，并且MDA-9在调节侵袭中起重要作用 和由HCC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HCC患者中共扩增。我们在细胞中发现了AEG-1和MDA-9之间的一种新的相互作用 人HCC细胞的膜，并证明它们合作促进HCC。我们现在已经 开发了一种新型的、特异性的MDA-9小分子抑制剂（PDZ 1 i），表现出优异的PK和ADME 性质，其显著降低人HCC细胞的侵袭，并显著抑制人HCC 与索拉非尼（一种FDA批准的用于不可切除HCC的药物）组合的异种移植。PDZ 1 i显示 对AEG-1已被敲除的人HCC细胞异种移植物生长的额外抑制作用 出去本提案的长期目标是为HCC开发有效的靶向治疗， 将为HCC患者提供显著的生存益处。我们当前的目标是严格评估 PDZ 1 i和PAMAM-AEG-1 si以及PDZ 1 i和索拉非尼联合疗法在免疫活性中的应用 小鼠肝癌模型，并破译AEG-1和MDA-9合作的分子机制 推广HCC。所有这些组件都是创新的，具有很高的机械和平移 意义索拉非尼常规用于HCC治疗，如果 在我们提出的动物模型中被证明是成功的，有可能被快速跟踪评估， 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 已经被FDA批准，并指出RNAi治疗在目前的HCC临床中显示出希望， 试验，期望PDZ 1 i和PAMAM-AEG-1 si的结果得到有效和快速的转化 组合疗法来实践。成功完成我们的研究有望建立一个 有效的治疗方案，将有助于显着延长生命的分数， HCC患者。