cGAS-STING Pathway Targeting Replicative Adenoviruses with CD46 Tropism and AFP Promoter Conditional Replication Restriction for the Treatment of Hepatocellular Carcinoma

cGAS-STING 通路靶向具有 CD46 趋向性和 AFP 启动子的复制腺病毒条件性复制限制用于治疗肝细胞癌

• 批准号: 10436626
• 负责人: Bolni Marius Nagalo
• 金额: $ 12.83万
• 依托单位: UNIV OF ARKANSAS FOR MED SCIS
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10436626
• 关键词: Ablation; Address; Adenovirus Vector; Adenoviruses; Adult; Affect; African American; Antiviral Agents; Asian Americans; Attenuated; BAY 54-9085; Bacteria; CD46 Antigen; Cancer Etiology; Carcinoma; Cell Line; Cells; Cessation of life; Chemoembolization; Clinical; Cyclic GMP; Cytotoxic Chemotherapy; DNA Viruses; Data; Development; Development Plans; Diagnosis; Elements; Enhancers; Evaluation; Excision; External Beam Radiation Therapy; Fetal Liver; Fiber; Funding; Genes; Genetic Transcription; Genome; Germ Cell Cancers; Glycoproteins; Goals; Host Defense Mechanism; Immune; Immune checkpoint inhibitor; In Vitro; Individual; Internal Ribosome Entry Site; Latino; Lead; Liver; Malignant Epithelial Cell; Malignant Neoplasms; Malignant neoplasm of liver; Membrane Proteins; Mentored Research Scientist Development Award; Mentorship; Minority Groups; Modeling; Native Americans; Nature; Neoplasm Metastasis; Normal Cell; Oncology; Oncolytic; Operative Surgical Procedures; Organoids; Outcome; Pathway interactions; Patients; Peer Review; Plasma; Primary carcinoma of the liver cells; Promoter Regions; Proteins; RNA Viruses; Radioembolization; Recombinants; Regulation; Research; Research Personnel; Safety; Seroprevalences; Stimulator of Interferon Genes; Subgroup; Testing; Tissues; Training; Transgenes; Transplantation; Tropism; United States; United States National Institutes of Health; Viral; Viral Vector; Virotherapy; Yolk Sac; alpha-Fetoproteins; base; carcinogenesis; career development; conditionally replicative adenovirus; curative treatments; cytotoxicity; design; experience; gene therapy; hepatocellular carcinoma cell line; high reward; in vivo evaluation; inhibitor/antagonist; innovation; mortality; novel; novel therapeutic intervention; novel therapeutics; oncolysis; oncolytic adenovirus; oncolytic vector; oncolytic virotherapy; overexpression; patient derived xenograft model; preclinical evaluation; promoter; public health relevance; racial minority; receptor; research and development; skills; tumor; tumor xenograft; vector

ABSTRACT In the United States, hepatocellular carcinoma (HCC) is the ninth leading cause of cancer mortality, with about 30,000 new liver cancer cases diagnosed annually. HCC disproportionately affects individuals from racial/minority populations including Asian Americans, Latinos, Native Americans and African Americans. CD46 (Cluster of differentiation 46) targeting oncolytic adenoviruses (OA) represents a promising novel therapeutic platform, given their low seroprevalence and high expression of CD46 in HCC, and ease of manipulation of OA genomes. The cGAS-STING pathway represents the major immune mechanism for neutralization of DNA viruses, including OAs. I propose the development and pre-clinical evaluation of recombinant oncolytic adenoviruses with increased potency in the setting of tumor selectivity in the treatment of hepatocellular cancer. Increased potency of vectors will be achieved through targeting and inhibiting the cGAS-STING pathway. This central tenet to the project is a very high reward in nature and if successful, has the potential to have a profound impact not only in HCC research but also will have broad application pertaining to novel therapies in other cancers where oncolytic vectors can be used. The proposed research and career development plan enclosed in this application would provide additional training and mentorship to enable me to progress toward becoming an independent investigator in the field of oncolytic virotherapy for advanced liver cancer. It would also provide substantial preliminary research that will serve as the basis for an R01 application to be submitted during the final year of the K01 award.

抽象的 在美国，肝细胞癌（HCC）是癌症死亡的第九大原因，大约有 每年诊断出 30,000 例新肝癌病例。 HCC 不成比例地影响以下人群 种族/少数民族人口，包括亚裔美国人、拉丁美洲人、美洲原住民和非裔美国人。 CD46（分化簇 46）靶向溶瘤腺病毒 (OA) 是一种有前途的新型药物 鉴于其在 HCC 中的低血清阳性率和高 CD46 表达，并且易于 OA 基因组的操作。 cGAS-STING 通路代表了主要的免疫机制 中和 DNA 病毒，包括 OA。我建议开发和临床前评估 重组溶瘤腺病毒在肿瘤选择性治疗中具有增强的效力 肝细胞癌。通过靶向和抑制载体，可以提高载体的效力。 cGAS-STING 途径。该项目的核心原则本质上是一个非常高的回报，如果成功， 不仅对 HCC 研究产生深远影响，而且具有广泛的应用潜力 涉及可以使用溶瘤载体的其他癌症的新疗法。拟议的研究 本申请中包含的职业发展计划将为以下人员提供额外的培训和指导 使我能够成为溶瘤病毒治疗领域的独立研究者 晚期肝癌。它还将提供大量的初步研究，作为后续研究的基础。 R01 申请应在 K01 奖项的最后一年提交。