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

摘要 在美国，肝细胞癌是导致癌症死亡的第九大原因，约有 每年新诊断肝癌病例3万例。肝癌对以下人群的影响不成比例 种族/少数民族人口，包括亚裔美国人、拉丁裔美国人、美洲原住民和非洲裔美国人。 针对溶瘤腺病毒(OA)的CD46(分化簇46)代表着一种有前途的新的 治疗平台，鉴于其低血清阳性率和CD46在肝细胞癌中的高表达，以及 操纵骨性关节炎基因组。CGAS-STING途径代表着主要的免疫机制 中和DNA病毒，包括OAS。我建议开发和临床前评估 重组溶瘤腺病毒在治疗中提高肿瘤选择性的效力 肝细胞癌。提高载体的效力将通过靶向和抑制 CGAS刺痛途径。该项目的核心原则本质上是非常高的回报，如果成功， 这一潜力不仅对肝癌研究产生深远影响，而且具有广泛的应用前景 关于可以使用溶瘤载体的其他癌症的新疗法。拟议的研究 和职业发展计划将提供额外的培训和指导，以 使我成为溶瘤病毒治疗领域的一名独立研究员 晚期肝癌。它还将提供大量的初步研究，作为 R01申请将在K01奖项的最后一年提交。

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.