An Inducible Swine Hepatocellular Carcinoma Platform for Enhanced Therapeutic Development

项目摘要 肝细胞癌（HCC）是全球第四大最常见的健康负担， 世界上最致命的癌症肝癌的有效治疗策略有限，尤其是在晚期 由于肿瘤异质性、潜在的患者合并症以及缺乏确定的疾病生物标志物， 管理晚期疾病的总生存率仅为5- 14%，这表明改进的治疗是可行的。 needed.从历史上看，啮齿动物一直是主要的临床前模型，但这些研究的结果 没有转化为成功的人类应用。这些模型和其他模型的局限性包括 肿瘤发生的遗传和分子机制，免疫和肿瘤微环境的不一致， 在大小、解剖学和生理学上有显著差异。这些模式的缺陷造成了障碍， 识别可靶向的生物标志物，开发设备和成像技术，药物治疗，以及 活检和手术技术，所有这些都是必要的，以改善肝癌患者的结果。创建 一个平台，其临床前测试将转化为HCC管理这些领域的创新，我们有 开发了使用体细胞基因编辑在小型猪肝脏中诱导HCC的方法。我们的迷你猪平台 是治疗开发的理想选择，因为小型猪的大小、生理学、解剖学和代谢密切相关， 与人类有关。此外，肝功能、节段解剖、胆管树和肝血管系统是 与人类非常相似。到目前为止，我们已经证明了这种方法在开发固体肝脏方面的可行性 在HCC患者中鉴定出诱导的分子变化，在本提案中，我们 我们的目标是通过改进我们的HCC迷你猪模型，推进我们的HCC平台用于精准医学创新 以概括最常见的人HCC亚型的特异性分子表型。我们会进行 使用标准全身治疗索拉非尼的药物研究，以确定我们的猪模型是否有反应 对人类病人来说。这些目标的实现将有助于验证我们新颖的迷你猪平台， 赛格威进入未来的研究（1）评估分子靶向治疗的安全性和有效性，药物输送 器械和肿瘤栓塞、消融和冷冻技术，（2）开发新的成像技术 方法，（3）研究肿瘤发生的过程，以及（4）鉴定用于早期诊断的生物标志物， 治疗策略迷你猪HCC平台将为HCC带来创新方法，转化结果 临床前研究，通过提高临床试验的成功率来改善临床患者的结局， 有效和高效的方式。在第二阶段的工作中，这些模型将根据 相关合并症，如基础肝病，并在临床试验样情况下验证为 商业化的概念。

PROJECT SUMMARY Hepatocellular carcinoma (HCC) is a global health burden ranking as the fourth most common and second deadliest cancer in the world. Effective therapeutic strategies for HCC, especially at advanced stages, are limited due to tumor heterogeneity, underlying patient comorbidities, and lack of identified biomarkers for disease management. Overall survival rates for advanced disease are just 5-14%, indicating that improved therapies are needed. Historically, rodents have served as the predominant preclinical model, but results in these studies have not translated to successful human application. Limitations of these and other models include variations in the genetic and molecular mechanisms of tumorigenesis, inconsistencies in immunity and tumor microenvironments, and marked differences in size, anatomy, and physiology. Shortcomings of these models create barriers to identifying targetable biomarkers, developing device and imaging technologies, pharmaceutical treatments, and techniques for biopsy and surgery, all of which are necessary to improve outcomes for HCC patients. To create a platform whose preclinical testing will translate to innovation in these fields of HCC management, we have developed methods to induce HCC in the liver of minipigs using somatic cell gene editing. Our minipig platform is ideal for therapeutic development as the size, physiology, anatomy, and metabolism of minipigs are closely related to humans. Moreover, liver function, segmental anatomy, biliary tree, and hepatic vasculature are markedly similar to humans. To date, we have proven the feasibility of this approach in developing solid liver tumors rapidly and reproducibly with induced molecular changes identified in HCC patients. In this proposal, we aim to advance our HCC platform for use in precision medicine innovation by refining our HCC minipig models to recapitulate the molecular phenotype specific to the most common subtype of human HCC. We will conduct a drug study with the standard of care systemic therapy, sorafenib, to determine if our swine model responds comparably to human patients. Achievement of these aims will help validate our novel minipig platform, and segway into future studies (1) evaluating the safety and efficacy of molecularly targeted therapies, drug delivery devices, and tumor embolization, ablation, and cryotherapeutic technologies, (2) developing novel imaging methods, (3) studying processes of tumorigenesis, and (4) identifying biomarkers for early diagnosis and therapeutic strategies. The minipig HCC platform will bring innovative approaches to HCC, translating results preclinical studies to improved patient outcomes in the clinic by bolstering clinical trial success rates in a cost- effective and time-efficient manner. In Phase II work, these models will be refined and developed in the context of relevant co-morbidities such as underlying liver disease and validated in clinical trial-like scenarios as proof of concept for commercialization.