An Inducible Swine Hepatocellular Carcinoma Platform for Enhanced Therapeutic Development

项目总结 肝细胞癌是一种全球性的健康负担，排在第四位和第二位 世界上最致命的癌症。肝癌的有效治疗策略是有限的，尤其是在晚期。 由于肿瘤的异质性，潜在的患者并存，以及缺乏已确定的疾病生物标志物 管理层。晚期疾病的总体存活率只有5%-14%，这表明改进的治疗方法 需要的。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程序。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。这些模式的缺点给 识别目标生物标记物，开发设备和成像技术，药物治疗，以及 活检和手术的技术，所有这些都是改善肝细胞癌患者预后所必需的。要创建 这个平台的临床前试验将转化为肝癌管理领域的创新，我们拥有 开发了利用体细胞基因编辑在小型猪的肝脏中诱导肝癌的方法。我们的迷你小猪平台 是治疗开发的理想选择，因为小型猪的大小、生理、解剖和新陈代谢密切相关 与人类有亲缘关系。此外，肝功能、节段解剖、胆管树和肝血管 与人类明显相似。到目前为止，我们已经证明了这种方法在开发实体肝方面的可行性。 在肝细胞癌患者中发现的具有诱导分子变化的快速和可重复性的肿瘤。在这项提案中，我们 目的通过改进我们的肝细胞癌小型猪模型，促进我们的肝细胞癌平台在精准医学创新中的应用 重述人类肝细胞癌最常见亚型的分子表型。我们将进行 一项以全身治疗为标准的药物研究，以确定我们的猪模型是否有反应 与人类患者相当。这些目标的实现将有助于验证我们的新型微型猪平台，以及 赛格威进入未来研究(1)评估分子靶向治疗、药物传递的安全性和有效性 设备，以及肿瘤栓塞、消融和冷冻治疗技术，(2)开发新的成像技术 方法，(3)研究肿瘤的发生过程；(4)寻找早期诊断和治疗的生物标志物。 治疗策略。小型猪肝细胞癌平台将为肝细胞癌带来创新的方法，翻译结果 临床前研究通过提高临床试验成功率来改善临床患者的结果，成本- 有效和省时的方式。在第二阶段的工作中，这些模型将在以下背景下进行细化和开发 相关的合并症，如潜在的肝病，并在类似临床试验的情况下得到验证，作为 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.