An Inducible Swine Hepatocellular Carcinoma Platform for Enhanced Therapeutic Development

用于增强治疗开发的诱导猪肝细胞癌平台

基本信息

批准号：
10758109
负责人：
Derek Matthew Korpela
金额：
$ 34.22万
依托单位：
RECOMBINETICS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10758109
关键词：
Ablation Acceleration Achievement Address Anatomy Animal Model Animals Autopsy BAY 54-9085 Biological Markers Biopsy CRISPR/Cas technology Cirrhosis Clinic Clinical Clinical Trials DNA Sequence Alteration DNA sequencing Data Development Devices Diagnosis Diagnostic Disease Disease Management Drug Delivery Systems Early Diagnosis Enrollment Etiology Excision Failure Family suidae Fibrosis Future Genes Genetic Genetic Induction Hepatic Histopathology Human Image Imaging technology Immunity Immunologics Injections Intervention Knock-out Life Liver Liver diseases Liver neoplasms Malignant Neoplasms Malignant neoplasm of liver Measurement Medical Device Metabolism Methods Miniature Swine Modeling Molecular Molecular Profiling Monitor Nature Oncogenes Operative Surgical Procedures Outcome Pathologic Pathology Patient-Focused Outcomes Patients Pharmaceutical Preparations Pharmacologic Substance Phase Physiological Physiology Pre-Clinical Model Preclinical Testing Primary Malignant Neoplasm of Liver Primary carcinoma of the liver cells Process Radiation therapy Recurrence Refractory Reproducibility Research Personnel Risk Rodent Safety Solid Stage at Diagnosis Steatohepatitis Survival Rate Systemic Therapy Techniques Technology Testing Therapeutic Therapeutic Embolization Time Translating Transplantation Surgery Tumor Burden Tumor Suppressor Genes Tumor Tissue Unresectable Variant Virus Diseases Work advanced disease beta catenin biliary tract biomarker identification biomarker validation cancer diagnosis chemotherapy clinically relevant commercialization comorbidity cost effective effective therapy global health imaging modality improved improved outcome innovation liver cancer model liver function molecular modeling molecular phenotype molecular subtypes molecular targeted therapies mortality novel optimal treatments overexpression palliative patient population patient subsets pharmacokinetics and pharmacodynamics porcine model precision medicine preclinical study prevent response somatic cell gene editing specific biomarkers standard of care success targeted treatment therapeutic development therapeutic evaluation therapeutically effective tool tumor tumor heterogeneity tumor microenvironment tumorigenesis two-arm study ultrasound

项目摘要

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.

项目摘要肝细胞癌（HCC）是全球健康负担，排名第四，第二个最常见和第二个世界上最致命的癌症。 HCC的有效治疗策略，尤其是在高级阶段，有限由于肿瘤异质性，基本的患者合并症以及缺乏疾病的生物标志物管理。晚期疾病的总生存率仅为5-14％，表明改善的疗法是需要。从历史上看，啮齿动物一直是主要的临床前模型，但在这些研究中的结果已有未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，大小，解剖学和生理学上有明显的差异。这些模型的缺点为识别有针对性的生物标志物，开发设备和成像技术，药物处理以及活检和手术的技术，所有这些都是为了改善HCC患者的预后所必需的。创建一个平台，其临床前测试将转化为HCC管理领域的创新，我们有开发了使用体细胞基因编辑在微型植物中诱导肝脏中HCC的方法。我们的Minipig平台非常适合治疗发育，因为Minipig的大小，生理，解剖学和代谢非常紧密与人类有关。此外，肝功能，分段解剖学，胆道树和肝脉管系统是与人类明显相似。迄今为止，我们已经证明了这种方法在发展固体肝脏中的可行性肿瘤在HCC患者中鉴定出诱导的分子变化迅速而可重复。在这个建议中，我们旨在通过完善我们的HCC Minipig模型来推动我们的HCC平台用于精密医学创新概括特定于人类HCC最常见亚型的分子表型。我们将进行使用护理标准的全身治疗标准的药物研究索拉非尼，以确定我们的猪模型是否反应与人类患者相比。实现这些目标将有助于验证我们的新颖Minipig平台，并且 Segway进入未来的研究（1）评估分子靶向疗法的安全性和功效，药物输送设备和肿瘤栓塞，消融和冷冻治疗技术，（2）开发新型成像方法，（3）研究肿瘤发生过程，以及（4）识别生物标志物的早期诊断和治疗策略。 Minipig HCC平台将为HCC带来创新的方法，转化结果临床前研究通过加强成本的临床试验成功率来改善诊所的患者结局有效且效率的方式。在第二阶段的工作中，这些模型将在上下文中进行完善和开发相关的合并症，例如潜在的肝病，并在类似临床试验的情况下进行了验证作为证明商业化的概念。