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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.

项目总结