Employing Novel Porcine Models of Orthotopic Pancreatic Cancer to Evaluate Histotripsy Based Tumor Ablation Strategies

采用新型猪原位胰腺癌模型来评估基于组织解剖的肿瘤消融策略

• 批准号: 9807506
• 负责人: Irving C Allen
• 金额: $ 19.43万
• 依托单位: VIRGINIA POLYTECHNIC INST AND ST UNIV
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9807506
• 关键词: Ablation; Acoustics; Animal Model; Animals; Blood Vessels; Caliber; Carcinoma in Situ; Cell Transplantation; Cell Transplants; Cessation of life; Clinical; Clinical Trials; Communities; Connective Tissue; Cryosurgery; Diagnosis; Disease; Duct (organ) structure; Electroporation; Evaluation; Excision; Family suidae; Feedback; Focused Ultrasound Therapy; Future; Gnotobiotic; Housing; Human; IL2RG gene; Image; Implant; In Situ; Injections; Institution; Location; Malignant Neoplasms; Malignant neoplasm of pancreas; Mammals; Mechanics; Methods; Modeling; Neoplasm Metastasis; Nodule; Normal tissue morphology; Operative Surgical Procedures; Organ; Pancreas; Pathogenesis; Patients; Physiological; Pre-Clinical Model; Property; Recurrence; Research; Rodent Model; Safety; Shapes; Structure; Survival Rate; Techniques; Technology; Testing; Therapeutic; Thermal Ablation Therapy; Time; Tissues; Tumor Tissue; Ultrasonography; United States; Work; Xenograft procedure; base; cancer type; clinical translation; experimental study; fight against; image guided; in vivo; mechanical properties; member; microwave electromagnetic radiation; novel; novel therapeutic intervention; outcome forecast; pancreatic cancer cells; pancreatic cancer model; pancreatic cancer patients; pancreatic neoplasm; pre-clinical; preservation; radio frequency; real-time images; side effect; therapeutic development; treatment optimization; treatment strategy; tumor; tumor ablation; tumor microenvironment; tumor progression; tumor xenograft

PROJECT SUMMARY: Pancreatic cancer accounts for approximately 3% of all cancers in the United States and approximately 7% of all cancer related deaths. New treatment paradigms are direly needed. Among the emerging treatment strategies, advances in tumor ablation techniques have shown significant promise in both clinical and pre-clinical cancer studies. This proposal will focus on histotripsy, which is the first completely non-invasive, non-thermal, and non-ionizing ablation method capable of overcoming many of the limitations of the majority of other tumor ablation strategies. Histotripsy is an ultrasound ablation method that destroys tissue through the precise control of acoustic cavitation that can selectively destroy tumor tissue while preserving critical structures within the target organ. This method has shown significant initial promise, but has never been evaluated in the pancreas. To date, the lack of clinically and physiologically relevant pre-clinical pancreatic cancer models has been a significant limitation to the development of therapeutic strategies, including histotripsy. To circumvent this limitation, our research team has developed a novel immunodeficient pig model (RAG2/IL2RG) that is ideal for human tumor xenograft studies that we will adapt to study pancreatic cancer in situ. The objective of this proposal is to develop histotripsy as a non-invasive, non-thermal, and image-guided ablation method for in situ ablation of pancreatic tumors. Here, we will implant human pancreatic tumor cells (Panc01) into specific regions of the pancreas of our unique immunodeficient pigs to generate pre-clinical animal models of pancreatic cancer that are superior to any of the current state-of-the-art animal models available to study this disease. We will then use these animals to refine and optimize our histotripsy treatment strategies. Our overarching hypothesis is that histotripsy can achieve safe and selective ablation of pancreatic tumors without inducing unwnanted clinical side effects. Specific Aim 1 will develop a histotripsy treatment strategy for achieving highly targeted pancreas ablation. This Aim will test the hypothesis that a histotripsy treatment strategy can be developed to achieve safe and selective ablation of pancreatic tissue. The long-term safety of histotripsy ablation of pancreas tissue near critical structures will also be evaluated in this Aim. Specific Aim 2 will utilize histotripsy to ablate tumors in an orthotopic porcine model of pancreatic cancer. This Aim will test the hypothesis that histotripsy is capable of selectively imaging and treating orthotopic pancreatic tumors in our unique porcine models. Here, we believe that the orthotopic pancreatic tumor will demonstrate significantly altered mechanical properties and unique changes in the tumor microenvironment compared to the healthy tissue that can significantly impact treatment strategies, which are best evaluated in situ in a large mammal model. This work is significant as it could shift treatment paradigms associated with pancreatic cancer and provide the research community with a new model for therapeutic strategy evaluation.

项目概要： 在美国，胰腺癌约占所有癌症的 3% 占所有癌症相关死亡的 7%。迫切需要新的治疗范例。在新兴的治疗方法中 策略，肿瘤消融技术的进步在临床和临床前都显示出巨大的前景 癌症研究。该提案将重点关注组织解剖学，这是第一个完全非侵入性、非热、 和非电离消融方法能够克服大多数其他肿瘤的许多局限性 消融策略。组织切断术是一种通过精确控制破坏组织的超声消融方法 声空化可以选择性地破坏肿瘤组织，同时保留目标内的关键结构 器官。这种方法已显示出显着的初步前景，但从未在胰腺中进行过评估。迄今为止， 缺乏临床和生理相关的临床前胰腺癌模型是一个重要的问题 限制了治疗策略的发展，包括组织解剖学。为了规避这个限制，我们的 研究团队开发出一种新型免疫缺陷猪模型（RAG2/IL2RG），非常适合人类肿瘤 我们将采用异种移植研究来研究原位胰腺癌。 该提案的目标是将组织解剖学发展为一种非侵入性、非热力和图像引导的方法 用于原位消融胰腺肿瘤的消融方法。在这里，我们将植入人类胰腺肿瘤细胞 (Panc01) 进入我们独特的免疫缺陷猪的胰腺的特定区域，以产生临床前动物 胰腺癌模型优于目前任何最先进的动物模型 研究这种疾病。然后我们将使用这些动物来完善和优化我们的组织解剖治疗策略。 我们的首要假设是组织解剖学可以实现胰腺肿瘤的安全和选择性消融 不会引起不必要的临床副作用。具体目标 1 将制定组织解剖治疗策略 以实现高度针对性的胰腺消融。该目标将检验以下假设：组织解剖治疗 可以制定策略来实现胰腺组织的安全和选择性消融。的长期安全性 该目标还将评估关键结构附近胰腺组织的组织解剖消融。具体目标2 将利用组织解剖学消融原位猪胰腺癌模型中的肿瘤。这个目标将 检验组织解剖学能够选择性地成像和治疗原位胰腺肿瘤的假设 我们独特的猪模型。在这里，我们相信原位胰腺肿瘤将表现出显着的 与健康的相比，改变了机械性能和肿瘤微环境的独特变化 可以显着影响治疗策略的组织，最好在大型哺乳动物中进行原位评估 模型。这项工作意义重大，因为它可以改变与胰腺癌相关的治疗模式 为研究界提供治疗策略评估的新模型。