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

项目总结： 胰腺癌约占美国所有癌症的3%，约 占所有癌症相关死亡人数的7%。迫切需要新的治疗模式。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。这项提议将重点放在组织碎石术上，这是第一个完全非侵入性、非热疗、 而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。组织摩擦是一种通过精确控制来破坏组织的超声消融方法。 声空化可以选择性地摧毁肿瘤组织，同时保留目标内的关键结构 管风琴。这种方法最初显示出了显著的前景，但从未在胰腺中进行过评估。到目前为止， 缺乏临床和生理上相关的临床前胰腺癌模型是一个重要的 限制治疗策略的发展，包括组织诊断学。为了绕过这一限制，我们的 研究小组开发了一种新的免疫缺陷猪模型(RAG2/IL2RG)，该模型适用于人类肿瘤 异种移植研究，我们将适应研究胰腺癌的原位。 这项建议的目标是发展一种非侵入性、非热敏性和图像引导的组织诊断学 原位消融治疗胰腺肿瘤的方法。在这里，我们将植入人胰腺肿瘤细胞 (Panc01)进入我们独特的免疫缺陷猪胰腺的特定区域，以产生临床前动物 胰腺癌模型优于目前可用的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改进和优化我们的组织摩擦学治疗策略。 我们的主要假设是组织学可以实现安全和选择性的胰腺肿瘤消融。 不会引起意想不到的临床副作用。具体目标1将制定组织摩擦学治疗策略 以达到高度靶向的胰腺切除。这一目标将检验这样一种假设，即一种组织尿道学治疗 可以制定策略来实现安全和选择性的胰腺组织消融。的长期安全性 关键结构附近的胰腺组织的组织化学消融也将在这一目标中进行评估。具体目标2 将利用组织摩擦学来切除原位猪胰腺癌模型中的肿瘤。这一目标将 验证组织摩擦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显著显示 与健康人相比，肿瘤微环境的机械特性和独特变化 可显著影响治疗策略的组织，最好在大型哺乳动物身上进行原位评估 模特。这项工作意义重大，因为它可以改变与胰腺癌和 为研究界提供一种新的治疗策略评估模式。

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.