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

项目概要： 胰腺癌约占美国所有癌症的3%， 7%的癌症相关死亡。迫切需要新的治疗模式。在新兴的治疗方法中， 肿瘤消融技术的进步在临床和临床前都显示出了巨大的前景， 癌症研究。这项建议将集中在组织破坏，这是第一个完全非侵入性，非热， 并且非电离消融方法能够克服大多数其它肿瘤的许多局限性 消融策略组织摧毁术是一种超声消融方法，通过精确控制 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.这种方法已经显示出显着的初步承诺，但从未在胰腺中进行过评估。到目前为止， 临床和生理学相关的临床前胰腺癌模型的缺乏已经是一个显著的问题， 限制了治疗策略的发展，包括组织摧毁术。为了规避这一限制， 一个研究小组开发了一种新的免疫缺陷猪模型（RAG 2/IL 2 RG），该模型是人类肿瘤的理想模型。 异种移植研究，我们将适应原位研究胰腺癌。 该提案的目的是发展组织摧毁术作为一种非侵入性，非热，和图像引导 用于胰腺肿瘤的原位消融的消融方法。在这里，我们将植入人类胰腺肿瘤细胞 （Panc 01）植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 胰腺癌模型上级任何现有技术的动物模型， 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摧毁治疗策略。 我们的总体假设是，组织摧毁术可以实现安全和选择性消融胰腺肿瘤 而不会引起不希望的临床副作用。具体目标1将制定组织摧毁治疗策略 用于实现高度靶向的胰腺消融。该目的将检验组织破坏治疗 可以开发策略以实现胰腺组织安全和选择性消融。的长期安全性 在本目标中，还将评价关键结构附近胰腺组织的组织摧毁术消融。具体目标2 将利用组织摧毁术消融胰腺癌原位猪模型中的肿瘤。这一目标将 检验组织摧毁术能够选择性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示出显著的 与健康人相比，肿瘤微环境的机械特性和独特变化发生改变 可以显著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， 为研究界提供了一种新的治疗策略评估模型。

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.