Deploying Histotripsy Based Tumor Ablation Strategies to Treat Pancreatic Cancer

项目摘要：胰腺癌约占美国所有癌症的3% 约占所有与癌症相关的死亡人数的7%。迫切需要新的治疗模式。新兴肿瘤 消融技术在临床和临床前癌症研究中都显示出巨大的前景。这项建议 将重点放在组织摩擦学上，这是第一个非侵入性、非电离、非热疗、图像引导的肿瘤消融术 一种通过精确控制声空化来摧毁肿瘤的方式，能够克服 目前正在为这种恶性肿瘤开发的其他肿瘤消融方式的许多局限性。 最近，我们的研究小组完成了概念验证研究，证明组织试验在 靶向胰腺并产生持续、快速和完全的消融，即使在接近危急的情况下也是如此 结构。有趣的是，我们的团队和其他人的研究也表明，组织旅行在诱导 全身抗肿瘤反应，导致局部和转移部位的治疗后肿瘤消退。 然而，对这一现象的确切机制和控制水平仍不清楚。这样做的目的是 建议利用我们的临床前小鼠和新的猪动物模型来扩展初步数据 在此建议书中提出，以生成支持未来发展所需的关键机械、安全和功效数据 胰腺癌患者的临床试验。我们最重要的假设是，组织试验可以实现安全和 选择性局部消融治疗胰腺肿瘤，改善全身抗肿瘤免疫反应。特定的 目的1：为精确、完整的胰腺肿瘤切除确定组织学治疗参数。 我们的初步数据证明了胰腺组织电切术的总体可行性。这一目标将 检验组织学可以实现精确、有效和完全切除胰腺肿瘤的假设 不损伤重要结构，如大血管、胆管和肠道。特定目标2： 建立胰腺癌的组织学治疗策略，以优化肿瘤消融和 全身性抗肿瘤免疫反应。这一目标将检验组织试验是一种有效的 体内精确、完整的胰腺肿瘤消融术的治疗方法。我们还假设，由于 独特的组织学特征，局部肿瘤消融可产生可预测和可调节的全身性抗肿瘤宿主 免疫反应，减少转移负担，防止复发。具体目标3：定义组织旅行 利用生理和临床相关的治疗参数并确定其安全性 猪胰腺癌模型。猪在解剖学、体型和体型等方面更接近人类病人 仪器刻度。这一目标将检验组织摩擦学参数可以被有效地建立的假设 在生理和临床相关的原位条件下消融原位胰腺肿瘤。 意义：本提案中概述的研究将证明组织尿路感染的安全性和有效性 并将为临床转化为人类患者提供必要的关键数据。

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. Emerging 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 non-invasive, non-ionizing, non-thermal, image-guided tumor ablation modality that destroys tumors through the precise control of acoustic cavitation and is capable of overcoming many of the limitations of the other tumor ablation modalities currently under development for this malignancy. Recently, our research team completed proof-of-concept studies demonstrating that histotripsy is effective at targeting the pancreas and produces consistent, fast, and complete ablations, even in proximity to critical structures. Intriguingly, work by our team and others has also shown that histotripsy is effective in inducing systemic anti-tumor responses, resulting in post-treatment tumor regression both locally and at metastatic sites. However, the exact mechanism and level of control of this phenomenon is still unclear. The objective of this proposal is to utilize our pre-clinical mouse and novel pig animal models to expand upon the preliminary data presented in this proposal to generate critical mechanistic, safety, and efficacy data necessary to support future clinical trials in pancreatic cancer patients. Our overarching hypothesis is that histotripsy can achieve safe and selective focal ablation of pancreatic tumors and improve systemic anti-tumor immune responses. SPECIFIC AIM 1: Determine histotripsy treatment parameters for precise and complete pancreatic tumor ablation. Our preliminary data demonstrates the general feasibility of histotripsy ablation in the pancreas. This Aim will test the hypothesis that histotripsy can achieve precise, efficient, and complete ablation of pancreatic tumors without injuring critical structures, such as major blood vessels, bile ducts, and intestines. SPECIFIC AIM 2: Establish histotripsy treatment strategies for pancreatic cancer that optimize tumor ablation and systemic anti-tumor immune responses. This Aim will test the hypothesis that histotripsy is an effective treatment modality for precise and complete pancreatic tumor ablation in vivo. We also postulate that due to the unique features of histotripsy, focal tumor ablation results in predictable and tunable systemic anti-tumor host immune responses reducing metastatic burden and preventing recurrence. SPECIFIC AIM 3: Define histotripsy treatment parameters and determine its safety profile utilizing physiologically and clinically relevant porcine models of pancreatic cancer. Pigs better mimic human patients in terms of anatomy, size, and instrument scale. This Aim will test the hypothesis that histotripsy parameters can be established to effectively ablate orthotopic pancreatic tumors under physiologically and clinically relevant in situ conditions. SIGNIFICANCE: The studies outlined in this proposal will demonstrate the safety and efficacy of histotripsy for pancreatic cancer ablation and will provide critical data necessary for clinical translation to human patients.