Deploying Histotripsy Based Tumor Ablation Strategies to Treat Pancreatic Cancer

部署基于组织解剖学的肿瘤消融策略来治疗胰腺癌

• 批准号: 10612053
• 负责人: Irving C Allen
• 金额: $ 45.71万
• 依托单位: VIRGINIA POLYTECHNIC INST AND ST UNIV
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-01 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10612053
• 关键词: Ablation; Acoustics; Aftercare; Anatomy; Animal Model; Antitumor Response; Blood Vessels; Cancer cell line; Cessation of life; Chemotherapy and/or radiation; Clinical; Clinical Trials; Complication; Data; Development; Diagnosis; Diameter; Disease; Dose; Duct (organ) structure; Electroporation; Family suidae; Feedback; Focused Ultrasound Therapy; Future; Human; Immune response; Immunocompetent; Immunocompromised Host; In Situ; Injury; Intestines; Location; Malignant Neoplasms; Malignant neoplasm of pancreas; Mechanics; Methods; Modality; Modeling; Mus; Nodule; Pancreas; Pancreatic duct; Pancreatitis; Patients; Physiological; Pre-Clinical Model; Prognosis; Pulse Pressure; Recurrence; Research; Risk; Rupture; Safety; Shapes; Site; Stenosis; Structure; Survival Rate; Techniques; Testing; Therapeutic; Time; Tissues; Transducers; Treatment Protocols; United States; Unresectable; Work; anti-tumor immune response; bile duct; clinical translation; clinically relevant; effective therapy; fighting; image guided; improved; in vivo; instrument; ionization; millimeter; mouse model; novel; novel therapeutic intervention; pancreatic cancer cells; pancreatic cancer model; pancreatic cancer patients; pancreatic neoplasm; patient derived xenograft model; physical property; porcine model; pre-clinical; preservation; prevent; real-time images; response; translation to humans; treatment strategy; tumor; tumor ablation; 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. 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.

项目摘要：在美国，胰腺癌约占所有癌症的 3% 约占所有癌症相关死亡的 7%。迫切需要新的治疗范例。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。这个提议 将专注于组织解剖学，这是第一个非侵入性、非电离、非热、图像引导的肿瘤消融术 通过精确控制声空化来破坏肿瘤的方式，并且能够克服 目前正在针对这种恶性肿瘤开发的其他肿瘤消融方式存在许多局限性。 最近，我们的研究团队完成了概念验证研究，证明组织解剖学在以下方面是有效的： 瞄准胰腺并产生一致、快速和完整的消融，即使在接近危急的情况下也是如此 结构。有趣的是，我们团队和其他人的工作也表明组织解剖学可以有效诱导 全身抗肿瘤反应，导致治疗后局部和转移部位的肿瘤消退。 然而，这种现象的确切机制和控制水平仍不清楚。此举的目的 建议利用我们的临床前小鼠和新型猪动物模型来扩展初步数据 本提案中提出的目的是生成支持未来所需的关键机械、安全性和有效性数据 胰腺癌患者的临床试验。我们的首要假设是组织解剖学可以实现安全和 选择性局部消融胰腺肿瘤并改善全身抗肿瘤免疫反应。具体的 目标 1：确定组织解剖治疗参数，以实现精确、完整的胰腺肿瘤消融。 我们的初步数据证明了胰腺组织解剖消融的一般可行性。这个目标将 检验组织解剖学可以实现胰腺肿瘤精准、高效、彻底消融的假设 不损伤关键结构，如主要血管、胆管和肠道。具体目标 2： 建立胰腺癌的组织解剖治疗策略，优化肿瘤消融和 全身抗肿瘤免疫反应。该目标将检验以下假设：组织解剖学是一种有效的方法。 体内精确、完整胰腺肿瘤消融的治疗方式。我们还假设，由于 组织解剖学的独特特征，局灶性肿瘤消融产生可预测和可调节的全身抗肿瘤宿主 免疫反应减少转移负担并预防复发。具体目标 3：组织解剖学的定义 治疗参数并利用生理和临床相关性确定其安全性 猪胰腺癌模型。猪在解剖结构、体型和功能方面更好地模仿人类患者 仪器刻度。该目标将检验这样的假设：可以建立组织解剖参数以有效地 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解剖学的安全性和有效性 胰腺癌消融，并将为人类患者临床转化提供必要的关键数据。

项目成果

Improved Therapeutic Delivery Targeting Clinically Relevant Orthotopic Human Pancreatic Tumors Engrafted in Immunocompromised Pigs Using Ultrasound-Induced Cavitation: A Pilot Study.

• DOI: 10.3390/pharmaceutics15061585
• 发表时间: 2023-05-24
• 期刊: Pharmaceutics
• 影响因子: 5.4
• 作者: Imran KM;Tintera B;Morrison HA;Tupik JD;Nagai-Singer MA;Ivester H;Council-Troche M;Edwards M;Coutermarsh-Ott S;Byron C;Clark-Deener S;Uh K;Lee K;Boulos P;Rowe C;Coviello C;Allen IC
• 通讯作者: Allen IC

NLRX1 functions as a tumor suppressor in Pan02 pancreatic cancer cells.

• DOI: 10.3389/fonc.2023.1155831
• 发表时间: 2023
• 期刊: Frontiers in oncology
• 影响因子: 4.7