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.

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%。迫切需要新的治疗模式。新发肿瘤 消融技术在临床和临床前癌症研究中都显示出显著的前景。这项建议 将专注于组织摧毁术，这是第一种非侵入性，非电离，非热，图像引导的肿瘤消融术 一种通过精确控制声空化来破坏肿瘤的方式， 目前正在开发的用于这种恶性肿瘤的其他肿瘤消融方式的许多局限性。 最近，我们的研究团队完成了概念验证研究，证明组织摧毁术在 靶向胰腺，并产生一致、快速和完全的消融，即使在接近关键的 结构.有趣的是，我们的团队和其他人的工作也表明，组织摧毁术在诱导 全身性抗肿瘤反应，导致局部和转移部位的治疗后肿瘤消退。 然而，这一现象的确切机制和控制水平仍不清楚。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 本提案中提出了生成支持未来研究所需的关键机制、安全性和有效性数据的建议。 胰腺癌患者的临床试验。我们的首要假设是组织摧毁术可以实现安全且 胰腺肿瘤的选择性局部消融和改善全身抗肿瘤免疫应答。具体 目的1：确定精确和完整的胰腺肿瘤消融的组织摧毁治疗参数。 我们的初步数据证明了胰腺组织破坏消融术的一般可行性。这一目标将 检验组织摧毁术可以实现胰腺肿瘤精确、有效和完全消融的假设 而不损伤关键结构，例如主要血管、胆管和肠。具体目标2： 建立胰腺癌的组织摧毁治疗策略，优化肿瘤消融， 全身性抗肿瘤免疫应答。该目的将检验组织破坏术是有效的 精确和完整的胰腺肿瘤体内消融治疗模式。我们还假设，由于 组织摧毁术的独特功能，局灶性肿瘤消融导致可预测和可调的全身抗肿瘤宿主 免疫应答降低转移负荷和预防复发。具体目标3：定义组织摧毁术 治疗参数，并利用生理学和临床相关信息确定其安全性 胰腺癌的猪模型。猪在解剖结构、大小和 仪表刻度该目的将检验假设，即可以建立组织破坏参数，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。 重要性：本提案中概述的研究将证明组织破坏术用于 胰腺癌消融，并将提供临床转化为人类患者所需的关键数据。

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