Ultrasound-enhanced drug penetration for treatment of pancreatic cancer

超声增强药物渗透治疗胰腺癌

基本信息

批准号：
10198853
负责人：
JOO HA HWANG
金额：
$ 54.36万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-01 至 2023-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10198853
关键词：
Abdomen Acute Affect Algorithms Animal Model Animals Area Cancer Etiology Characteristics Clinical Clinical Treatment Clinical Trials Conduct Clinical Trials DNA Sequence Alteration Desmoplastic Development Devices Doxorubicin Elements Family suidae Focused Ultrasound Therapy Frequencies Genetically Engineered Mouse Grant Guidelines Hemorrhage Histologic Histopathology Human Image Investigation KPC model Knowledge Link Malignant Neoplasms Malignant neoplasm of pancreas Maps Measurement Mechanics Modeling Monitor Office Visits Pancreas Pancreatic Ductal Adenocarcinoma Patients Penetration Perfusion Pharmaceutical Preparations Physiologic pulse Procedures Protocols documentation Public Health Reporting Resectable Safety Series Survival Rate Symptoms System Techniques Therapeutic Time Tissues Transducers Translating Translational Research Treatment Protocols Ultrasonic Transducer Ultrasonography United States Work Xenograft procedure base blood perfusion chemotherapy clinical application clinical translation design detector gemcitabine image guided imaging probe improved in vivo innovation mortality new technology novel pancreatic cancer model pancreatic cancer patients pancreatic neoplasm preclinical evaluation pressure research clinical testing response safety and feasibility safety assessment standard of care subcutaneous therapeutically effective tissue injury treatment duration tumor

项目摘要

PROJECT SUMMARY Pancreas cancer is the fourth leading cause of cancer mortality in the United States, with very few effective therapeutic options. The median survival rate for resectable tumors is only 2 years, and systemic chemotherapy with gemcitabine only offers a modest survival benefit. The main characteristic of pancreas tumors that makes chemotherapy treatment difficult is the extensive stromal desmoplasia, which decreases blood perfusion, increases the intratumoral pressure and impedes the delivery of chemotherapy. Disrupting the stromal barrier would both increase perfusion and permeabilize the tumor, enhancing penetration of chemotherapy. In our initial grant period we successfully demonstrated that mechanical disruption of the stroma using pulsed high intensity focused ultrasound (pHIFU)-induced cavitation resulted in enhanced penetration of doxorubicin by up to 4.5-fold. These results were obtained in an in vivo genetically engineered mouse model (KPC mouse) of pancreatic ductal adenocarcinoma, using an optimized ultrasound-guided pHIFU small animal treatment system. The KPC model, unlike xenograft or subcutaneous models, closely recapitulates the genetic mutations, clinical symptoms and histopathology found in human pancreatic cancer. These results are readily translatable to patient treatment. In this renewal application we propose to evaluate the tumor response and survival of KPC mice treated with pHIFU and systemic administration of gemcitabine. We will then develop a new ultrasound-guided pHIFU clinical system that incorporates Bubble Doppler imaging algorithms to enable monitoring of pHIFU therapy. The system will be designed, fabricated and characterized following FDA guidelines. The main paradigm shift compared to the small animal studies is the design of ultrasound transducers that produce less focused, lower frequency (sub-MHz) HIFU beams that affect larger tissue areas and may have a different physical mechanism of cavitation nucleation compared to high- frequency, highly focused transducers used previously. We hypothesize that this change will: 1) shorten treatment duration; 2) provide deeper penetration depth; 3) allow the use of lower pHIFU pressure amplitudes and therefore improve safety. The other major innovation of this proposal is the further development of a unique cavitation mapping technique, discovered by our group during the initial grant period and termed Bubble Doppler, which enables ultrasound-based monitoring of pHIFU therapy in real-time. We will complete preclinical evaluation of the feasibility and safety of pHIFU treatments using Bubble Doppler monitoring in porcine pancreas in a series of acute and short term survival studies. In parallel, a clinical trial using this therapy device will be designed. All relevant reports will be compiled to apply for an investigational device exemption (IDE) to US FDA to conduct a clinical trial in patients with pancreatic cancer.

项目摘要胰腺癌是美国癌症死亡率的第四个主要原因，很少有效治疗选择。可切除肿瘤的中位生存率仅为2年，并且是全身性的吉西他滨化学疗法仅具有适中的生存优势。胰腺肿瘤的主要特征使化学疗法的治疗变得困难的是广泛的基质脱木质，可降低血液灌注，增加肿瘤内压力并阻碍化疗的递送。破坏基质障碍物既会增加灌注并透化肿瘤，从而增强化学疗法的穿透性。在我们的初始授予期我们成功证明了使用脉冲高的基质的机械破坏强度聚焦超声（PHIFU）诱导的空化导致阿霉素通过上升增强至4.5倍。这些结果是在体内基因工程小鼠模型（KPC小鼠）中获得的胰腺导管腺癌，使用优化的超声引导的PHIFU小动物治疗系统。与异种移植或皮下模型不同，KPC模型紧密地概括了遗传突变，临床在人胰腺癌中发现的症状和组织病理学。这些结果很容易翻译成患者治疗。在此续签应用中，我们建议评估KPC小鼠的肿瘤反应和存活率用PHIFU和吉西他滨的全身给药治疗。然后，我们将开发新的超声引导 PHIFU临床系统结合了气泡多普勒成像算法以启用PHIFU的监测治疗。该系统将按照FDA指南进行设计，制造和表征。主要范式与小型动物研究相比，转移的是超声传感器的设计，这些换能器的专注较少，较低的频率（sub-mHz）HIFU光束会影响较大的组织区域，并且可能具有不同的物理与以前使用的高频率的高频相比，气核成核的机理。我们假设这种变化将：1）缩短治疗持续时间； 2）提供更深的渗透深度； 3）允许使用较低的PHIFU压力振幅，从而提高安全性。另一个主要创新该提议是我们小组发现的独特空化映射技术的进一步发展在最初的赠款期间并称为气泡多普勒，可以对PHIFU进行超声监测实时治疗。我们将完成PHIFU处理的可行性和安全性的临床前评估在一系列急性和短期生存研究中，使用猪胰腺中的气泡多普勒监测。在并行，将设计使用该疗法装置的临床试验。所有相关报告将被编译以申请为了向美国FDA进行研究设备豁免（IDE），以对胰腺患者进行临床试验癌症。