Optimizing Ultrasound Enhanced Delivery of Therapeutics

摘要 胰腺癌是美国第三大最常见的癌症， 2013年新增病例4.3万例。它是男性和女性癌症相关死亡的第四大原因。 尽管如此，胰腺导管腺癌的生存率没有显著提高， 在过去的30多年里，坏疽性口炎（PDAC）患者。因此，有一个相当大的和紧迫的 临床需要制定有效的药物输送和治疗监测的创新策略， 从而改善PDAC患者的预后。我们的建议旨在开发对比度增强的 超声介导的图像引导药物递送（CEUS-IGDD）是这种方法，并将其从 从实验室到诊所具体任务旨在提高对控制的理解和方法 和监测这个IGDD平台，最初的临床重点是提高标准的有效性， 用于治疗不能手术的PDAC的化学治疗剂。 从本质上讲，这个项目构成了一个多学科的挑战（技术，生物，物理和生物）。 医学），我们的战略，以解决关键障碍，因此团结了一个跨学科的学术团队 以及来自通用电气全球研究院（GE）、豪克兰大学医院（Haukeland University Hospital）和 卑尔根（合：卑尔根）、托马斯杰斐逊大学（TJU）和拉什大学医学中心， 以色列理工学院和葛兰素史克（GSK）的努力更为有限。 目标1将开发工具和方法，以确定最佳条件（声学状态，气泡类型）， 最大化药物输送，最小化诊断范围声能的应用。Aim 2利用两个COM- 补充建立的胰腺癌小鼠模型，使用人MIA PaCa-2luc（卑尔根）和 PANC-1（TJU）细胞系。将使用生物分布数据和定量分析评价CEUS-IGDD的疗效。 用于监测治疗反应的定量成像方法，预期中位生存期至少为5 治疗组的中位肿瘤体积减少50%， 药物单独该提案的主要重点是目标3，其中一项为期三年的多中心临床试验， 对120例转移性或局部晚期和手术不可切除的患者进行了研究 PDAC将在TJU和卑尔根进行。所有患者将接受标准化疗， 一半接受CEUS-IGDD。将通过定量超声比较患者结局， 评估、CT成像（包括RECIST标准）、ECOG分级和免疫组织化学，以评估局部 无进展生存期和总生存期，主要终点是增加化疗次数， IGDD组治疗周期比对照组减少75%。

Abstract Pancreatic cancer is the third most common cancer diagnosed in the United States, with more than 43,000 new cases in 2013. It is the fourth leading cause of cancer-related death in both men and women. Nonetheless, there has been no significant improvement in survival for pancreatic ductal adenocarci- noma (PDAC) patients over the past 30+ years. For this reason, there is a considerable and urgent clinical need to develop innovative strategies for effective drug delivery and treatment monitoring, re- sulting in improved outcomes for patients with PDAC. Our proposal aims at developing contrast-enhanced ultrasound-mediated image-guided drug delivery (CEUS-IGDD) to be that methodology and to translate it from the lab to the clinic. The specific tasks are designed to improve the understanding and methodology for control and monitoring of this IGDD platform, with an initial clinical focus on enhancing the effectiveness of standard chemotherapeutics for treatment of inoperable PDAC. Inherently this project constitutes a multidisciplinary challenge (technological, biological, physical, and medical), and our strategy to address the critical barriers therefore unites an interdisciplinary team of academic and industrial investigators from GE Global Research (GE), Haukeland University Hospital and University of Bergen (together: Bergen), Thomas Jefferson University (TJU), and Rush University Medical Center with more limited efforts by the Israel Institute of Technology and GlaxoSmithKline (GSK). Aim 1 will develop tools and methods to ascertain optimal conditions (acoustic regime, bubble type) for maximum drug delivery with minimal application of diagnostic-range acoustic energy. Aim 2 utilizes two com- plementary established pancreatic adenocarcinoma mouse models, using human MIA PaCa-2luc (Bergen) and PANC-1 (TJU) cell lines. The efficacy of CEUS-IGDD will be evaluated using biodistribution data and quan- titative imaging methods to monitor treatment response expecting a greater median survival of at least 5 days and a median tumor volume reduction of 50% in the treated group compared to animals receiving drug alone. The main focus of this proposal is Aim 3, where a three year, multi-center clinical trial en- rolling one hundred and twenty (120) patients with metastatic or locally advanced and surgically unresectable PDAC will be conducted at TJU and Bergen. All patients will undergo standard of care chemotherapy, with one-half receiving adjunctive CEUS-IGDD. Patient outcomes will be compared by quantitative ultrasound as- sessment, CT imaging including RECIST criteria, ECOG grade, and immunohistochemistry to assess local progression-free and overall survival with the main endpoint being to increase the number of chemo- therapy cycles by 75% in the IGDD group relative to controls.