Optimizing Ultrasound Enhanced Delivery of Therapeutics

优化超声增强治疗的输送

• 批准号: 9337418
• 负责人: Flemming Forsberg
• 金额: $ 62.44万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-25 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9337418
• 关键词: Academic Medical Centers; Acoustics; Address; Adjuvant; Animals; Biodistribution; Biological; Cancer Etiology; Cell Line; Cessation of life; Clinic; Clinical; Clinical Trials; Contrast Media; Custom; Data; Development; Diagnostic; Disease; Drug Delivery Systems; Eastern Cooperative Oncology Group; Effectiveness; Enrollment; Environment; Equipment; Excision; Goals; Human; Image Enhancement; Immunohistochemistry; In Vitro; Industrialization; Institutes; Israel; Lead; Leadership; Liver; Malignant neoplasm of pancreas; Mediating; Medical; Methodology; Methods; Microbubbles; Monitor; Multi-Institutional Clinical Trial; Operative Surgical Procedures; Organ; Outcome; Pancreas; Pancreatic Adenocarcinoma; Pancreatic Ductal Adenocarcinoma; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Pharmacotherapy; Pre-Clinical Model; Protocols documentation; Publishing; Radiation; Research; Research Personnel; Solid Neoplasm; Survival Rate; System; Systemic Therapy; Techniques; Technology; Therapeutic; Translating; Tumor Volume; Ultrasonography; United States; Universities; University Hospitals; Unresectable; Woman; X-Ray Computed Tomography; base; cancer diagnosis; chemotherapy; clinical investigation; clinical practice; clinically translatable; contrast enhanced; design; human study; image-guided drug delivery; imaging modality; imaging platform; improved; improved outcome; innovation; men; mouse model; multidisciplinary; new therapeutic target; novel; pre-clinical research; programs; quantitative imaging; quantitative ultrasound; standard of care; tool; treatment response

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.

抽象的 胰腺癌是美国第三大常见癌症，超过 2013 年新增病例 43,000 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并没有显着改善。 过去 30 多年的坏疽性口炎 (PDAC) 患者。为此，有一个相当大且紧迫的任务 临床需要制定有效药物输送和治疗监测的创新策略，重新 从而改善 PDAC 患者的预后。我们的建议旨在开发对比度增强 超声介导的图像引导药物输送（CEUS-IGDD）就是这种方法，并将其转化为 实验室到诊所。具体任务旨在提高对控制的理解和方法 并监测该 IGDD 平台，最初的临床重点是提高标准的有效性 用于治疗无法手术的 PDAC 的化疗药物。 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 因此，我们解决关键障碍的战略联合了一个跨学科的学术团队 以及来自 GE 全球研究院 (GE)、豪克兰大学医院和英国大学的工业研究人员 卑尔根（统称：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 将开发工具和方法来确定最佳条件（声学状态、气泡类型） 以最少的诊断范围声能应用实现最大的药物输送。目标2利用两个com- 使用人 MIA PaCa-2luc (Bergen) 和 PANC-1 (TJU) 细胞系。 CEUS-IGDD 的功效将使用生物分布数据和定量数据进行评估 用于监测治疗反应的滴定成像方法预计中位生存期至少为 5 与接受治疗的动物相比，治疗组的中位肿瘤体积减少了 50% 单独用药。该提案的主要重点是目标 3，即一项为期三年的多中心临床试验 滚动一百二十 (120) 名患有转移性或局部晚期且无法手术切除的患者 PDAC 将在 TJU 和卑尔根进行。所有患者都将接受标准护理化疗， 一半接受辅助 CEUS-IGDD。将通过定量超声比较患者的结果： 评估、CT 成像（包括 RECIST 标准、ECOG 分级和免疫组织化学）来评估局部 无进展生存期和总生存期，主要终点是增加化疗的数量 与对照组相比，IGDD 组的治疗周期延长了 75%。