Ultrasound-induced blood-brain/tumor barrier disruption in brain metastases

脑转移中超声诱导的血脑/肿瘤屏障破坏

• 批准号: 8506197
• 负责人: Ferenc A Jolesz
• 金额: $ 39.65万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-05 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8506197
• 关键词: Ablation; Animals; Blood; Blood - brain barrier anatomy; Blood Vessels; Brain; Brain Diseases; Brain Neoplasms; Breast Cancer Cell; Caring; Central Nervous System Diseases; Clinical; Clinical Trials; Contrast Media; Cranial Irradiation; Data; Devices; Dose; Drug Delivery Systems; ERBB2 gene; Effectiveness; FDA approved; Focused Ultrasound Therapy; Goals; Grant; Growth; Hour; Image; Instruction; Lead; Life; Magnetic Resonance Imaging; Metastatic malignant neoplasm to brain; Methods; Microbubbles; Modeling; Monoclonal Antibodies; Neoplasm Metastasis; Neoplasms in Vascular Tissue; Outcome; Pathway interactions; Patients; Permeability; Pharmaceutical Preparations; Pharmacotherapy; Procedures; Radiation; Radiation therapy; Rattus; Relapse; Relative (related person); Research; Roche brand of trastuzumab; Safety; Site; System; Techniques; Technology; Testing; Tissues; Tracer; Trastuzumab; Tyrosine Kinase Inhibitor; Ultrasonography; Work; base; chemotherapy; clinical efficacy; comparative efficacy; cranium; efficacy testing; erbB-2 Receptor; expectation; improved; lapatinib; malignant breast neoplasm; nonhuman primate; outcome forecast; patient population; receptor; safety testing; small molecule; sound; tumor

When ultrasound bursts are combined with a circulating microbubble agent, a temporary disruption in the blood-brain barrier (BBB) is induced that lasts for several hours. This procedure, when combined with ultra- sound devices that can accurately and safely focus an ultrasound beam through the intact skull, has a great potential as a completely noninvasive and targeted method to deliver drugs to the brain. Numerous animal studies have shown that this method does not produce any significant damage to the brain and can also in- crease the permeability of tumor blood vessels. While this technology has potential for a wide range of brain disorders, we think it is likely that initial tests of the method will be in brain tumors. Brain metastases, for which there may already exist drugs that are effective outside the brain, may be a good target to test clinical efficacy. This project aims to perform studies that are needed before we can start a clinical trial to test the efficacy of BBB and blood-tumor barrier disruption for targeted drug delivery in brain tumors. We are aiming to be ready to test the efficacy of this technique in breast cancer brain metastases patients, and we have tai- lored the research around that application. We will perform three studies that evaluate safety and effective- ness of focused ultrasound induced BBB disruption under scenarios we will encounter in a clinical trial. First, we will evaluate the relative efficacy of the two currently-approved agents for treating HER2-positive breast cancer, trastuzumab (Herceptin(R)) and lapatinib (Tykerb(R)). Next, we will evaluate the safety and effectiveness of inducing BBB disruption in the brain and in brain tumors after radiation therapy, a scenario that we expect to encounter in patients. Finally, we will test the safety of repeatedly disrupting extensive volumes in the brain in nonhuman primates using a clinical MRI-guided transcranial focused ultrasound system. These is- sues all need to be resolved before initiating clinical trials. At the end of the grant, we expect to have the data necessary to begin clinical trials on the efficacy of this promising image-guided targeted drug delivery method. RELEVANCE (See instructions); Ineffective drug delivery caused by the blood-brain barrier, limited permeability of tumor blood vessels, and other factors are thought to lead to the poor outcomes of patients with breast cancer metastases in the brain. Focused ultrasound, when combined with a microbubble agent, offers a noninvasive method to get around these barriers and deliver effective doses of drugs to the brain and to brain tumors. Here we will perform the work needed before we can begin clinical trials evaluating the efficacy of this method.

当超声爆发与循环微泡剂结合在一起时， 诱导血脑屏障（BBB）持续数小时。此过程与超级 可以准确，可以安全地将超声梁通过完整头骨进行的声音设备，具有很好的 作为一种完全无创和有针对性的方法，可以将药物输送到大脑。许多动物 研究表明，该方法不会对大脑造成任何重大损害，也可能会影响 折痕肿瘤血管的渗透性。虽然这项技术具有广泛的大脑 疾病，我们认为该方法的初始测试可能会在脑肿瘤中进行。脑转移，用于 可能已经存在在大脑外有效的药物，可能是测试临床的好靶点 功效。该项目旨在进行需要进行的研究，然后我们才能开始临床试验以测试 BBB和血肿瘤屏障破坏脑肿瘤中靶向药物的功效。我们的目标 准备测试该技术在乳腺癌脑转移患者中的功效，我们有 涉及该应用程序的研究。我们将进行三项评估安全性和有效的研究 在临床试验中将遇到的情况下，聚焦超声诱发的BBB诱发了中断。第一的， 我们将评估两种当前批准的药物治疗HER2阳性乳房的相对疗效 癌症，曲妥珠单抗（Herceptin（R））和Lapatinib（Tykerb（R））。接下来，我们将评估安全性和有效性 放射治疗后诱导大脑和脑肿瘤中的BBB破坏，我们期望的一种情况 在患者中遇到。最后，我们将测试反复破坏大量卷的安全性 非人类灵长类动物中的大脑使用临床MRI引导的经颅聚焦超声系统。这些是 - SUE所有人都需要在启动临床试验之前解决。在赠款结束时，我们希望拥有数据 开始有关这种有希望的图像引导的靶向药物的疗效的临床试验所必需的 方法。 相关性（请参阅说明）； 由血脑屏障引起的无效药物输送，肿瘤血管的渗透性有限，以及 人们认为其他因素会导致大脑乳腺癌转移患者的结局不佳。 当与微泡剂结合使用时，聚焦超声提供了一种无创的方法来解决 这些障碍并为大脑和脑肿瘤提供有效剂量的药物。在这里，我们将执行 在我们开始评估该方法疗效的临床试验之前，需要的工作。