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.

当超声波爆发与循环微泡剂结合时，会暂时破坏 血脑屏障（BBB）被诱导，持续数小时。此过程与超 声音设备可以准确、安全地通过完整的头骨聚焦超声波束，具有很大的优势 作为一种完全无创且有针对性的向大脑输送药物的方法的潜力。众多的动物 研究表明，这种方法不会对大脑产生任何重大损害，而且还可以- 增加肿瘤血管的通透性。虽然这项技术具有广泛的大脑潜力 疾病，我们认为该方法的初步测试可能会在脑肿瘤中进行。脑转移瘤，对于 可能已经存在对脑外有效的药物，可能是临床测试的一个很好的目标 功效。该项目旨在进行必要的研究，然后我们才能开始临床试验来测试 BBB 和血肿瘤屏障破坏对脑肿瘤靶向药物输送的功效。我们的目标是 准备好测试这项技术对乳腺癌脑转移患者的疗效，我们有 喜欢围绕该应用程序的研究。我们将进行三项研究来评估安全性和有效性- 我们在临床试验中会遇到的情况下，聚焦超声会引起血脑屏障破坏。第一的， 我们将评估目前批准的两种药物治疗 HER2 阳性乳腺的相对疗效 癌症、曲妥珠单抗 (Herceptin(R)) 和拉帕替尼 (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 BBB 破坏，这是我们预期的情况 遇到患者。最后，我们将测试反复破坏大量卷的安全性 使用临床 MRI 引导的经颅聚焦超声系统对非人类灵长类动物的大脑进行研究。这些是—— 所有诉讼都需要在启动临床试验之前得到解决。在资助结束时，我们期望获得数据 有必要开始对这种有前途的图像引导靶向药物输送的功效进行临床试验 方法。 相关性（参见说明）； 血脑屏障、肿瘤血管通透性有限导致药物输送无效， 其他因素被认为是导致乳腺癌脑转移患者预后不良的原因。 聚焦超声波与微泡剂结合使用，提供了一种非侵入性的绕过方法 这些屏障并向大脑和脑肿瘤输送有效剂量的药物。在这里我们将执行 在我们开始临床试验评估这种方法的功效之前还需要做一些工作。