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.

当超声脉冲与循环微泡剂结合时， 血脑屏障（BBB）被诱导，持续数小时。当这个过程与超- 声音设备，可以准确和安全地集中超声波束通过完整的头骨，有很大的 作为一种完全非侵入性和有针对性的方法将药物输送到大脑的潜力。许多动物 研究表明，这种方法不会对大脑造成任何重大损害，而且还可以- 增加肿瘤血管的通透性。虽然这项技术有潜力广泛的大脑 我们认为，该方法的初步试验可能会在脑肿瘤中进行。脑转移，用于 可能已经存在在脑外有效的药物，可能是临床测试的一个很好的靶点。 功效这个项目的目的是在我们开始临床试验之前进行必要的研究， BBB和血肿瘤屏障破坏对脑肿瘤中靶向药物递送的功效。我们的目标 准备好测试这项技术在乳腺癌脑转移患者中的疗效，我们有太多的- 我很喜欢围绕这个应用程序的研究。我们将进行三项研究来评估安全性和有效性- 聚焦超声诱导的血脑屏障破坏的可能性，我们将在临床试验中遇到的情况下。第一、 我们将评估目前批准的两种药物治疗HER 2阳性乳腺癌的相对疗效， 癌症，曲妥珠单抗（赫赛汀（R））和拉帕替尼（Tykerb（R））。接下来，我们将评估安全性和有效性 在放射治疗后诱导脑和脑肿瘤中的血脑屏障破坏， 在病人身上遇到的。最后，我们将测试重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- 所有这些问题都需要在开始临床试验之前解决。在拨款结束时，我们希望得到数据， 有必要开始临床试验的有效性，这种有前途的图像引导靶向药物输送 法 相关性（参见说明）; 由血脑屏障、肿瘤血管的有限渗透性和 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，当与微泡剂相结合时，提供了一种非侵入性的方法， 这些屏障并将有效剂量的药物输送到大脑和脑肿瘤。在这里，我们将执行 在我们开始临床试验评估这种方法的有效性之前，还需要做一些工作。