Prevention and treatment of brain micrometastases of breast cancer

乳腺癌脑微转移的预防和治疗

基本信息

批准号：
8501822
负责人：
Paul R Lockman
金额：
$ 31.33万
依托单位：
TEXAS TECH UNIVERSITY HEALTH SCIS CENTER
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-04-01 至 2013-11-01
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8501822
关键词：
Autopsy Blood Blood - brain barrier anatomy Blood Vessels Brain Breast Cancer Cell Caliber Cancer Patient Cells Cessation of life Data Development Diagnosis Disease Disseminated Malignant Neoplasm Dose Drug Delivery Systems ERBB2 gene Effectiveness Extravasation Goals Growth Human Imaging Techniques Invaded Lesion Life Link Magnetic Resonance Imaging Mammary Neoplasms Metastatic Lesion Metastatic Neoplasm to the Central Nervous System Metastatic malignant neoplasm to brain Methodology Methods Micrometastasis Modeling Multimodal Imaging Neoplasm Metastasis Nervous System Physiology Neuraxis Outcome Patients Penetration Permeability Pharmaceutical Preparations Phosphotransferases Play Pre-Clinical Model Prevention Public Health Radiation Refractory Relapse Research Resistance Role Signal Pathway Signal Transduction Site Stable Disease Structure Testing Therapeutic Transforming Growth Factors Translating Treatment Efficacy Vascular Endothelial Growth Factors Woman Work brain tissue cancer cell chemotherapy cytotoxic cytotoxicity density drug distribution drug efficacy experience gamma secretase improved in vivo inhibitor/antagonist innovation killings malignant breast neoplasm meetings notch protein novel strategies palliative pre-clinical prevent public health relevance receptor research and development response therapeutic target therapy development tumor uptake

项目摘要

DESCRIPTION (provided by applicant): Brain metastases pose a significant problem for women with advanced metastatic diseases. The rate of brain metastasis has increased significantly in the last 10 years, approaching or exceeding 35% in subpopulations of metastatic breast cancer patients, particularly those with Her2+ or "triple-negative" tumors. After diagnosis of multiple metastatic lesions, patients typically die within one to two years. Gap: Treatment of brain metastases is primarily palliative due to limited curative effectiveness of radiation, surger, and poor delivery of chemotherapy across the blood-brain barrier (BBB). This proposal focuses on preventing metastasis seeding and initial growth in brain using preclinical models. Hypothesis: By reducing the efficiency of metastatic cancer cell penetration into brain and increasing drug delivery and efficacy in early micrometastatic lesions, we will decrease large metastases development and improve both neurological function and overall survival. Aim 1: Demonstrate that brain invasion of metastatic breast cancer cells can be inhibited at the level of the BBB: Preliminary data indicate TGF-¿ inhibition reduces brain invasion, at the level of the BBB, of triple negative human metastatic breast cancer cells in vivo ~70-80%. This work is extended to characterize mechanisms of how TGF-¿ inhibition reduces BBB cell invasion and the role Her2+ plays in BBB invasion. Aim 2: Elucidate the causal relationship between blood-tumor barrier permeability changes and chemotherapeutic uptake and effect in brain micrometastases of breast cancer: Preliminary data suggest that, contrary to common assumptions, most micrometastatic lesions (<500 ¿m diameter) of breast cancer in brain show marked changes in metastatic vasculature structure and function, including vessel co- option, reduced vascular density, enhanced permeability, and elevated VEGF expression. In this Aim, work will be completed to characterize BBB changes in micrometastases, with the goal of identifying selective difference in micrometastases, such as VEGF and Notch, which can be used for targeted therapeutic benefit. Aim 3: Develop novel strategies to modulate blood-brain barrier permeability to improve therapeutic efficacy for brain micrometastases treatment: Preliminary data demonstrate that inhibition of vascular endothelial Notch signaling in both large and small brain metastases in the presence of VEGF results in targeted increases in BBB permeability. In this Aim, the targeted increases in permeability are exploited to improve chemotherapy delivery, cytotoxic effect and overall survival in three preclinical tumor models. Impact: The goal of this proposal is to develop novel approaches to reduce breast cancer cell invasion to brain, to modulate BBB permeability and improve chemotherapy uptake into CNS metastases, with an overall purpose to reduce brain metastases related death. The work requires state-of-the-art cell targeting, BBB permeability, and drug distribution methods to link barrier changes in selected small tumors with overall brain metastasis invasion and growth.

描述（由适用提供）：脑转移对患有晚期转移性疾病的女性构成了重大问题。在过去的10年中，脑转移率显着升高，在转移性乳腺癌患者（尤其是患有HER2+或“三阴性”肿瘤的患者）的亚群中接近或超过35％。诊断出多个转移性病变后，患者通常在一到两年内死亡。差距：由于辐射，外科手术和化学疗法在整个血脑屏障（BBB）中的治疗有效性有限，因此脑转移的治疗是主要的姑息治疗。该提案着重于使用临床前模型预防大脑中的转移播种和初始生长。假设：通过降低转移性癌细胞渗透到大脑中的效率，并提高早期微转移病变的药物递送和效率，我们将降低大型转移的发展并提高神经系统功能和整体生存。目的1：证明可以在BBB的水平上抑制转移性乳腺癌细胞的大脑侵袭：初步数据表明TGF-oo抑制可降低BBB水平的脑部侵袭，BBB的水平是三型阴性人类转移性乳腺癌细胞的体内，体内〜70-80％。这项工作扩展到表征TGF- - 抑制如何减少BBB细胞侵袭以及HER2+在BBB侵袭中的作用的机制。 Aim 2: Elucidate the causal relationship between blood-tumor barrier permeability changes and chemotherapeutic uptake and effect in brain micrometastases of breast cancer: Preliminary data suggest that, contrast to common assumptions, most micrometastatic lesions (<500 ¿m diameter) of breast cancer in brain show marked changes in metastatic vasculature structure and function, including vessel co-option, reduced vascular density,增强的渗透性和VEGF表达升高。在此目标中，将完成以表征微型转移中BBB变化的工作，目的是识别微型转移（例如VEGF和Notch）的选择性差异，例如VEGF和Notch，可用于有针对性的治疗益处。目标3：制定新的策略来调节血脑屏障的渗透性，以提高脑微转移治疗的治疗效率：初步数据表明，在BBB渗透率中靶向的VEGF结果的情况下，大型和小脑转移中的血管内皮内皮Notch信号抑制。在此目标中，在三种临床前肿瘤模型中，利用了靶向渗透性的靶向增加，以改善化学疗法的递送，细胞毒性效应和总生存期。影响：该提案的目的是开发新的方法来减少乳腺癌细胞侵入大脑，调节BBB的通透性并改善化学疗法对中枢神经系统转移的摄取，从而总体目的是减少与脑转移相关的死亡。这项工作需要最先进的细胞靶向，BBB渗透性和药物分布方法，以将选定的小肿瘤的屏障变化与整体脑转移和生长联系起来。