Prevention and treatment of brain micrometastases of breast cancer

描述(由申请人提供)：脑转移对患有晚期转移性疾病的妇女来说是一个严重的问题。脑转移率在过去10年中显著增加，在转移性乳腺癌患者中接近或超过35%，特别是那些Her2+或三阴性肿瘤患者。在诊断出多个转移灶后，患者通常会在一到两年内死亡。GAP：脑转移瘤的治疗主要是姑息治疗，因为放疗、外科手术的疗效有限，而且通过血脑屏障(BBB)的化疗效果不佳。这项建议侧重于使用临床前模型预防脑内转移、播种和初始生长。假设：通过降低转移癌细胞进入大脑的效率，增加早期微转移灶的药物输送和疗效，我们将减少大的转移灶的发展，并改善神经功能和总体生存。目的1：证明转移性乳腺癌细胞的脑侵袭可以在血脑屏障水平上被抑制：初步数据表明，在体内，抑制转化生长因子-�可以在血脑屏障水平上降低三重阴性的人转移性乳腺癌细胞的脑侵袭力~70-80%。这项工作被扩展到表征转化生长因子-�抑制如何减少血脑屏障细胞侵袭的机制，以及Her2+在血脑屏障侵袭中所起的作用。目的：阐明血-肿瘤屏障通透性改变与乳腺癌脑微转移的化疗摄取和疗效之间的因果关系：初步数据显示，大多数乳腺癌脑内微转移灶(直径500�m)表现出显著的转移血管结构和功能改变，包括血管选择性、血管密度降低、通透性增强和血管内皮生长因子表达增加。为此，将完成对微转移瘤血脑屏障变化的研究，目的是确定微转移瘤的选择性差异，如血管内皮生长因子和Notch，这些差异可用于靶向治疗。目的3：开发调节血脑屏障通透性的新策略，以提高脑微转移治疗的疗效：初步数据显示，在血管内皮生长因子存在的情况下，在大小脑转移瘤中抑制血管内皮细胞Notch信号会导致血脑屏障通透性的靶向性增加。为了达到这个目的，在三种临床前肿瘤模型中，我们利用靶向渗透性的增加来改善化疗药物的传递、细胞毒作用和总体存活率。影响：这项建议的目标是开发新的方法来减少乳腺癌细胞对脑的侵袭，调节血脑屏障通透性，并改善对中枢神经系统转移的化疗摄取，总体目的是减少脑转移相关的死亡。这项工作需要最先进的细胞靶向、血脑屏障渗透性和药物分配方法，以将选定的小肿瘤的屏障变化与整体脑转移侵袭和生长联系起来。

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.