Prevention and treatment of brain micrometastases of breast cancer

描述（由申请人提供）：脑转移对晚期转移性疾病的女性造成了严重的问题。在过去10年中，脑转移率显著增加，在转移性乳腺癌患者亚群中接近或超过35%，特别是那些具有Her 2+或“三阴性”肿瘤的患者。在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：脑转移瘤的治疗主要是姑息性的，这是由于放射、手术的疗效有限，以及化疗药物难以穿过血脑屏障（BBB）。该提案的重点是使用临床前模型预防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脑中的效率并增加药物递送和早期微转移性病变的疗效，我们将减少大转移的发展并改善神经功能和总生存率。目标1：证明转移性乳腺癌细胞的脑侵袭可以在BBB水平被抑制：初步数据表明TGF-β抑制在BBB水平降低了体内三阴性人转移性乳腺癌细胞的脑侵袭~70- 80%。这项工作扩展到表征TGF-β抑制如何减少BBB细胞侵袭的机制以及Her 2+在BBB侵袭中的作用。目标二：阐明乳腺癌脑微转移中血肿瘤屏障通透性变化与化疗药物摄取和效应之间的因果关系：初步数据表明，与常见假设相反，大多数微转移病灶（<500分）直径20 μ m）的脑内乳腺癌的转移性血管结构和功能显示出显著的变化，包括血管共选择，血管密度降低，渗透性增强，VEGF表达升高。在这一目标中，将完成表征微转移中BBB变化的工作，目的是确定微转移中的选择性差异，如VEGF和Notch，可用于靶向治疗获益。目标3：开发调节血脑屏障通透性的新策略，以提高脑微转移瘤治疗的疗效：初步数据表明，在VEGF存在的情况下，抑制大脑转移瘤和小脑转移瘤中的血管内皮Notch信号传导，可靶向增加BBB通透性。在这一目标中，利用靶向增加渗透性来改善三种临床前肿瘤模型中的化疗递送、细胞毒性效应和总存活率。影响：该提案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BBB渗透性并改善CNS转移的化疗吸收，总体目的是减少脑转移相关死亡。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，以将选定的小肿瘤中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.