Prevention and treatment of brain micrometastases of breast cancer

乳腺癌脑微转移的预防和治疗

• 批准号: 9259976
• 负责人: Paul R Lockman
• 金额: $ 30.71万
• 依托单位: WEST VIRGINIA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-12-18 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9259976
• 关键词: Autopsy; Blood; Blood - brain barrier anatomy; Blood Vessels; Brain; Breast Cancer Cell; Caliber; Cancer Patient; Cells; Cessation of life; Clinical; Data; Development; Diagnosis; Disease; Disseminated Malignant Neoplasm; Dose; Drug Delivery Systems; Effectiveness; Extravasation; Goals; Growth; Human; Imaging Techniques; Invaded; Lesion; Life; Link; MDA MB 231; Magnetic Resonance Imaging; Mammary Neoplasms; Metastatic Neoplasm to the Central Nervous System; Metastatic breast cancer; 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; notch protein; novel strategies; palliative; pre-clinical; prevent; public health relevance; receptor; research and development; response; targeted treatment; therapy development; tumor; uptake

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（由申请人提供）：脑转移是晚期转移性疾病女性的一个重要问题。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，特别是Her2+或“三阴性”肿瘤患者，脑转移率接近或超过35%。在诊断出多发性转移性病变后，患者通常在一到两年内死亡。空白：脑转移的治疗主要是姑息性的，因为放疗、手术的疗效有限，化疗通过血脑屏障（BBB）的传递能力差。本研究的重点是利用临床前模型预防脑转移的播种和初始生长。假设：通过降低转移性癌细胞渗透到大脑的效率，增加早期微转移灶的药物递送和疗效，我们将减少大转移的发展，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可在血脑屏障水平上受到抑制：初步数据表明，TGF-抑制可使体内三阴性人转移性乳腺癌细胞在血脑屏障水平上的脑侵降低70-80%。这项工作扩展到表征TGF-抑制如何减少血脑屏障细胞侵袭的机制以及Her2+在血脑屏障侵袭中的作用。目的2：阐明乳腺癌脑微转移患者血肿瘤屏障通透性改变与化疗吸收和疗效之间的因果关系：初步数据表明，与通常的假设相反，大多数乳腺癌脑微转移灶（直径<500 μ m）的转移性血管结构和功能发生显著变化，包括血管共选择、血管密度降低、通透性增强和VEGF表达升高。在本研究中，我们将完成表征微转移灶血脑屏障变化的工作，目的是确定微转移灶的选择性差异，如VEGF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：初步数据表明，在VEGF存在的情况下，对大、小脑转移的血管内皮Notch信号的抑制可导致血脑屏障通透性的靶向增加。在本研究中，在三种临床前肿瘤模型中，利用靶向性增加通透性来改善化疗递送、细胞毒性作用和总生存期。影响：本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，调节血脑屏障的通透性，提高化疗对中枢神经系统转移的吸收，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、血脑屏障通透性和药物分布方法来将选定的小肿瘤的屏障变化与整体脑转移的侵袭和生长联系起来。

项目成果

Semi-automated rapid quantification of brain vessel density utilizing fluorescent microscopy.

• DOI: 10.1016/j.jneumeth.2016.06.012
• 发表时间: 2016-09-01
• 期刊: Journal of neuroscience methods
• 影响因子: 3
• 作者: Bohn KA;Adkins CE;Mittapalli RK;Terrell-Hall TB;Mohammad AS;Shah N;Dolan EL;Nounou MI;Lockman PR
• 通讯作者: Lockman PR

Liposomal Irinotecan Accumulates in Metastatic Lesions, Crosses the Blood-Tumor Barrier (BTB), and Prolongs Survival in an Experimental Model of Brain Metastases of Triple Negative Breast Cancer.

• DOI: 10.1007/s11095-017-2278-0
• 发表时间: 2018-01-09
• 期刊: Pharmaceutical research
• 影响因子: 3.7
• 作者: Mohammad AS;Griffith JI;Adkins CE;Shah N;Sechrest E;Dolan EL;Terrell-Hall TB;Hendriks BS;Lee H;Lockman PR
• 通讯作者: Lockman PR

Anti-cancer Antibody Trastuzumab-Melanotransferrin Conjugate (BT2111) for the Treatment of Metastatic HER2+ Breast Cancer Tumors in the Brain: an In-Vivo Study.

抗癌抗体曲妥珠单抗 - 甲状腺素铁蛋白共轭物（BT2111）用于治疗大脑中的转移性HER2+乳腺癌肿瘤：一项体内研究。

• DOI: 10.1007/s11095-016-2015-0
• 发表时间: 2016-12
• 期刊: Pharmaceutical research
• 影响因子: 3.7
• 作者: Nounou MI;Adkins CE;Rubinchik E;Terrell-Hall TB;Afroz M;Vitalis T;Gabathuler R;Tian MM;Lockman PR
• 通讯作者: Lockman PR

Permeability across a novel microfluidic blood-tumor barrier model.

新型微流体血液肿瘤屏障模型的渗透性。

• DOI: 10.1186/s12987-017-0050-9
• 发表时间: 2017-01-23
• 期刊: Fluids and barriers of the CNS
• 影响因子: 7.3
• 作者: Terrell-Hall TB;Ammer AG;Griffith JI;Lockman PR
• 通讯作者: Lockman PR

P-glycoprotein mediated efflux limits substrate and drug uptake in a preclinical brain metastases of breast cancer model.

• DOI: 10.3389/fphar.2013.00136
• 发表时间: 2013
• 期刊: Frontiers in pharmacology
• 影响因子: 5.6
• 作者: Adkins CE;Mittapalli RK;Manda VK;Nounou MI;Mohammad AS;Terrell TB;Bohn KA;Yasemin C;Grothe TR;Lockman JA;Lockman PR
• 通讯作者: Lockman PR