Fate and efficacy of targeted therapies for metastatic tumors

转移性肿瘤靶向治疗的命运和疗效

基本信息

批准号：
9428627
负责人：
Khalid A Shah
金额：
$ 38.87万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-01 至 2021-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9428627
关键词：
Adopted Agonist Apoptosis Apoptotic Arteries Blood - brain barrier anatomy Blood Vessels Boston Brain Brain Neoplasms Breast Cancer Patient Cell Death Cell Proliferation Cell Therapy Cessation of life Clinic Clinical Collaborations Cranial Irradiation Data Deposition Development Diagnosis Engineering Epidermal Growth Factor Receptor Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Epigenetic Process Epithelial Estrogen Receptors Failure Genetic Goals Histone Deacetylase Histone Deacetylase Inhibitor Home environment Homing Human Human Engineering Image Impaired cognition Incidence Induction of Apoptosis Injectable Injection of therapeutic agent Intracarotid Intracranial Neoplasms Mammary Neoplasms Mediating Mesenchymal Mesenchymal Stem Cells Metastatic breast cancer Metastatic malignant neoplasm to brain Metastatic to Modality Modeling Molecular Mus Neoplasm Metastasis Operative Surgical Procedures Optics Pathology Pathway interactions Patients Permeability Positron-Emission Tomography Primary Neoplasm Progesterone Receptors Publishing Radiation therapy Residual Tumors Role Savings Signal Pathway Signal Transduction Site Stem cells Systemic Therapy TNFRSF10A gene TNFRSF10B gene TNFSF10 gene Testing Therapeutic Time Translating Treatment Efficacy Tumor-Derived Variant base cancer cell clinically translatable design efficacy testing imaging biomarker improved in vitro testing in vivo in vivo imaging killings malignant breast neoplasm mouse model nanobodies neoplastic cell nerve stem cell novel optical imaging prevent radiotracer receptor relating to nervous system response screening success targeted agent targeted treatment triple-negative invasive breast carcinoma tumor tumor growth tumor progression

项目摘要

ABSTRACT Patients with advanced breast cancer have a high propensity to metastasize to the brain with human epidermal growth factor receptor (EGFR) positive and triple-negative breast cancer (TNBC; estrogen receptor, progesterone receptor and Her2 negative) subtypes showing the highest incidence of brain metastases. Most patients have multiple metastatic lesions at the time of diagnosis making surgery an inadequate therapeutic option on its own. Furthermore, impaired cognitive decline induced by whole-brain radiation therapy (WBRT) and the tight blood brain barrier (BBB) preventing the brain permeability of systemic therapies in the brain pose challenges for the success of existing therapies and result in failure to improve overall patient survival. To effectively treat multiple highly aggressive breast metastatic foci in the brain, there is an urgent need to develop tumor specific multi-targeting agents that simultaneously target multiple aberrant signaling pathways in TNBC and utilize delivery vehicles which specifically seek metastatic foci in the brain. In our previously published and preliminary studies, we have 1) extensively demonstrated that engineered human and mouse neural stem cells (NSC) and mesenchymal stem cells (MSC) home extensively to primary and metastatic tumors in the brain and provide on-site means to deliver novel tumor specific agents; and 2) engineered EGFR-specific nanobodies (ENb) and their pro-apoptotic variant, bi- functional ENb-TRAIL and shown its potential to target both cell proliferation and death pathways in a mechanism based manner in broad spectrum of tumor cells. The long term goal of this proposal is to test the mechanism based therapeutic efficacy of systemically delivered NSC-ENb-TRAIL in TNBC derived mouse models of breast to brain metastasis that mimic the clinical scenario of breast metastatic tumor growth and progression. We will initially screen established and patient derived TNBC lines for their response to EGFR and DR4/5 targeted therapies and assess their propensity to metastasize to brain. The mechanism based response of TNBC to NSC-ENb-TRAIL and the fate and therapeutic efficacy of NSC-ENb-TRAIL in brain metastasis mouse models generated from brain seeking patient derived TNBC lines will be assessed. We hypothesize that simultaneous targeting of EGFR and DR4/5 will significantly influence epithelial-mesenchymal transition (EMT) and tumor growth and progression. Based on our exciting preliminary data on the combined use BBB permeable histone deacetylase inhibitor (HDACi), CN147 and ENb-TRAIL and the previous findings that concomitant use of HDACi with DR4/5 agonists and EGFR inhibitors, the combined therapeutic efficacy of NSC-ENb-TRAIL and CN147 will be assessed. We hypothesize that ENb- TRAIL and HDACi will have therapeutic efficacy in metastatic TNBC with a broader range of genetic backgrounds and with varying sensitivity to ENb-TRAIL in vivo. The proposed studies in this application are likely to unravel the mechanism-based, targeted stem cell mediated therapies for metastatic breast tumors. We envision designing a strategy in which NSC-ENb-TRAIL will be injected intra-arterially to target the metastatic tumor deposits in the brain of metastatic breast cancer patients. This will have a major impact in saving the lives of many cancer patients.

抽象的晚期乳腺癌患者具有很高的人表皮转移至脑部的倾向生长因子受体（EGFR）阳性和三阴性乳腺癌（TNBC；雌激素受体、孕激素受体和 Her2 阴性）亚型显示脑转移发生率最高。大多数患者有诊断时存在多个转移病灶，使得手术本身并不是一种足够的治疗选择。此外，全脑放射治疗（WBRT）和血脑紧张引起的认知能力下降受损屏障（BBB）阻碍大脑系统治疗的脑通透性，这对治疗的成功提出了挑战现有的疗法并导致无法提高患者的总体生存率。有效治疗多发高度脑部侵袭性乳腺转移灶，迫切需要开发肿瘤特异性多靶点同时针对 TNBC 中的多个异常信号通路并利用递送载体的药物专门寻找大脑中的转移灶。在我们之前发表的初步研究中，我们有 1) 广泛证明，工程化的人类和小鼠神经干细胞（NSC）和间充质干细胞 (MSC) 广泛定位于大脑中的原发性和转移性肿瘤，并提供现场手段来递送新的肿瘤特异性药物； 2) 工程化 EGFR 特异性纳米抗体 (ENb) 及其促凋亡变体，bi- 功能性 ENb-TRAIL 并显示出其在机制中靶向细胞增殖和死亡途径的潜力基于广谱肿瘤细胞的方式。该提案的长期目标是测试基于的机制系统性递送 NSC-ENb-TRAIL 在 TNBC 衍生的小鼠乳腺至大脑模型中的治疗效果模拟乳腺转移性肿瘤生长和进展的临床情况的转移。我们将首先筛选已建立的和患者衍生的 TNBC 系对 EGFR 和 DR4/5 靶向治疗的反应，评估他们转移到大脑的倾向。 TNBC 对 NSC-ENb-TRAIL 的基于机制的反应和 NSC-ENb-TRAIL 在脑转移小鼠模型中的命运和治疗效果将评估寻求患者衍生的 TNBC 系。我们假设同时靶向 EGFR 和 DR4/5将显着影响上皮间质转化（EMT）和肿瘤生长和进展。基于关于联合使用 BBB 渗透性组蛋白脱乙酰酶抑制剂 (HDACi) CN147 的令人兴奋的初步数据和 ENb-TRAIL 以及之前的研究结果，即 HDACi 与 DR4/5 激动剂和 EGFR 抑制剂同时使用，将评估 NSC-ENb-TRAIL 和 CN147 的联合治疗效果。我们假设 ENb- TRAIL 和 HDACi 对具有更广泛遗传背景的转移性 TNBC 具有治疗功效并且在体内对 ENb-TRAIL 具有不同的敏感性。本申请中提出的研究可能会揭示基于机制的靶向干细胞介导的转移性乳腺肿瘤治疗。我们设想设计一个将 NSC-ENb-TRAIL 动脉内注射以靶向大脑中的转移性肿瘤沉积物的策略转移性乳腺癌患者。这将对挽救许多癌症患者的生命产生重大影响。