Fate and efficacy of targeted therapies for metastatic tumors

摘要 晚期乳腺癌患者有很高的转移到人类表皮脑部的倾向。 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。大多数患者都有 诊断时的多发转移灶使手术本身不足以作为治疗选择。 此外，全脑放射治疗(WBRT)和血脑紧张所致的认知功能减退 屏障(BBB)阻止系统疗法在大脑中的脑部渗透对成功的 现有的治疗方法，导致未能提高患者的总体存活率。有效治疗高度多发性 侵袭性乳腺转移灶在脑内，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，工程化的人和小鼠神经干细胞(NSC)和间充质干细胞 (MSC)是脑内原发和转移肿瘤的广泛发源地，并提供现场手段来提供新的 肿瘤特异性药物；2)工程的EGFR特异性纳米抗体(ENB)及其促凋亡变异体， 具有功能的eNB-TRAIL，并显示其在一种机制中同时针对细胞增殖和死亡途径的潜力 以广谱的肿瘤细胞为基础。这项提议的长期目标是测试基于 系统递送NSC-ENB-TRAIL对TNBC源性小鼠胸脑移植模型的治疗作用 模拟乳腺转移瘤生长和进展的临床情景的转移。我们最初会 筛选已建立和患者来源的TNBC系，以了解他们对EGFR和DR4/5靶向治疗的反应 评估他们转移到脑的倾向。TNBC对NSC-eNB-TRAIL和TRAIL的应答机制 NSC-ENB-TRAIL在小鼠脑转移瘤模型中的去向及治疗效果 寻找患者来源的TNBC系将被评估。我们假设同时靶向EGFR和 DR4/5将显著影响上皮-间充质转化(EMT)和肿瘤的生长和发展。基座 关于联合使用血脑屏障通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表明，HDACi与DR4/5激动剂和EGFR抑制剂一起使用， 将评估NSC-eNB-TRAIL和CN147的联合治疗效果。我们假设eNb- TRAIL和HDACi将对具有更广泛遗传背景的转移性TNBC具有疗效 在体内对eNB-TRAIL具有不同的敏感性。本申请中提议的研究可能会揭开 转移性乳腺肿瘤的基于机制的靶向干细胞介导性治疗。我们设想设计一种 NSC-ENB-TRAIL动脉内注射靶向脑转移瘤沉积的策略 转移性乳腺癌患者的比例。这将对挽救许多癌症患者的生命产生重大影响。

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.