Targeting Brain Tumor Stem Cells Through Novel Therapeutic Combinations

描述(申请人提供)：尽管开发了新的靶向治疗方法，但被诊断为晚期或转移性癌症的患者的总体存活率几乎没有变化。大多数癌症护理的基础仍然是细胞毒疗法--放射和化疗--它能杀死快速增殖的细胞。目前的药物开发继续在允许的生长条件下筛选药物，读数是增殖的替代品。然而，这些策略只能提供渐进的改善，因为体内的微环境肿瘤条件和复杂的细胞参与通过与治疗耐药、血管生成和肿瘤进展相关的遗传和非遗传变异促进了肿瘤内的异质性。目前正在开发多种方法，以改进对这些关键肿瘤细胞变异体中可用药靶点的识别。我们和其他人正在研究肿瘤异质性的一个来源--癌症干细胞假说中包含的分化层次。我们认为癌症干细胞表型是可塑性的，并由细胞自主和外部信号定义，因此高通量分析，尽管已有报道，但可能不能完全代表癌症干细胞的状态。我们之前已经证明，脑肿瘤干细胞对辐射具有抵抗力，并能促进肿瘤血管生成。基于这一背景，我们假设，抑制脑瘤干细胞而不是正常组织干细胞中活跃的关键生存通路将增强当前脑瘤治疗的疗效。具体地说，我们建议：1.评价一种新型脑肿瘤干细胞靶向剂的抗血管生成能力。2.确定新型脑肿瘤干细胞靶向剂联合贝伐单抗的治疗效果。3.确定一种新型脑肿瘤干细胞靶向剂联合放化疗的疗效。我们希望这些研究将为直接转化为治疗试验奠定基础。 与公共卫生相关：胶质母细胞瘤是所有人类癌症中最致命的癌症之一，尽管接受了放射、化疗和最近的药物治疗，这些药物阻止新的血管生长来喂养肿瘤。在胶质母细胞瘤中，被称为癌症干细胞的细胞在实验室研究中被发现对放射和化疗具有抵抗力，并能刺激新血管的生长。我们将测试攻击癌症干细胞的方法，以使它们对当前脑癌治疗的效果敏感。

DESCRIPTION (provided by applicant): The overall survival for patients diagnosed with advanced or metastatic cancers has changed little despite the development of novel targeted therapeutics. The basis of most cancer care remains cytotoxic therapy - radiation and chemotherapy - that kills rapidly proliferating cells. Current drug development continues to screen for agents under permissive growth conditions with readouts that are surrogates for proliferation. However, these strategies provide only incremental improvements as in vivo microenvironmental tumor conditions and the complex cellular involvement promote heterogeneity within the tumor through genetic and non-genetic variations associated with therapeutic resistance, angiogenesis, and tumor progression. Multiple approaches are under development to improve the identification of druggable targets within these critical tumor cell variants. We and others are investigating one source of tumor heterogeneity - the differentiation hierarchy incorporated within the cancer stem cell hypothesis. We believe that the cancer stem cell phenotype is plastic and defined by both cell autonomous and external cues so high throughput analyses, although reported, may not fully represent the cancer stem cell state. We have previously demonstrated that brain tumor stem cells are resistant to radiation and also promote tumor angiogenesis. Based on this background, we hypothesize that inhibiting key survival pathways active in brain tumor stem cells but not normal tissue stem cells will augment the efficacy of current brain tumor therapies. Specifically, we propose to: 1. Evaluate the anti-angiogenic capacity of a novel brain tumor stem cell targeting agent. 2. Determine the therapeutic efficacy of a novel brain tumor stem cell targeting agent in combination with bevacizumab. 3. Determine the therapeutic efficacy of a novel brain tumor stem cell targeting agent in combination with radiation and chemotherapy. We hope that these studies will lay the foundation for direct translation into therapeutic trials. PUBLIC HEALTH RELEVANCE: Glioblastomas are among the deadliest of all human cancers despite treatment with radiation, chemotherapy, and - most recently - drugs that block new blood vessel growth to feed tumors. Within glioblastomas, cells called cancer stem cells have been found that in laboratory studies are resistant to radiotherapy and chemotherapy and also stimulate new blood vessels to grow. We will test ways of attacking the cancer stem cells to sensitize them to the effects of current brain cancer treatments.