Targeting Brain Tumor Stem Cells Through Novel Therapeutic Combinations

描述（由申请人提供）：尽管开发了新的靶向治疗方法，但诊断为晚期或转移性癌症的患者的总生存期几乎没有变化。大多数癌症护理的基础仍然是细胞毒性疗法--放疗和化疗--可以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试剂，其读数是增殖的替代物。然而，这些策略仅提供增量改善，因为体内微环境肿瘤状况和复杂的细胞参与通过与治疗抗性、血管生成和肿瘤进展相关的遗传和非遗传变异促进肿瘤内的异质性。目前正在开发多种方法，以改善这些关键肿瘤细胞变体中可药用靶点的鉴定。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线索定义，因此高通量分析，尽管有报道，但可能不能完全代表癌症干细胞状态。我们以前已经证明，脑肿瘤干细胞对辐射有抵抗力，并且还促进肿瘤血管生成。基于这一背景，我们假设抑制脑肿瘤干细胞而不是正常组织干细胞中活跃的关键存活途径将增强目前脑肿瘤治疗的疗效。具体而言，我们建议：1.一种新型脑肿瘤干细胞靶向药物抗血管生成能力的评价。 2.确定新型脑肿瘤干细胞靶向剂与贝伐单抗联合治疗的疗效。 3.确定一种新型脑肿瘤干细胞靶向剂联合放疗和化疗的治疗效果。我们希望这些研究将为直接转化为治疗试验奠定基础。 公共卫生相关性：胶质母细胞瘤是所有人类癌症中最致命的一种，尽管使用了放射治疗，化疗，以及最近的药物来阻止新血管生长以滋养肿瘤。在胶质母细胞瘤中，在实验室研究中发现称为癌症干细胞的细胞对放疗和化疗有抵抗力，并且还刺激新血管生长。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.