Targeting Brain Tumor Stem Cells Through Novel Therapeutic Combinations

描述（由申请人提供）：尽管发展了新的靶向治疗方法，但晚期或转移性癌症患者的总生存期几乎没有变化。大多数癌症治疗的基础仍然是细胞毒性治疗——放射和化疗——杀死快速增殖的细胞。目前的药物开发继续筛选在允许生长条件下的药物，其读数是增殖的替代品。然而，这些策略只能提供渐进式的改善，因为体内微环境肿瘤条件和复杂的细胞参与通过与治疗耐药性、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，以提高对这些关键肿瘤细胞变体中可药物靶点的识别。我们和其他人正在研究肿瘤异质性的一个来源——肿瘤干细胞假说中包含的分化层次。我们认为，癌症干细胞的表型是可塑的，由细胞自主和外部信号共同决定，因此高通量分析虽然有报道，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有抵抗力，也促进肿瘤血管生成。基于这一背景，我们假设抑制脑肿瘤干细胞而非正常组织干细胞中活跃的关键存活通路将增强当前脑肿瘤治疗的疗效。具体而言，我们建议：1。评估一种新型脑肿瘤干细胞靶向药物的抗血管生成能力。2. 确定一种新型脑肿瘤干细胞靶向药物与贝伐单抗联合的治疗效果。3. 确定一种新型脑肿瘤干细胞靶向药物与放化疗联合治疗的疗效。我们希望这些研究将为直接转化为治疗试验奠定基础。

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.