Adaptive EdU Therapy for Brain Tumors

描述（由申请人提供）：迫切需要治疗多形性胶质母细胞瘤（GBM）的新方法。这些新方法可能包括新的治疗药物和新的药物递送方案，这些方案旨在降低毒性并将重点从肿瘤根除转移到肿瘤管理。我们已经表明，合成的胸苷类似物5-乙炔基-2 '-脱氧尿苷（EdU）具有显著的抗癌活性（Ross等人，2011），并且初步证据表明“适应性”给药范例中的EdU可以建立异种移植的人GBM肿瘤的长期停滞。标准化疗试图用接近患者最大耐受量的药物剂量根除所有癌细胞。这种方法杀死了许多癌细胞，可以有效地延长生存期，但有两个严重的问题：第一，它几乎总是选择耐药细胞。 第二，它通过使患者生病而导致生活质量低下。适应性治疗背后的理论（借用自生态种群动力学; Gatenby等人，2009; Gatenby，2009; Wolkenhauer等人，2010年）是最连续的，高剂量的药物方案将最终导致耐药细胞的出现，占主导地位的肿瘤。然而，在没有药物治疗的情况下，耐药细胞比无耐药细胞更不“适合”（即分裂更慢）;也就是说，为了变得耐药，细胞必须 以牺牲其他功能为代价，这种牺牲表现为扩张速度放缓。在没有药物的情况下，非耐药细胞将通过更快地扩张和支配肿瘤资源来竞争和抑制耐药细胞。然而，在高剂量药物的存在下，情况正好相反。通过这种方式，肿瘤最终仅由抗性细胞组成，并且变得难以治疗。适应性治疗根据肿瘤反应调整药物剂量;如果肿瘤生长，则剂量增加，但当肿瘤稳定或缩小时再次降低。希望是杀死足够多的非耐药细胞以防止肿瘤不受控制地生长，但不要太多，以至于取消了对非耐药细胞的限制。通过这种方式，肿瘤将始终由药物敏感细胞组成，这些细胞可以通过动态剂量调整随着时间的推移而被修剪和管理，尽管它可能不会被完全根除。在此，我们建议：1）优化用于使用小鼠异种移植物治疗人GBM的适应性EdU方案; 2）比较适应性EdU方案与标准治疗方法在治疗小鼠异种移植物中的人GBM中的功效;以及3）评估EdU施用对神经和造血干细胞小生境的潜在负面后果。这些研究的总体目标是通过测试使用新的化疗候选物的适应性治疗方法的潜力来改善人类胶质瘤的治疗选择。除了引入一种新的抗癌化合物外，我们的提案还有可能从根本上改变各种现有治疗方案的给药模式。

DESCRIPTION (provided by applicant): There is a pressing need for new approaches in the treatment of glioblastoma multiforme (GBM). These new approaches will likely encompass both new therapeutic agents, and novel drug delivery regimens that seek to reduce toxicity and change the focus from tumor eradication to tumor management. We have shown that the synthetic thymidine analog, 5-ethynyl-2'-deoxyuridine (EdU), has profound anti-cancer activities (Ross, et al., 2011), and preliminary evidence suggests that EdU in an "adaptive" dosing paradigm can establish long-term stasis of xenografted human GBM tumors. Standard chemotherapy attempts to eradicate all cancer cells with drug doses that are near the maximum tolerated by the patient. This approach kills many cancer cells and can effectively prolong survival, but suffers from two serious problems: first, it nearly always selects for drug-resistant cells, allowing them to dominate the tumor; second, it contributes to poor quality of life by making patients quite ill. The theory behind adaptive therapy (borrowed from ecological population dynamics; Gatenby, et al., 2009; Gatenby, 2009; Wolkenhauer, et al., 2010) is that most continuous, high-dose drug regimens will eventually lead to the appearance of resistant cells that dominate the tumor. However, resistant cells are less "fit" (i.e. divide slower) than no-resistant cells in the absence of drug treatment; that is, in order to become resistant a cell must pay a cost by sacrificing other functions, and this sacrifice is manifested as a slower expansion. In the absence of drug, the non-resistant cells will outcompete and suppress the resistant cells by expanding faster and dominating the resources of the tumor. However, in the presence of high doses of drug the reverse is true. In this way tumors eventually consist only of resistant cells, and become refractory to treatment. Adaptive therapy adjusts drug dose according to the tumor response; if the tumor grows, then the dose is raised, but is lowered again when the tumor stabilizes or shrinks. The hope is to kill enough non-resistant cells to prevent the tumor from growing uncontrollably, but not so many that the constraints on the non-resistant cells are removed. In this way, the tumor will always consist of drug-sensitive cells that can -with dynamic dosage adjustments - be trimmed and managed over time, though it will likely not be completely eradicated. Here we propose to: 1) optimize an adaptive EdU protocol for the treatment of human GBM using mouse xenografts; 2) compare the efficacy of the adaptive EdU protocol to a standard therapy approach in the treatment of human GBM in mouse xenografts; and 3) assess potential negative consequences of EdU administration on the neural and hematopoietic stem cell niches. The overarching goal of these studies is improve treatment options for human glioma by testing the potential of an adaptive therapy approach using a novel chemotherapeutic candidate. In addition to introducing a new anti-cancer compound, our proposal has the potential to radically change dosing paradigms for a variety of existing treatment options.