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给药方案，这些方案寻求降低毒性，并将重点从肿瘤根除转向肿瘤管理。我们已经证明，人工合成的胸腺嘧啶类似物5-乙基-2'-脱氧尿苷（EdU）具有深远的抗癌活性（Ross等，2011），初步证据表明，EdU在“适应性”剂量模式下可以建立移植的人类GBM肿瘤的长期停滞。标准化疗试图用接近患者最大耐受剂量的药物根除所有癌细胞。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：首先，它几乎总是选择耐药的

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.