Development of Sapacitabine Therapy in Leukemias

治疗急性白血病的有效疗法是逐步发展起来的，并随着发展而进步。 具有不同作用机制的药剂。沙巴滨，口服生物利用型的CNDAC(2‘-氰基- 2‘-脱氧-1-/3-D-阿糖胞苷)，是一种有效的胞嘧啶核苷类似物。 新颖的作用机制。CNDAC的设计是基于这样的概念：一旦它的三磷酸盐 加入到DMA中，添加随后的脱氧核苷酸将引发3-消除，导致 3‘-5’磷酸二酯键的断裂和被掺入的类似物向链末端的转化 核苷酸，CNddC。在I期临床研究中，沙巴他滨的作用机制是独一无二的 在治疗药物中，因为它导致DNA中的单链缺口，该缺口由 不能延长，并且不能修复。我们的假设是，沙巴他滨将引发新的 检测DMA损伤、修复损伤和激活细胞的药效学反应 将作为生物标志物的周期检查点，以指导萨巴他滨单独和联合治疗的临床开发 与这些通路的靶向抑制剂相结合。我们将在小学进行翻译研究 白血病细胞的体外和治疗，这将补充和延长正在进行的实验室研究。 检验这一假说的具体目的是：1.评价阿司匹林的药代动力学和药效学 用于复发/难治性白血病患者的L/111期临床试验中的沙巴滨，2.特征 细胞对沙巴他滨反应的生物标志物，3.制定临床翻译的实验室理论基础 基于机理的沙巴他滨与小分子抑制剂的组合。我们的总体目标是 该提案旨在彻底了解细胞对沙巴滨的反应，这将 确定具有预后价值的生物标志物，以优化患者选择和给药时间表 在临床上，并为联合使用以抑制DMA损伤为目标的药物提供依据 传感器、DNA修复机制和失调的检查点控制。摘要：我们已经确定了 一种以不同于所有其他药物的方式杀死癌细胞的候选药物。我们已经证明了它 对对标准治疗无效的白血病患者进行积极治疗，并建议 实验室和临床研究，可能会增加其治疗这些和其他癌症的有效性。

Effective therapies for acute leukemias have been developed incrementally, advanced by the development of agents with different mechanisms of action. Sapacitabine, the orally bioavailable form of CNDAC (2'-Ccyano- 2'-deoxy-1-/3-D-ara¿>/no-pentofuranosyl- cytosine), is a potent cytosine nucleoside analogue with a novel mechanism of action. The design of CNDAC was based on the concept that once its triphosphate is incorporated into DMA, the addition of a subsequent deoxynucleotide would initiate 3-elimination, resulting in cleavage of the 3'-5' phosphodiester linkage and conversion of incorporated analogue to a chain-terminating nucleotide, CNddC. Clinically active in phase I studies, the mechanisms of action of sapacitabine are unique among therapeutic agents, as it causes a single strand nick in DMA that is terminated by a nucleotide that cannot be extended and is resistant to repair. Our hypothesis is that sapacitabine will elicit novel pharmacodynamic responses for detecting DMA damage, for repair of the lesions, and for activation of cell cycle checkpoints that will serve as biomarkers to guide clinical development of sapacitabine alone and in combination with targeted inhibitors of these pathways. We will conduct translational studies in primary leukemia cells in vitro and during therapy that will complement and extend ongoing laboratory investigations. The specific aims for testing this hypothesis are: 1. Evaluate pharmacokinetics and pharmacodynamics of sapacitabine during phase l/ll clinical trials in patients with relapsed/refractory leukemias, 2. Characterize biomarkers for cellular responses to sapacitabine, 3. Formulate laboratory rationales for clinical translation of mechanism-based combinations of sapacitabine with small molecule inhibitors. The overall goal of our proposal is aimed at developing a thorough understanding of cellular responses to sapacitabine that will identify biomarkers that have prognostic value to optimize patient selection and schedules of administration in the clinic, and to provide rationales for combinations with agents targeted at inhibiting DMA damage sensors, DNA repair mechanisms, and dysregulating checkpoint controls. Lay abstract: We have identified a drug candidate that kills cancer cells in ways that are different from all other drugs. We have shown that it active treatment in humans with leukemia who have not responded to standard therapies, and propose laboratory and clinical studies that may increase its effectiveness at treating these and other cancers.