Development of Sapacitabine Therapy in Leukemias

急性白血病的有效疗法已经逐渐发展， 不同作用机制的代理人。沙帕他滨，CNDAC的口服生物可利用形式（2 '-C氰基- 2 '-脱氧-1-/3-D-ara-/no-pentofuranosyl- cytosine），是一种有效的胞嘧啶核苷类似物， 新的作用机制。CNDAC的设计是基于这样的概念，即一旦其三磷酸盐被 如果DNA被掺入DMA中，随后的脱氧核苷酸的加入将引发3-消除，导致 3 ′-5 ′磷酸二酯键的断裂和掺入的类似物转化为链终止的 核苷酸，CNddC。在I期研究中具有临床活性，沙帕他滨的作用机制是独特的 在治疗剂中，因为它在DMA中引起单链切口，该切口由核苷酸终止， 不能延伸并且难以修复。我们的假设是，sapacitabine将引起新的 用于检测DMA损伤、用于修复损伤和用于细胞活化的药效学应答 周期检查点，将作为生物标志物，指导临床开发沙帕他滨单用和联合应用。 与这些途径的靶向抑制剂组合。我们将在小学进行翻译研究 白血病细胞在体外和治疗过程中，将补充和扩展正在进行的实验室研究。 检验这一假设的具体目的是：1。评价以下药物的药代动力学和药效学 在复发性/难治性白血病患者中进行的I/II期临床试验期间，表征 对沙帕他滨的细胞应答的生物标志物，3.制定临床翻译的实验室依据 基于机制的沙帕他滨与小分子抑制剂的组合。我们的总体目标是 该提案旨在深入了解对萨帕他滨的细胞反应， 鉴定具有预后价值生物标志物以优化患者选择和给药时间表 并为与靶向抑制DMA损伤的药物联合用药提供依据 传感器、DNA修复机制和检查点控制失调。摘要：我们已经确定 一种以不同于其他所有药物的方式杀死癌细胞的候选药物。我们已经证明， 积极治疗对标准疗法无反应的白血病患者，并建议 实验室和临床研究，可能会增加其在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.