Sapacitabine therapy to create synthetic lethality in DNA repair-deficient CLL

描述(由申请人提供)：在过去的十年中，慢性淋巴细胞性白血病的治疗有了显著的进步。氟达拉滨和其他嘌呤核苷类似物的引入大大改善了相对于烷基化试剂的反应。1-3随后，这两类药物的组合，特别是氟达拉滨和环磷酰胺，被证明优于单一药物氟达拉滨。4-6最近包括抗体疗法的战略，特别是利妥昔单抗，大大增加了慢性淋巴细胞性白血病患者的完全应答率。4，7-11，有迹象表明，对氟达拉滨-环磷酰胺-利妥昔单抗(FCR)疗法的反应增加了总存活率。12然而，复发仍然存在问题，耐药性的发展仍然是慢性淋巴细胞性白血病治疗的主要挑战。这种抗药性可能部分归因于某些基因改变。ATM基因11q22-23处的缺失发生在一半的复发/难治患者中。这些患者中约50%的残留等位基因突变使CLL细胞双链断裂的同源重组(HR)修复失活。由于沙巴他滨导致单端双链断裂，缺乏ATM的细胞被选择性地敏化。我们推测，沙巴滨在缺乏ATM功能的CLL细胞中的新作用机制，因此是通过同源重组修复损伤的，将产生合成杀伤力并赋予杀伤特异性。我们将在11q22-23缺失的复发/难治性CLL患者中进行萨巴滨联合环磷酰胺和利妥昔单抗的临床试验，具体目的如下：1)验证缺乏ATM功能(同源重组修复)的CLL将选择性地对含沙巴他滨的治疗敏感的假设，其总有效率更高，起效时间更长；2)识别疾病缺乏ATM功能的CLL患者，并分析针对该参数的临床反应。在缺失11q22-23、缺乏ATM功能的患者中展示有效性，将是对这一高危患者组治疗的重大进步，并将验证ATM作为含有沙巴他滨的CLL治疗的靶点，以及3)对从参加试验的患者获得的CLL样本进行调查，这将转化 在这些初级CLL细胞的模型系统中的发现。

DESCRIPTION (provided by applicant): There has been remarkable progress in the treatment of CLL during the last decade. The introduction of fludarabine and other purine nucleoside analogs generated a significant improvement in responses relative to alkylating agents.1-3 Subsequently combinations of these two classes of agents, in particular fludarabine and cyclophosphamide, were proved superior to single agent fludarabine.4-6 Recently strategies to include antibody therapy, particularly with rituximab have given substantial increases in the complete response rate for CLL patients.4, 7-11 and an indication of increased overall survival in response to fludarabine-cytoxan-rituximab (FCR) therapy.12 Nevertheless, relapses remain problematic and development of drug resistance continues to be a major challenge in CLL treatment.11. Such drug resistance may in part be due to certain genetic alterations. A deletion at 11q22-23, the site of the ATM gene, occurs in half of relapsed/refractory patients. Mutation of the residual allele in approximately 50% of these patients inactivates homologous recombination (HR) repair of double strand breaks in CLL cells. Because Sapacitabine causes one-ended double strand breaks, cells that lack ATM are selectively sensitized. We hypothesize that the novel mechanism of action of Sapacitabine in CLL cells that lack ATM function, and are therefore are in repairing the lesion by homologous recombination, will create synthetic lethality and confer specificity of killing. We will conduct a clinical trial of Sapacitabine combined with cyclophosphamide and rituximab in relapsed/refractory patients with CLL who exhibit deletion 11q22-23 with the following specific aims: 1) test the hypothesis that CLL lacking ATM function (homologous recombination repair) will be selectively sensitized to Sapacitabine- containing therapy as indicated by a greater overall response rate and longer response duration; 2) identify CLL patients whose disease lacks ATM function, and analyze clinical response with respect to this parameter. Demonstrating efficacy in patients with deletion 11q22-23, lacking ATM function, would be a significant advance in treatment for this high-risk group of patients, and would validate ATM as a target for Sapacitabine- containing therapy in CLL, and 3) conduct investigations with CLL samples obtained from patients entered on the trial that will translate the findings in models systems to these primary CLL cells.