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

沙帕西他滨疗法可在 DNA 修复缺陷的 CLL 中产生合成致死率

基本信息

批准号：
8519387
负责人：
WILLIAM K PLUNKETT
金额：
$ 30.82万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-01 至 2015-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8519387
关键词：
11q 11q22 11q22.3 ATM deficient ATM function ATM gene Acute Myelocytic Leukemia Affect Alkylating Agents Alleles Antibody Therapy Bioavailable Biological Assay Biological Models Cell Line Cell Survival Cells Chromosomes, Human, Pair 11 Clinical Clinical Trials Cyclophosphamide DNA DNA Damage DNA Repair DNA biosynthesis DNA strand break Deoxycytidine Development Disease Disease Progression Disease remission Drug Formulations Drug resistance Excision Repair Exhibits Future Genetic Goals In Vitro In complete remission Incidence Investigation Laboratories Lesion Location Malignant Neoplasms Modeling Mutate Mutation Nonhomologous DNA End Joining Nucleotides Pathway interactions Patients Pharmaceutical Preparations Phosphorylation Prior Therapy Process Proliferating Purine Nucleosides Refractory Relapse Relative (related person)Residual state Role Safety Sampling Site Specificity Structure Testing Time Translating Treatment Failure Work analog arm base design ds-DNA fludarabine gene function high risk homologous recombination improved killings leukemia novel nucleoside analog public health relevance recombinational repair repaired response rituximab success tripolyphosphate

项目摘要

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.

描述（由申请人提供）：过去十年中，CLL 的治疗取得了显着进展。相对于烷化剂，氟达拉滨和其他嘌呤核苷类似物的引入显着改善了反应。1-3 随后这两类药物（特别是氟达拉滨和环磷酰胺）的组合被证明优于单一药物氟达拉滨。4-6包括抗体治疗（尤其是利妥昔单抗）在内的策略已显着提高了 CLL 患者的完全缓解率。4, 7-11 并表明总体生存率有所提高氟达拉滨-环磷酰胺-利妥昔单抗 (FCR) 疗法。12 然而，复发仍然是个问题，耐药性的发展仍然是 CLL 治疗的主要挑战。11。这种耐药性可能部分是由于某些基因改变造成的。一半的复发/难治性患者出现 11q22-23（ATM 基因位点）缺失。这些患者中约 50% 的残留等位基因突变使 CLL 细胞中双链断裂的同源重组 (HR) 修复失活。由于 Sapacitabine 会导致单端双链断裂，因此缺乏 ATM 的细胞会被选择性地致敏。我们假设 Sapacitabine 在缺乏 ATM 功能的 CLL 细胞中的新作用机制，因此通过同源重组修复病变，将产生合成致死性并赋予杀伤特异性。我们将在 11q22-23 缺失的复发/难治性 CLL 患者中进行沙帕西他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) 检验缺乏 ATM 功能（同源重组修复）的 CLL 将被选择性地治疗的假设对含沙帕西他滨的治疗敏感，表现为更高的总体缓解率和更长的缓解持续时间； 2) 识别缺乏ATM功能的CLL患者，并分析该参数的临床反应。在 11q22-23 缺失、缺乏 ATM 功能的患者中证明疗效，将是这一高危患者组治疗的重大进步，并将验证 ATM 作为 CLL 中含沙帕西他滨治疗的靶标，以及 3) 进行研究从参加试验的患者身上获取的 CLL 样本将转化为这些原代 CLL 细胞模型系统的发现。