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）：在过去的十年中，CLL的治疗取得了显着进展。氟达拉滨和其他嘌呤核苷类似物的引入相对于烷基化剂的反应产生显着改善。1-3随后组合的组合，尤其是氟达拉滨和环磷酰胺的组合，特别是在单一药物的抗反应中，尤其是对抗体疗法的完整率，该策略均得到了较高的效果。患者4、7-11，以及响应氟达拉滨 - 酸性rituximab（FCR）治疗的总体生存率提高的指示。12然而，复发仍然有问题，耐药性的发展仍然是CLL治疗的重大挑战。1111。这种耐药性可能部分是由于某些遗传改变。 ATM基因部位的11q22-23删除发生在复发/难治性患者的一半。在这些患者中，残留等位基因的突变使CLL细胞中双链断裂的同源重组（HR）修复。由于sapacitabine会导致单端双链断裂，因此缺乏ATM的细胞被选择性地敏化。我们假设sapacitabine在CLL细胞中缺乏ATM功能的新型作用机理，因此正在通过同源重组来修复病变，将产生合成的致死性和杀戮的特异性。 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）确定疾病缺乏ATM功能的CLL患者，并分析有关此参数的临床反应。证明缺乏ATM功能的删除11q22-23患者的功效将是该高风险患者的治疗方案的重大进步，并将验证ATM作为CLL中含有Sapacitabine-含有sapacitabine-含有Sapacitabine的靶标，而3）进行调查，并通过在试验中获得的CLL样品进行调查，该cll spects the the the Ins the Trans the Transe trans the Transe the Clans the Clans the Trange trange trans the Trange the Transe the CLLL样本这些主要CLL细胞的模型系统中的发现。