Phosphatase Targets of Lenalidomide in Myelodysplastic Syndrome

来那度胺治疗骨髓增生异常综合征的磷酸酶靶点

基本信息

批准号：
8282883
负责人：
ALAN F LIST
金额：
$ 42.42万
依托单位：
H. LEE MOFFITT CANCER CTR & RES INST
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-07-01 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8282883
关键词：
5q31 Accounting Adverse effects Affect Aging American Apoptosis Attenuated Biological Biology CC-5013 Cell Cycle Arrest Cells Chemosensitization Chromosomes Clinical Combined Modality Therapy Cytogenetics Development Disease Dysmyelopoietic Syndromes Dysplasia Eastern Cooperative Oncology Group Erythrocyte Transfusion Erythrocytes Erythroid Erythropoiesis Erythropoietin Erythropoietin Receptor Frequencies G2/M Transition Genome Mappings Genomics Goals Growth Factor Heterogeneity Investigation Karyotype Laboratories Lesion Link Medical Metaphase Microscopic Minority Molecular Target PTPRC gene Patients Pattern Phase Phase II Clinical Trials Phosphoric Monoester Hydrolases Phosphorylation Population Prevalence Principal Investigator Probability Production Protein Isoforms Protein Phosphatase 2A Regulatory Subunit PR53 Protein Tyrosine Phosphatase Recombinant Erythropoietin Refractory Regulation Reliance Resistance Resources Risk Role STAT5A gene Scanning Serum Signal Transduction Specimen Speed TFRC gene Testing Thalidomide Therapeutic Transcription Coactivator Transfusion analog base chromosome 5q loss cytotoxicity darbepoetin alfa density experience improved insight lenalidomide molecular marker novel phase 3 study phosphatase inhibitor pre-clinical progenitor recombinant human erythropoietin resistance mechanism response treatment response

项目摘要

The principal objective of this proposal is to characterize biologic variables affecting treatment response and resistance in a Phase III Intergroup trial, E2905, testing the benefit of combined treatment with lenalidomide (LEN) and darbepoetin alpha (DA) in patients with myelodysplastic syndrome (MDS). Ineffective erythropoiesis remains the principle therapeutic challenge in MDS with only a minority of patients experiencing sustained benefit from recombinant erythropoietin (EPO). Investigations by the Principal Investigator have shown that LEN has erythropoietic activity in lower risk MDS patients who have failed EPO treatment. Our laboratory investigations indicate that LEN promotes erythropoiesis in MDS by two distinct mechanisms; (1) selective suppression of chromosome 5q deletion (del5q) clones, and (2) potentiation of the EPO receptor (R)/STAT5 signal. The capacity of LEN to augment the EPO-R signal and promote erythropoiesis will be tested in E2905 in which patients with low probability of EPO response will receive LEN with or without DA treatment. Response rate and duration may be influenced by several biological variables including low endogenous EPO production (LEN only), ineffective EPO-R signal enhancement, karyotypically unresolved 5q deletions, and modulation of relevant LEN cell targets. We hypothesize that LEN restores effective erythropoiesis through inhibition of phosphatase targets that are karyotype-specific: (a) inhibition of the CD45 phosphatase in non- del5q MDS to potentiate the EPO-R/STAT5 signal, and (b) inhibition of the haplo-deficient Cdc25c and PP2A phosphatases in del5q clones leading to selective clonal suppression. To characterize biological variables affecting treatment response and resistance in E2905, and the regulation of the EPO-R signal in MDS, we propose the following Specific Aims: 1. To evaluate the effect of CD45 isoform profile on LEN potentiation of EPO-induced STAT5 phosphorylation in CD71+ erythroid precursors and the relationship to erythroid response. 2. To characterize molecular targets relevant to lenalidomide cytotoxicity in del5q cells. 3. To evaluate the frequency of cryptic chromosome 5q31 deletions in patients with non-del5q MDS by array- based genomic scan, and to determine the relationship to hematologic response. With the aging of the American population, MDS is rapidly increasing in prevalence with proportional demand on medical resources. The proposed investigations should provide important insight into mechanism of disease biology and the development of novel more effective therapeutics.

该提案的主要目的是表征影响治疗反应和的生物变量在III期群中试验E2905中的抗性，测试了与列纳莱度胺合并治疗的好处（LEN）和DARBEPOETINα（DA）患有骨髓增生综合征（MDS）的患者。无效的红血病仍然是MD的主要治疗挑战，只有少数患者经历持续的患者受益于重组红细胞生成素（EPO）。首席研究人员的调查表明 LEN在EPO治疗失败的较低风险MDS患者中具有红细胞生成活性。我们的实验室调查表明，Len通过两种不同的机制促进MDS中的红细胞生成。（1）选择性抑制5q缺失（DEL5Q）克隆的染色体抑制，（2）EPO受体（R）/STAT5的增强信号。 LEN增强EPO-R信号和促进促红细胞生成的能力将在E2905中进行测试其中EPO反应概率较低的患者将接受或不接受DA治疗的LEN。缓解率和持续时间可能受到几种生物学变量（包括低内源性EPO）的影响生产（仅LEN），无效的EPO-R信号增强，核型上未解决的5Q缺失和相关LEN细胞靶标的调节。我们假设Len通过抑制特异性核型的磷酸酶靶标：（a）在非 - DEL5Q MDS增强EPO-R/STAT5信号，以及（b）抑制单倍体缺陷型CDC25C和PP2A DEL5Q克隆中的磷酸酶导致选择性克隆抑制。表征生物变量影响E2905的治疗反应和耐药性，以及MDS中EPO-R信号的调节，我们提出以下具体目标： 1。评估CD45同工型对EPO诱导的STAT5磷酸化的影响在CD71+红细胞前体以及与红细胞反应的关系。 2。表征与Del5Q细胞中的Lenalidomide细胞毒性相关的分子靶标。 3。评估非del5q MD的患者的5q31染色体5q31缺失的频率基于基因组扫描，并确定与血液学反应的关系。随着美国人口的衰老，MD的患病率随着比例需求而迅速增加关于医疗资源。拟议的调查应提供对疾病机制的重要见解生物学和新型更有效治疗学的发展。