Phosphatase Targets of Lenalidomide in Myelodysplastic Syndrome

该提案的主要目的是表征影响治疗反应的生物学变量， III期组间试验E2905中的耐药性，该试验测试了与来那度胺联合治疗的益处 (LEN)和达贝泊苷α（DA）在骨髓增生异常综合征（MDS）患者中的作用。无效性红细胞生成 仍然是MDS的主要治疗挑战，只有少数患者经历持续的 重组促红细胞生成素（EPO）。主要调查员的调查显示， LEN在EPO治疗失败的低风险MDS患者中具有红细胞生成活性。本实验室 研究表明LEN通过两种不同的机制促进MDS中的红细胞生成：（1）选择性 染色体5 q缺失（del 5 q）克隆的抑制，和（2）EPO受体（R）/STAT 5的增强 信号了将在E2905中测试LEN增强EPO-R信号和促进红细胞生成的能力 其中EPO应答可能性低的患者将接受LEN联合或不联合DA治疗。 应答率和持续时间可能受到几个生物学变量的影响，包括低内源性EPO 产生（仅LEN），EPO-R信号增强无效，核型未分辨的5 q缺失，以及 调节相关LEN细胞靶点。我们假设LEN通过以下途径恢复有效的红细胞生成： 抑制核型特异性的磷酸酶靶标：（a）抑制非核型细胞中的CD 45磷酸酶， del 5 q MDS增强EPO-R/STAT 5信号，和（B）抑制单倍缺陷型Cdc 25 c和PP 2 A 导致选择性克隆抑制的Del 5 Q克隆中的磷酸酶。来表征生物变量 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CD 45亚型谱对LEN增强EPO诱导的STAT 5磷酸化的作用 在CD 71+红系前体细胞中的表达以及与红系反应的关系。 2.表征del 5 q细胞中来那度胺细胞毒性相关的分子靶点。 3.通过微阵列技术评估非del 5 q MDS患者中隐性染色体5 q31缺失的频率， 基于基因组扫描，并确定与血液学反应的关系。随着美国人口的老龄化，MDS的患病率迅速增加，需求量也成比例 医疗资源。拟议的调查应提供重要的深入了解疾病的机制 生物学和开发新的更有效的治疗方法。

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.