Phosphatase Targets of Lenalidomide in Myelodysplastic Syndrome

这项建议的主要目标是表征影响治疗反应的生物变量和 测试来那度胺联合治疗的益处的第三阶段组间试验E2905的耐药性 骨髓增生异常综合征(MDS)患者外周血中LAN和DA的变化无效的红细胞生成 仍然是MDS的主要治疗挑战，只有少数患者经历了 受益于重组促红细胞生成素(EPO)。首席调查员的调查显示， LEN在EPO治疗失败的低危MDS患者中具有红细胞生成活性。我们的实验室 研究表明，LEN通过两种不同的机制促进MDS患者的红细胞生成：(1)选择性 抑制染色体5q缺失(Del5q)克隆，以及(2)EPO受体(R)/STAT5的增强 信号。LEN增强EPO-R信号和促进红细胞生成的能力将在E2905中进行测试 其中EPO应答概率较低的患者将接受LEN，无论是否接受DA治疗。 应答率和持续时间可能受到几个生物变量的影响，包括低内源性EPO 生产(仅限LEN)，无效的EPO-R信号增强，核型未解决的5q缺失，以及 相关晶状体细胞靶点的调制。我们假设Len通过 核型特异的磷酸酶靶标的抑制：(A)非淋巴细胞CD45磷酸酶的抑制 Del5q MDS增强EPO-R/STAT5信号，以及(B)抑制单链缺陷的CDC25c和PP2A Del5q克隆中的磷酸酶导致选择性克隆抑制。对生物变量进行表征 影响E2905细胞的治疗反应和耐药性，以及对MDS患者EPO-R信号的调节 提出以下具体目标： 1.探讨CD45亚型在EPO诱导的STAT5磷酸化中对晶状体增强作用的影响 CD71+红系前体细胞与红系反应的关系。 2.研究来那度胺对Del5q细胞毒性的分子靶点。 3.应用微阵列技术检测非缺失5q MDS患者染色体5q31缺失频率。 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的患病率正在迅速增加，需求成比例 关于医疗资源。拟议的调查应该为疾病的发病机制提供重要的见解。 生物学和新的更有效的疗法的发展。

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.