Phosphatase Targets of Lenalidomide in Myelodysplastic Syndrome

描述（由申请人提供）：本提案的主要目的是描述影响III期组间试验E2905中治疗应答和耐药的生物学变量，该试验旨在检测来那度胺（LEN）和达贝泊苷α（DA）联合治疗骨髓增生异常综合征（MDS）患者的获益。无效的红细胞生成仍然是MDS的主要治疗挑战，只有少数患者从重组促红细胞生成素（EPO）中持续获益。主要研究者的研究表明，LEN在EPO治疗失败的低风险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中的红细胞生成：（1）选择性抑制染色体5 q缺失（del 5 q）克隆，和（2）增强EPO受体（R）/STAT 5信号。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）、无效的EPO-R信号增强、核型未分辨的5 q缺失和相关LEN细胞靶点的调节。我们假设LEN通过抑制具有核型特异性的磷酸酶靶标来恢复有效的红细胞生成：（a）抑制非del 5 q MDS中的CD 45磷酸酶以增强EPO-R/STAT 5信号，和（B）抑制del 5 q克隆中的单倍缺陷型Cdc 25 c和PP 2A磷酸酶，导致选择性克隆抑制。为了表征影响E2905中治疗反应和抗性的生物学变量，以及MDS中EPO-R信号的调节，我们提出以下具体目的：1.评价CD 45亚型谱对LEN增强EPO诱导的CD 71+红系前体细胞中STAT 5磷酸化的影响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.通过基于阵列的基因组扫描评估非del 5 q MDS患者中隐性染色体5 q31缺失的频率，并确定与血液学缓解的关系。随着美国人口的老龄化，MDS的患病率迅速增加，对医疗资源的需求也成比例。拟议的调查应提供重要的洞察疾病的生物学机制和新的更有效的治疗方法的发展。

DESCRIPTION (provided by applicant): 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.