Phosphatase Targets of Lenalidomide in Myelodysplastic Syndrome

描述（由申请人提供）：本申请的主要目的是在一项III期组间试验E2905中表征影响治疗反应和耐药性的生物学变量，该试验测试来那度胺（LEN）和达贝泊丁（DA）联合治疗骨髓增生异常综合征（MDS）患者的益处。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红细胞生成素（EPO）中获得持续的益处。首席研究员的研究表明，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的红细胞生成；(1)选择性抑制染色体5q缺失（del5q）克隆，(2)增强EPO受体(R)/STAT5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，在E2905中，EPO应答可能性较低的患者将接受LEN伴或不伴DA治疗。反应率和持续时间可能受到几个生物学变量的影响，包括内源性EPO产量低（仅LEN），无效的EPO- r信号增强，核型未解析的5q缺失以及相关LEN细胞靶标的调节。我们假设LEN通过抑制核型特异性磷酸酶靶点来恢复有效的红细胞生成：(a)抑制非del5q MDS中的CD45磷酸酶以增强EPO-R/STAT5信号，以及(b)抑制del5q克隆中单倍体缺陷的Cdc25c和PP2A磷酸酶导致选择性克隆抑制。为了研究影响E2905治疗反应和耐药的生物学变量，以及MDS中EPO-R信号的调控，我们提出了以下具体目标：探讨CD45亚型对epo诱导的CD71+红细胞前体STAT5磷酸化LEN增强的影响及其与红细胞反应的关系。2. 表征来那度胺对del5q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del5q MDS患者隐匿染色体5q31缺失的频率，并确定其与血液学反应的关系。随着美国人口的老龄化，MDS患病率迅速上升，对医疗资源的需求也成正比。所提出的研究应该为疾病生物学机制和开发新的更有效的治疗方法提供重要的见解。

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.