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

• 批准号: 7864317
• 负责人: ALAN F LIST
• 金额: $ 44.22万
• 依托单位: H. LEE MOFFITT CANCER CTR & RES INST
• 依托单位国家: 美国
• 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/7864317
• 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; Erythrocyte Transfusion; Erythrocytes; Erythroid; Erythropoiesis; Erythropoietin; Erythropoietin Receptor; Frequencies; G2/M Transition; Genome Mappings; Genomics; Goals; Growth Factor; Heterogeneity; Investigation; 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

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.

描述（由申请人提供）：该提案的主要目的是表征影响治疗反应和抗药性的生物变量，在III期群体间试验中，E2905，测试了与Lenalidomide（LEN）和Darbepoetin alpha（DA）共同治疗的益处。无效的红细胞生成仍然是MDS的主要治疗挑战，只有少数患者受到重组红细胞生成素（EPO）的持续益处。首席研究者的调查表明，LEN在EPO治疗失败的较低风险的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，以及（2）EPO受体（R）/STAT5信号的增强。 LEN在E2905中测试LEN增强EPO-R信号和促进红血病的能力将进行测试，在E2905中，EPO反应概率较低的患者将接受或不接受DA治疗的LEN。反应率和持续时间可能会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，核型上未解决的5Q缺失以及相关LEN细胞靶标的调节。我们假设Len通过抑制特定于核型特异性的磷酸酶靶标通过抑制非del5q MD的CD45磷酸酶来抑制EPO-R/Stat5信号的抑制CD45磷酸酶来恢复有效的红细胞生成。抑制。为了表征E2905中影响治疗反应和耐药性的生物学变量，以及MDS中EPO-R信号的调节，我们提出了以下具体目的：1。评估CD45同工型对EPO诱导的STAT5 STAT5磷酸化的影响CD71+ Erythroid Protistors and eryyRrodrodrodrodrrodrrodrrodrodrodrod respents。 2。表征与Del5Q细胞中的Lenalidomide细胞毒性相关的分子靶标。 3。通过基于阵列的基因组扫描评估非del5q MD的患者中5q31染色体5q31缺失的频率，并确定与血液学反应的关系。随着美国人口的衰老，MD的患病率随着对医疗资源的比例需求而迅速增加。拟议的研究应为疾病生物学机理和新型更有效的治疗剂的发展提供重要的见解。