Impact of genetic variation on response to GO therapy in COG-AML clinical trials

COG-AML 临床试验中遗传变异对 GO 治疗反应的影响

• 批准号: 8303927
• 负责人: Jatinder K. Lamba
• 金额: $ 24.47万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-05 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8303927
• 关键词: ABCB1 gene; Acute Myelocytic Leukemia; Antibodies; Antigens; Apoptosis; CASP9 gene; Cell Death; Cell Line; Cell surface; Cells; Childhood; Children' s Oncology Group; Classification; Clinical; Clinical Research; Clinical Trials; Code; Cohort Studies; Complex; Cytokine Inducible SH2-Containing Protein; DNA Damage; DNA Double Strand Break; DNA Repair; DNA strand break; Development; Disease; Drug Efflux; Drug usage; Enrollment; Gemtuzumab Ozogamicin; Generations; Genes; Genetic; Genetic Polymorphism; Genetic Variation; Glutathione S Transferase 3; Glutathione S-Transferase; Hematopoietic Neoplasms; Immunoconjugates; In Vitro; Individual; LIG4 gene; Lead; Left; Malignant Neoplasms; Mediating; Medical Research; Modeling; Molecular Cytogenetics; Monoclonal Antibodies; Newly Diagnosed; Normal Cell; Outcome; P-Glycoprotein; Participant; Pathway interactions; Patients; Phase; Phase III Clinical Trials; Prevention; Prognostic Marker; Protein Isoforms; Randomized; Relapse; Research; Risk; Role; Single Nucleotide Polymorphism; Specimen; Surface Antigens; Testing; Therapeutic; Toxic effect; Validation; Variant; XRCC4 gene; base; chemotherapy; clinically significant; cohort; cytotoxic; cytotoxicity; genetic variant; improved; insight; leukemia; novel; patient population; preclinical study; prospective; response; success; trafficking

DESCRIPTION (provided by applicant): An emerging approach in acute myeloid leukemia (AML) uses monoclonal antibodies as a means to deliver targeted therapy. The antigen currently most exploited is CD33, in particular with gemtuzumab ozogamicin (GO), an immunoconjugate that causes DNA strand breaks that elicit a DNA repair response and, if damage is overwhelming, lead to apoptosis and cell death. GO is efficacious in about one quarter of relapsed AML patients as single agent. Recent findings from a large phase 3 trial indicate that addition of GO to conventional chemotherapy significantly improves overall survival in a subset of newly diagnosed AML patients. The mechanisms underlying this substantial inter-patient variability of response remain poorly understood. We have previously demonstrated the importance of quantitative CD33 expression, internalization/trafficking of the CD33/GO complex, and drug efflux mediated by P-glycoprotein (encoded by ABCB1) for GO efficacy. Our preliminary studies now suggest significant associations between single nucleotide polymorphisms (SNPs) in CD33, ABCB1, and suppressor of cytokine signaling 3 (SOCS3), a gene implicated in CD33 degradation, with outcome in patients receiving GO-based therapy. Using specimens collected from participants enrolled in Children's Oncology Group (COG) trials COG-AAML03P1 and COG-AAML0531, both investigating the addition of GO to standard induction chemotherapy, we now propose to test our hypothesis that SNPs in CD33, ABCB1, SOCS3, glutathione-S-transferases, DNA-repair and DNA -damage response pathway genes (XRCC4/5, XPC, PARP1, LIG4, ATM, and ATR), and apoptosis-related genes (CASP9 and 3) are associated with response to GO-based therapy and altered CD33 function. The use of two study cohorts, including one that tested the benefit of GO in a randomized fashion, will not only allow an independent validation of our findings but also the separation of effects on GO efficacy from those on efficacy of standard chemotherapeutics. A detailed understanding of the interplay between SNPs and therapeutic response to GO and conventional chemotherapy will have significant consequences for disease prognostication and therapy. For example, integration of SNP information as independent prognostic markers into cytogenetic/molecular-based risk classification models would present an opportunity to increase our accuracy in forecasting therapeutic outcome in AML and allow the development of improved risk-stratified therapies, a major advancement over current strategies. Such an improvement is particularly important for GO, which has shown efficacy only in a subset of AML patients; prospective identification of these patient populations would lead to optimized use of GO through restriction to patients with high likelihood of response and prevention of unnecessary toxicities in others. However, our findings may extend to second-generation immunoconjugates targeting CD33 as well. Moreover, this research will provide novel insights into the impact of genetic polymorphisms on efficacy of standard therapeutics with broad implications for the treatment of AML. PUBLIC HEALTH RELEVANCE: One therapeutic approach for acute myeloid leukemia (AML), a difficult-to-treat blood cancer, uses an antibody called GO (a short term for gemtuzumab ozogamicin) that recognizes and damages leukemia cells while leaving most normal cells unaffected; however, there is substantial variability in clinical response to GO between individual patients. The proposed research seeks to improve our ability to predict these responses through in-depth study of genetic factors that influence the anti-cancer effects of GO. Success in these studies will enable better, more personalized use of GO based on likelihood of response, thereby leading to optimized use of this drug.

描述（由申请人提供）：急性髓样白血病（AML）的新兴方法使用单克隆抗体作为提供靶向治疗的一种手段。目前最受剥削的抗原是CD33，特别是用Gemtuzumab Ozogamicin（GO）（一种免疫偶联物），会导致DNA链断裂会引起DNA修复反应，如果损害造成损害，则导致凋亡和细胞死亡。在大约四分之一的复发AML患者中，GO是有效的。大型3期试验的最新发现表明，在新诊断的AML患者的一部分中，加入常规化学疗法可显着提高总体存活率。这种实质性反应变异性的基础机制仍然很少理解。我们先前已经证明了定量CD33表达，CD33/GO复合物的内在化/运输以及由P-糖蛋白（由ABCB1编码）介导的GO疗效的药物外排的重要性。我们的初步研究现在表明，CD33，ABCB1中的单核苷酸多态性（SNP）与细胞因子信号3（SOCS3）的抑制剂之间的显着关联，该基因与CD33降解有关，与接受GO基疗法的患者结合了结果。使用从参加儿童肿瘤学组（COG）试验的参与者收集的标本COG-AAML03P1和COG-AAML0531，都研究了加入到标准归纳化学疗法中的添加，我们现在建议测试我们的假设，即我们的假设，即CD33，CD33，ABCB1，SOCS3，Glutathione-s-s-s-s-s-nirose-dna-dna-dna-dna-dna-dna-dna-dna-dna-dna-dna-dna-dna-dna-dna-dna-dna-dna-dna-dna-dna-dna-dna-dna-dna-dna--基因（XRCC4/5，XPC，PARP1，LIG4，ATT和ATR）和与凋亡相关的基因（CASP9和3）与对基于GO的治疗和CD33功能的反应有关。使用两个研究队列，其中包括一个以随机方式测试GO的好处的同类，不仅可以独立验证我们的发现，而且还可以将对GO疗效的影响分离与标准化学治疗疗法的功效。对SNP与GO和常规化学疗法的治疗反应之间的相互作用的详细理解将对疾病的预后和治疗产生重大影响。例如，将SNP信息作为独立预后标记的整合到基于细胞遗传学/分子的风险分类模型中，将为提高我们在AML预测治疗结果的准确性，并允许改善风险分解的治疗疗法的准确性，这是当前策略的主要进步。这种改善对于GO尤其重要，GO仅在AML患者的一部分中显示出功效。对这些患者人群的前瞻性识别将导致对具有很可能反应和预防不必要毒性的患者进行优化使用GO通过限制。但是，我们的发现也可能扩展到针对CD33的第二代免疫偶联物。此外，这项研究将提供对遗传多态性对标准疗法功效的影响的新见解，对AML的治疗具有广泛的影响。 公共卫生相关性：一种难以治疗的血液癌的急性髓样白血病（AML）的一种治疗方法，使用一种称为GO的抗体（gemtuzumab ozogamicin的短期），识别和损害白血病细胞，而留下大多数正常细胞的抗体。但是，临床反应在个人之间存在很大差异 患者。拟议的研究旨在通过对影响GO抗癌作用的遗传因素进行深入研究来提高我们预测这些反应的能力。这些研究的成功将根据反应的可能性更好，更个性化的GO使用，从而导致对该药物的优化使用。