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

描述(由申请人提供)：一种治疗急性髓系白血病(AML)的新兴方法使用单抗作为提供靶向治疗的手段。目前使用最多的抗原是CD33，特别是与getuzumab ozogamicin(GO)一起使用，这是一种免疫结合物，可导致DNA链断裂，从而引发DNA修复反应，如果损伤严重，则会导致细胞凋亡和细胞死亡。作为单一药物，GO在约四分之一的复发AML患者中有效。一项大型3期试验的最新发现表明，在常规化疗的基础上加用GO可显著提高部分新诊断AML患者的总存活率。这种患者间反应的巨大变异性背后的机制仍然知之甚少。我们以前已经证明了CD33的定量表达、CD33/GO复合体的内化/运输以及由P-糖蛋白(由ABCB1编码)介导的药物外流对GO疗效的重要性。我们的初步研究表明，CD33、ABCB1的单核苷酸多态(SNPs)和细胞因子信号传导抑制因子3(SOCS3)基因(与CD33降解有关)与接受GO治疗的患者的预后显著相关。利用从儿童肿瘤组试验COG-AAML03P1和COG-AAML0531中收集的样本，这两个试验都在研究GO在标准诱导化疗中的添加，我们现在建议检验我们的假设，即CD33、ABCB1、SOCS3、谷胱甘肽S转移酶、DNA修复和DNA损伤反应通路基因(XRCC4/5、XPC、PARP1、LIG4、ATM和ATR)以及凋亡相关基因(CASP9和3)的SNP与基于GO的治疗反应和CD33功能改变有关。使用两个研究队列，其中一个以随机方式测试GO的益处，不仅可以独立验证我们的发现，还可以将GO疗效与标准化疗药物疗效的影响分开。详细了解SNPs与GO和常规化疗的治疗反应之间的相互作用，将对疾病预测和治疗产生重要影响。例如，将作为独立预后标志的SNP信息整合到细胞遗传学/基于分子的风险分类模型中，将提供一个机会来提高我们预测急性髓细胞白血病治疗结果的准确性，并允许开发改进的风险分层治疗，这是相对于当前策略的一个重大进步。这种改善对GO尤其重要，它只在AML患者中的一小部分患者中显示出疗效；对这些患者群体的前瞻性识别将导致对具有很高反应可能性的患者最佳地使用GO直通限制，并防止其他患者出现不必要的毒性。然而，我们的发现也可能扩展到针对CD33的第二代免疫结合物。此外，这项研究将为基因多态对标准疗法疗效的影响提供新的见解，对急性髓细胞白血病的治疗具有广泛的意义。

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.