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

描述（由申请人提供）：急性髓性白血病（AML）的一种新兴方法使用单克隆抗体作为靶向治疗的手段。目前开发最多的抗原是CD 33，特别是与吉妥珠单抗（gemtuzumab ozogamicin，GO），一种免疫缀合物，其引起DNA链断裂，引发DNA修复反应，并且如果损伤是压倒性的，则导致细胞凋亡和细胞死亡。GO作为单一药物在约四分之一的复发性AML患者中有效。一项大型3期试验的最新发现表明，在常规化疗中加入GO可显著改善新诊断的AML患者亚组的总生存期。这种患者间反应差异的机制仍然知之甚少。我们先前已经证明了定量CD 33表达、CD 33/GO复合物的内化/运输以及由P-糖蛋白（由ABCB 1编码）介导的药物外排对于GO疗效的重要性。我们的初步研究表明，CD 33、ABCB 1和细胞因子信号转导抑制因子3（SOCS 3）（一种与CD 33降解有关的基因）的单核苷酸多态性（SNP）与接受GO治疗的患者的结局之间存在显著相关性。使用从儿童肿瘤组（COG）试验COG-AAML 03 P1和COG-AAML 0531中招募的参与者收集的标本，这两项试验都研究了在标准诱导化疗中加入GO，我们现在建议检验我们的假设，即CD 33，ABCB 1，SOCS 3，谷胱甘肽-S-转移酶，DNA修复和DNA损伤反应途径基因中的SNP（XRCC 4/5、XPC、PARP 1、LIG 4、ATM和ATR）和前列腺增生相关基因（CASP 9和3）与对基于GO的治疗的应答和改变的CD 33功能相关。使用两个研究队列，包括一个以随机方式测试GO益处的队列，不仅可以独立验证我们的发现，还可以将对GO疗效的影响与对标准化疗药物疗效的影响分开。详细了解SNP与对GO和常规化疗的治疗反应之间的相互作用将对疾病诊断和治疗产生重大影响。例如，将SNP信息作为独立的预后标志物整合到基于细胞遗传学/分子的风险分类模型中，将有机会提高我们预测AML治疗结果的准确性，并允许开发改进的风险分层疗法，这是对当前策略的重大进步。这种改善对于GO尤其重要，GO仅在AML患者的一个亚组中显示出疗效;这些患者人群的前瞻性识别将通过限制具有高应答可能性的患者和预防其他患者中不必要的毒性来优化GO的使用。然而，我们的研究结果也可能扩展到靶向CD 33的第二代免疫缀合物。此外，这项研究将为遗传多态性对标准疗法疗效的影响提供新的见解，对AML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.