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

描述（由申请人提供）：一种新兴的治疗急性髓性白血病（AML）的方法，使用单克隆抗体作为提供靶向治疗的手段。目前利用最多的抗原是CD33，特别是与吉妥珠单抗ozogamicin （GO）一起使用，这是一种免疫偶联物，可导致DNA链断裂，引发DNA修复反应，如果损伤严重，则导致细胞凋亡和细胞死亡。氧化石墨烯单药治疗约四分之一的AML复发患者有效。最近一项大型3期试验的结果表明，在常规化疗中加入氧化石墨烯可显著提高部分新诊断的AML患者的总生存率。这种巨大的患者间反应差异背后的机制仍然知之甚少。我们之前已经证明了CD33的定量表达、CD33/氧化石墨烯复合物的内化/运输以及p -糖蛋白（由ABCB1编码）介导的药物外排对氧化石墨烯功效的重要性。我们目前的初步研究表明，CD33、ABCB1的单核苷酸多态性（snp）和细胞因子信号传导抑制因子3 (SOCS3)（一种与CD33降解有关的基因）与接受go治疗的患者的预后之间存在显著关联。使用从儿童肿瘤组（COG）试验COG- aaml03p1和COG- aaml0531参与者中收集的样本，这两个试验都研究了在标准诱导化疗中添加氧化石墨烯，我们现在提议验证我们的假设，CD33, ABCB1, SOCS3，谷胱甘肽- s转移酶，DNA修复和DNA损伤反应途径基因（XRCC4/5， XPC, PARP1, LIG4， ATM和ATR）中的snp，凋亡相关基因（CASP9和3）与对氧化石墨烯治疗的反应和CD33功能的改变有关。使用两个研究队列，其中一个以随机方式测试氧化石墨烯的益处，不仅可以对我们的发现进行独立验证，还可以将氧化石墨烯疗效的影响与标准化疗疗效的影响分离开来。详细了解snp与氧化石墨烯治疗反应和常规化疗之间的相互作用将对疾病预后和治疗产生重要影响。例如，将SNP信息作为独立的预后标记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，这是目前策略的一大进步。这种改善对氧化石墨烯尤其重要，氧化石墨烯仅对一部分AML患者有效；对这些患者群体进行前瞻性识别，将通过限制有高反应可能性的患者使用氧化石墨烯，并预防其他患者出现不必要的毒性，从而优化氧化石墨烯的使用。然而，我们的发现也可以扩展到针对CD33的第二代免疫偶联物。此外，这项研究将为基因多态性对标准治疗药物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.