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）：急性髓系白血病（AML）的一种新兴方法使用单克隆抗体作为提供靶向治疗的手段。目前最常用的抗原是 CD33，特别是吉妥珠单抗奥佐米星 (GO)，这是一种免疫缀合物，可导致 DNA 链断裂，从而引发 DNA 修复反应，如果损伤严重，会导致细胞凋亡和细胞死亡。 GO 作为单一药物对大约四分之一的复发性 AML 患者有效。一项大型 3 期试验的最新结果表明，在常规化疗中添加 GO 可以显着提高新诊断的 AML 患者的总体生存率。这种患者间反应的巨大差异背后的机制仍然知之甚少。我们之前已经证明了定量 CD33 表达、CD33/GO 复合物的内化/运输以及 P-糖蛋白（由 ABCB1 编码）介导的药物流出对 GO 功效的重要性。我们的初步研究现在表明，CD33、ABCB1 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）中的单核苷酸多态性 (SNP) 与接受基于 GO 的治疗的患者的结果之间存在显着关联。使用从参加儿童肿瘤学组 (COG) 试验 COG-AAML03P1 和 COG-AAML0531 的参与者收集的样本，这两项试验都研究在标准诱导化疗中添加 GO，我们现在建议检验我们的假设，即 CD33、ABCB1、SOCS3、谷胱甘肽中的 SNP -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）以及凋亡相关基因（CASP9 和 3）与基于 GO 的治疗的反应和 CD33 功能的改变相关。使用两个研究队列，包括以随机方式测试 GO 益处的队列，不仅可以独立验证我们的研究结果，还可以将 GO 疗效的影响与标准化疗药物的疗效分开。详细了解 SNP 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，将提供一个机会，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，这是目前的重大进步策略。这种改善对于 GO 来说尤其重要，因为 GO 仅在一部分 AML 患者中显示出疗效；对这些患者群体的前瞻性识别将通过限制高可能性反应的患者并预防其他人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针对 CD33 的第二代免疫偶联物。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 的治疗具有广泛的影响。 公共健康相关性：急性髓性白血病 (AML) 是一种难以治疗的血癌，其一种治疗方法是使用一种名为 GO（吉妥珠单抗奥佐米星的简称）的抗体，该抗体可识别并损害白血病细胞，同时使大多数正常细胞不受影响；然而，个体之间对 GO 的临床反应存在很大差异。 患者。拟议的研究旨在通过深入研究影响 GO 抗癌作用的遗传因素来提高我们预测这些反应的能力。这些研究的成功将使基于反应的可能性更好、更个性化地使用 GO，从而优化该药物的使用。