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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Exploratory/Developmental Grants (R21)
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Developmental Therapeutics Study Section (DT)
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Jessup, John M
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University of Minnesota Twin Cities
Schools of Pharmacy
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