Title of Research: The CIDDR Gene Expression Signature Predicts Response to Gemtuzumab Ozogamicin
Additional Authors: V. Shastri; A. Elsayed; R. Rafiee; R. Ries; S. Meshinchi; J. Lamba
Abstract:
In 2017, the FDA announced reapproval of gemtuzumab ozogamicin (GO), a CD33-directed immunoconjugate, for treatment of AML. While the future of GO in AML is bright, studies have shown that there is interpatient variability in GO response. Hitherto, efforts to understand this interpatient variation in regard to calicheamicin, the DNA-damaging cytoxin linked to the antibody portion of GO, have been limited. In this study, our group used LASSO regression to generate a calicheamicin-induced DNA-damage response (CIDDR) gene expression signature specifically predictive of clinical outcome and response to GO in pediatric AML patients. The CIDDR signature was subsequently applied to gene expression data from pediatric AML patients treated with (GO patients) and without GO (NoGO patients) to assign them a CIDDR score. Thereafter, patients were dichotomized into high and low score groups and the association of the score groups with clinical outcome and response was assessed. GO patients in the low CIDDR score group had superior five-year event-free survival (EFS; 65.2% vs 25.7%, P = 9.13*10-9) compared to the high CIDDR score group. Similar results were observed when assessing the association between CIDDR score groups and achievement of complete remission (low vs high: 82.8% vs 66.7% P = 0.04). However, these associations were not observed for NoGO patients. We further confirmed the effects of the role of the genes in the CIDDR signature in AML cell lines. In most cases, siRNA knockdown of genes within the CIDDR signature conferred a correlative difference in sensitivity to calicheamicin. Put together, these results hold promise as a tool for guiding clinical decisions regarding GO and efforts are ongoing to expand this investigation to bigger and more diverse AML cohorts.
About the author
Mohammed Gbadamosi is a fourth-year Ph.D. candidate in the Department of Pharmacotherapy and Translational Research at the University of Florida College of Pharmacy. Prior to joining the University of Florida, Mohammed received a B.S. degree in Biochemistry with a minor in Biochemical Engineering from the University of Delaware where his research focused on elucidating reaction mechanisms for photodynamic therapeutic agents. Currently, he conducts his doctoral research under the mentorship of Dr. Jatinder Lamba Ph.D. focused on understanding how interpatient variation influences response to immunotherapy in acute myeloid leukemia (AML) and leveraging that information to improve immunotherapeutic treatment strategies. Thus far research findings have been presented at local and national conferences receiving many awards and accolades. Outside the context of research, Mohammed has served in several professional and student organizations and is committed to promoting diversity and a warm academic community overall.