Christian A Fernandez

Dr. Christian Fernandez is an Associate Professor at Department of Pharmaceutical Sciences and a member of the Center for Pharmacogenetics at the University of Pittsburgh School of Pharmacy. He received his Ph.D. from the University of Iowa College of Pharmacy, and he completed his postdoctoral fellowship with Dr. Mary Relling at St. Jude Children's Research Hospital. The Fernandez lab is dedicated to advancing cancer research through the use of mechanistic pharmacology and pharmacogenomic approaches. Our current focus areas include investigating drug-induced immunogenicity and liver injury, developing targeted agents for acute lymphoblastic leukemia, preventing capecitabine-induced hand foot syndrome, and elucidating the role of the NFAT transcription factor on immune cells. Our goal is to improve cancer treatment and patient outcomes by deepening our understanding of these complex biological processes. The immunogenicity of protein-based therapeutics is a major problem that can lead to life-threatening complications and reduce or eliminate the therapeutic effects of biologics. The objectives of Dr. Fernandez's immunogenicity research are to elucidate the mechanism of adverse drug reaction by identifying polymorphisms (variations) in genes that can explain why certain patients are predisposed to developing immune responses to biologics, to identify therapeutic strategies that can block and maintain therapeutic drug concentrations, and to develop clinical laboratory tests that can monitor drug bioavailability and immunogenicity to indicate when a drug substitution is appropriate. Our drug-induced liver injury research focuses on understanding the hepatotoxicity associated with asparaginase, a biologic and essential component of multi-agent chemotherapy for childhood leukemias. Unfortunately, due to the high risk of hepatotoxicity, adult leukemia regimens avoid asparaginase. Our clinical pharmacogenomic research in this field has led to the identification of an association between the PNPLA3 I148M risk variant and asparaginase-induced liver injury. Moreover, our preclinical mechanistic research has revealed a novel mechanism of drug-induced toxicity involving crosstalk between multiple organs, including adipose tissue and the liver. As a result of this crosstalk, asparaginase leads to drug-induced fatty liver and sensitization to lipotoxicity. By further elucidating these complex mechanisms, we aim to improve our understanding of drug-induced liver injury and ultimately improve patient outcomes. Our research project on capecitabine-induced hand-foot syndrome is motivated by the experiences of our metastatic breast cancer (MBC) patients. Our aim is to delay disease progression and minimize the dose-limiting toxicity caused by this syndrome. To achieve this, we have planned a comprehensive pharmacogenetic clinical study that involves analyzing genes associated with capecitabine disposition. By identifying high-risk patients who are likely to develop hand-foot syndrome, we can tailor treatment plans that minimize the likelihood of this outcome. Our preclinical studies will also investigate the impact of capecitabine metabolites on the onset of hand-foot syndrome, and we will develop novel pharmacological strategies to counteract this toxicity. We hypothesize that factors that increase capecitabine activation, 5-FU metabolite formation, or pharmacodynamic effects will exacerbate the severity or incidence of hand-foot syndrome. However, we postulate that we can mitigate the syndrome locally without compromising the efficacy of capecitabine against MBC. This project is significant because it will enable personalized capecitabine therapy that delays MBC disease progression and the development of new metastases. In addition to our research aiming to attenuate toxicities to current pharmacotherapy, our research team is also actively investigating personalized medicine approaches for targeting acute lymphoblastic leukemias with poor prognosis. For these studies, we use patient leukemia samples to identify leukemias subtypes with constitutive activation of transcription factors involved in lymphocyte functions, perform mechanistic studies elucidating the role of these proteins on leukemia proliferation and disease progression, and develop small molecule inhibitors that can target the transcription factor signaling cascade. Altogether, the translational research performed by the Fernandez lab aims to enhance treatment outcomes by elucidating the underlying mechanisms of toxicity/cancer, identifying potential druggable targets, and performing drug discovery experiments to effectively translate bench work to clinical practice. Pharmacology Pharmacogenomics Acute lymphoblastic leukemia Drug-induced immunogenicity Drug-induced liver injury Immunopharmacology