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.
Pharmacogenomics
Acute lymphoblastic leukemia
Drug-induced immunogenicity
Drug-induced liver injury
Immunopharmacology
2020: The American Society for Pharmacology and Experimental Therapeutics (ASPET) Translational and Clinical Pharmacology (TCP) Early Career Award
2014: American Society of Hematology (ASH) Abstract Achievement Award
2012: National Institute of General Medical Sciences (NIGMS) Workshop for Postdoc Transitioning to Independent Positions Travel Award
2010: American Society of Gene & Cell Therapy (ASGCT) Abstract Travel Award
2010: St. Jude Children’s Research Hospital National Graduate Student Symposium Travel Award and Participant
Fernandez CA. Pharmacological strategies for mitigating anti-TNF biologic immunogenicity in rheumatoid arthritis patients. Curr Opin Pharmacol. 2022 Dec 27;68. PMID: 36580770.
Castanha PMS, Tuttle DJ, Kitsios GD, Jacobs JL, Braga-Neto U, Duespohl M, Rathod S, Marti MM, Wheeler S, Naqvi A, Staines B, Mellors J, Morris A, McVerry BJ, Shah F, Schaefer C, Macatangay BJC, Methe B, Fernandez CA, Barratt-Boyes SM, Burke D, Marques ETA. Contribution of Coronavirus-Specific Immunoglobulin G Responses to Complement Overactivation in Patients with Severe Coronavirus Disease 2019. J Infect Dis. 2022 Sep 13;226(5):766-777. doi: 10.1093/infdis/jiac091. PubMed PMID: 35267024; PubMed Central PMCID: PMC8992249.
Moharil P, Wan Z, Pardeshi A, Li J, Huang H, Luo Z, Rathod S, Zhang Z, Chen Y, Zhang B, Fernandez CA, Sun J, Li S. Engineering a folic acid-decorated ultrasmall gemcitabine nanocarrier for breast cancer therapy: Dual targeting of tumor cells and tumor-associated macrophages. Acta Pharm Sin B. 2022 Mar;12(3):1148-1162. doi: 10.1016/j.apsb.2021.09.024. Epub 2021 Sep 30. Review. PubMed PMID: 35530140; PubMed Central PMCID: PMC9072252.
Kumar GVN, Hoshitsuki K, Rathod S, Ramsey MJ, Kokai L, Kershaw EE, Xie W, Fernandez CA. Mechanistic studies of PEG-asparaginase-induced liver injury and hepatic steatosis in mice. Acta Pharm Sin B. 2021 Dec;11(12):3779-3790. doi: 10.1016/j.apsb.2021.11.022. Epub 2021 Dec 4. PubMed PMID: 35024306; PubMed Central PMCID: PMC8727916.
Bhingarkar A, Vangapandu HV, Rathod S, Hoshitsuki K, Fernandez CA. Amino Acid Metabolic Vulnerabilities in Acute and Chronic Myeloid Leukemias. Front Oncol. 2021;11:694526. doi: 10.3389/fonc.2021.694526. eCollection 2021. Review. PubMed PMID: 34277440; PubMed Central PMCID: PMC8281237.
Saito T, Wei Y, Wen L, Srinivasan C, Wolthers BO, Tsai CY, Harris MH, Stevenson K, Byersdorfer C, Oparaji JA, Fernandez C, Mukherjee A, Abu-El-Haija M, Agnihotri S, Schmiegelow K, Showalter MR, Fogle PW, McCulloch S, Contrepois K, Silverman LB, Ding Y, Husain SZ. Impact of acute lymphoblastic leukemia induction therapy: findings from metabolomics on non-fasted plasma samples from a biorepository. Metabolomics. 2021 Jun 27;17(7):64. doi: 10.1007/s11306-021-01814-2. PubMed PMID: 34175981.
Hoshitsuki K, Fernandez CA, Yang JJ. Pharmacogenomics for Drug Dosing in Children: Current Use, Knowledge, and Gaps. J Clin Pharmacol. 2021 Jun;61 Suppl 1:S188-S192. doi: 10.1002/jcph.1891. PubMed PMID: 34185912; PubMed Central PMCID: PMC8259917.
Guo W, Wang Y, Yang M, Wang Z, Wang Y, Chaurasia S, Wu Z, Zhang M, Yadav GS, Rathod S, Concha-Benavente F, Fernandez C, Li S, Xie W, Ferris RL, Kammula US, Lu B, Yang D. LincRNA-immunity landscape analysis identifies EPIC1 as a regulator of tumor immune evasion and immunotherapy resistance. Sci Adv. 2021 Feb;7(7). doi: 10.1126/sciadv.abb3555. Print 2021 Feb. PubMed PMID: 33568470; PubMed Central PMCID: PMC7875530.
Hoshitsuki K, Rathod S, Ramsey MJ, Zhu L, Moreland LW, Fernandez CA. Adalimumab Immunogenicity Is Negatively Correlated with Anti-Hinge Antibody Levels in Patients with Rheumatoid Arthritis. J Pharmacol Exp Ther. 2020 Dec;375(3):488-497. doi: 10.1124/jpet.120.000179. Epub 2020 Oct 2. PubMed PMID: 33008870; PubMed Central PMCID: PMC7718728.
Rathod S, Ramsey M, Finkelman FD, Fernandez CA. Genetic inhibition of NFATC2 attenuates asparaginase hypersensitivity in mice. Blood Adv. 2020 Sep 22;4(18):4406-4416. doi: 10.1182/bloodadvances.2020002478. PubMed PMID: 32931581; PubMed Central PMCID: PMC7509855.
Rathod S, Ramsey M, DiGiorgio D, Berrios R, Finkelman FD, Fernandez CA. Asparaginase immune complexes induce Fc-γRIII-dependent hypersensitivity in naive mice. FASEB J. 2019 Oct;33(10):10996-11005. doi: 10.1096/fj.201900857. Epub 2019 Jul 5. PubMed PMID: 31284767; PubMed Central PMCID: PMC6766650.
Xu J, Sun J, Ho PY, Luo Z, Ma W, Zhao W, Rathod SB, Fernandez CA, Venkataramanan R, Xie W, Yu AM, Li S. Creatine based polymer for codelivery of bioengineered MicroRNA and chemodrugs against breast cancer lung metastasis. Biomaterials. 2019 Jul;210:25-40. doi: 10.1016/j.biomaterials.2019.04.025. Epub 2019 Apr 26. PubMed PMID: 31054369; PubMed Central PMCID: PMC6538300.
Long K, Kostman SJ, Fernandez C, Burnett JC, Huryn DM. Do Zebrafish Obey Lipinski Rules?. ACS Med Chem Lett. 2019 Jun 13;10(6):1002-1006. doi: 10.1021/acsmedchemlett.9b00063. eCollection 2019 Jun 13. PubMed PMID: 31223462; PubMed Central PMCID: PMC6580538.
Long K, Kostman SJ, Fernandez CA, Burnett JC, Huryn DM. Do Zebrafish Obey Lipinski Rules. ACS Med. Chem. Lett. 2019 April; 10(6):1002-1006.
Rathod S, Ramsey M, Relling MV, Finkelman FD, Fernandez CA. Hypersensitivity reactions to asparaginase in mice are mediated by anti-asparaginase IgE and IgG and the immunoglobulin receptors FcεRI and FcγRIII. Haematologica. 2019 Feb;104(2):319-329. doi: 10.3324/haematol.2018.199448. Epub 2018 Sep 20. PubMed PMID: 30237274; PubMed Central PMCID: PMC6355496.
Liu Y, Fernandez CA, Relling MV. Response to "PNPLA3 rs738409 and Hepatotoxicity in Children With B-cell Acute Lymphoblastic Leukemia: A Validation Study in a Spanish Cohort". Clin Pharmacol Ther. 2017 Dec;102(6):907. doi: 10.1002/cpt.761. Epub 2017 Jul 26. PubMed PMID: 28744849.
Sun J, Liu Y, Chen Y, Zhao W, Zhai Q, Rathod S, Huang Y, Tang S, Kwon YT, Fernandez C, Venkataramanan R, Li S. Doxorubicin delivered by a redox-responsive dasatinib-containing polymeric prodrug carrier for combination therapy. J Control Release. 2017 Jul 28;258:43-55. doi: 10.1016/j.jconrel.2017.05.006. Epub 2017 May 12. PubMed PMID: 28501705; PubMed Central PMCID: PMC5525542.
Liu Y, Fernandez CA, Smith C, Yang W, Cheng C, Panetta JC, Kornegay N, Liu C, Ramsey LB, Karol SE, Janke LJ, Larsen EC, Winick N, Carroll WL, Loh ML, Raetz EA, Hunger SP, Devidas M, Yang JJ, Mullighan CG, Zhang J, Evans WE, Jeha S, Pui CH, Relling MV. Genome-Wide Study Links PNPLA3 Variant With Elevated Hepatic Transaminase After Acute Lymphoblastic Leukemia Therapy. Clin Pharmacol Ther. 2017 Jul;102(1):131-140. doi: 10.1002/cpt.629. Epub 2017 Apr 4. PubMed PMID: 28090653; PubMed Central PMCID: PMC5511775.
Karol SE, Larsen E, Cheng C, Cao X, Yang W, Ramsey LB, Fernandez CA, McCorkle JR, Paugh SW, Autry RJ, Lopez-Lopez E, Diouf B, Jeha S, Pui CH, Raetz EA, Winick NJ, Carroll WL, Hunger SP, Loh ML, Devidas M, Evans WE, Yang JJ, Relling MV. Genetics of ancestry-specific risk for relapse in acute lymphoblastic leukemia. Leukemia. 2017 Jun;31(6):1325-1332. doi: 10.1038/leu.2017.24. Epub 2017 Jan 18. PubMed PMID: 28096535; PubMed Central PMCID: PMC5462853.
Karol SE, Mattano LA Jr, Yang W, Maloney KW, Smith C, Liu C, Ramsey LB, Fernandez CA, Chang TY, Neale G, Cheng C, Mardis E, Fulton R, Scheet P, San Lucas FA, Larsen EC, Loh ML, Raetz EA, Hunger SP, Devidas M, Relling MV. Genetic risk factors for the development of osteonecrosis in children under age 10 treated for acute lymphoblastic leukemia. Blood. 2016 Feb 4;127(5):558-64. doi: 10.1182/blood-2015-10-673848. Epub 2015 Nov 20. PubMed PMID: 26590194; PubMed Central PMCID: PMC4742546.
Karol SE, Yang W, Van Driest SL, Chang TY, Kaste S, Bowton E, Basford M, Bastarache L, Roden DM, Denny JC, Larsen E, Winick N, Carroll WL, Cheng C, Pei D, Fernandez CA, Liu C, Smith C, Loh ML, Raetz EA, Hunger SP, Scheet P, Jeha S, Pui CH, Evans WE, Devidas M, Mattano LA Jr, Relling MV. Genetics of glucocorticoid-associated osteonecrosis in children with acute lymphoblastic leukemia. Blood. 2015 Oct 8;126(15):1770-6. doi: 10.1182/blood-2015-05-643601. Epub 2015 Aug 11. PubMed PMID: 26265699; PubMed Central PMCID: PMC4600016.
Fernandez CA, Smith C, Yang W, Mullighan CG, Qu C, Larsen E, Bowman WP, Liu C, Ramsey LB, Chang T, Karol SE, Loh ML, Raetz EA, Winick NJ, Hunger SP, Carroll WL, Jeha S, Pui CH, Evans WE, Devidas M, Relling MV. Genome-wide analysis links NFATC2 with asparaginase hypersensitivity. Blood. 2015 Jul 2;126(1):69-75. doi: 10.1182/blood-2015-02-628800. Epub 2015 May 18. PubMed PMID: 25987655; PubMed Central PMCID: PMC4492197.
Paugh SW, Bonten EJ, Savic D, Ramsey LB, Thierfelder WE, Gurung P, Malireddi RK, Actis M, Mayasundari A, Min J, Coss DR, Laudermilk LT, Panetta JC, McCorkle JR, Fan Y, Crews KR, Stocco G, Wilkinson MR, Ferreira AM, Cheng C, Yang W, Karol SE, Fernandez CA, Diouf B, Smith C, Hicks JK, Zanut A, Giordanengo A, Crona D, Bianchi JJ, Holmfeldt L, Mullighan CG, den Boer ML, Pieters R, Jeha S, Dunwell TL, Latif F, Bhojwani D, Carroll WL, Pui CH, Myers RM, Guy RK, Kanneganti TD, Relling MV, Evans WE. NALP3 inflammasome upregulation and CASP1 cleavage of the glucocorticoid receptor cause glucocorticoid resistance in leukemia cells. Nat Genet. 2015 Jun;47(6):607-14. doi: 10.1038/ng.3283. Epub 2015 May 4. PubMed PMID: 25938942; PubMed Central PMCID: PMC4449308.
Fernandez CA, Smith C, Karol SE, Ramsey LB, Liu C, Pui CH, Jeha S, Evans WE, Finkelman FD, Relling MV. Effect of premedications in a murine model of asparaginase hypersensitivity. J Pharmacol Exp Ther. 2015 Mar;352(3):541-51. doi: 10.1124/jpet.114.220780. Epub 2015 Jan 8. PubMed PMID: 25573198; PubMed Central PMCID: PMC4352598.
Fernandez CA, Smith C, Yang W, Daté M, Bashford D, Larsen E, Bowman WP, Liu C, Ramsey LB, Chang T, Turner V, Loh ML, Raetz EA, Winick NJ, Hunger SP, Carroll WL, Onengut-Gumuscu S, Chen WM, Concannon P, Rich SS, Scheet P, Jeha S, Pui CH, Evans WE, Devidas M, Relling MV. HLA-DRB1*07:01 is associated with a higher risk of asparaginase allergies. Blood. 2014 Aug 21;124(8):1266-76. doi: 10.1182/blood-2014-03-563742. Epub 2014 Jun 26. PubMed PMID: 24970932; PubMed Central PMCID: PMC4141516.
Fernandez CA, Stewart E, Panetta JC, Wilkinson MR, Morrison AR, Finkelman FD, Sandlund JT, Pui CH, Jeha S, Relling MV, Campbell PK. Successful challenges using native E. coli asparaginase after hypersensitivity reactions to PEGylated E. coli asparaginase. Cancer Chemother Pharmacol. 2014 Jun;73(6):1307-13. doi: 10.1007/s00280-014-2464-2. Epub 2014 Apr 27. PubMed PMID: 24771103; PubMed Central PMCID: PMC4137479.
Fernandez CA, Cai X, Elozory A, Liu C, Panetta JC, Jeha S, Molinelli AR, Relling MV. High-throughput asparaginase activity assay in serum of children with leukemia. Int J Clin Exp Med. 2013;6(7):478-87. Print 2013. PubMed PMID: 23936585; PubMed Central PMCID: PMC3731178.
Hicks JK, Crews KR, Hoffman JM, Kornegay NM, Wilkinson MR, Lorier R, Stoddard A, Yang W, Smith C, Fernandez CA, Cross SJ, Haidar C, Baker DK, Howard SC, Evans WE, Broeckel U, Relling MV. A clinician-driven automated system for integration of pharmacogenetic interpretations into an electronic medical record. Clin Pharmacol Ther. 2012 Nov;92(5):563-6. doi: 10.1038/clpt.2012.140. Epub 2012 Sep 19. PubMed PMID: 22990750; PubMed Central PMCID: PMC3589522.
Liu C, Kawedia JD, Cheng C, Pei D, Fernandez CA, Cai X, Crews KR, Kaste SC, Panetta JC, Bowman WP, Jeha S, Sandlund JT, Evans WE, Pui CH, Relling MV. Clinical utility and implications of asparaginase antibodies in acute lymphoblastic leukemia. Leukemia. 2012 Nov;26(11):2303-9. doi: 10.1038/leu.2012.102. Epub 2012 Apr 9. PubMed PMID: 22484422; PubMed Central PMCID: PMC3516853.
Fernandez CA, Smith C, Yang W, Lorier R, Crews KR, Kornegay N, Hicks JK, Stewart CF, Kawedia JD, Ramsey LB, Liu C, Evans WE, Relling MV, Broeckel U. Concordance of DMET plus genotyping results with those of orthogonal genotyping methods. Clin Pharmacol Ther. 2012 Sep;92(3):360-5. doi: 10.1038/clpt.2012.95. Epub 2012 Aug 8. PubMed PMID: 22871999; PubMed Central PMCID: PMC3516299.
Kawedia JD, Liu C, Pei D, Cheng C, Fernandez CA, Howard SC, Campana D, Panetta JC, Bowman WP, Evans WE, Pui CH, Relling MV. Dexamethasone exposure and asparaginase antibodies affect relapse risk in acute lymphoblastic leukemia. Blood. 2012 Feb 16;119(7):1658-64. doi: 10.1182/blood-2011-09-381731. Epub 2011 Nov 23. PubMed PMID: 22117041; PubMed Central PMCID: PMC3286344.
Fernandez CA, Baumhover NJ, Duskey JT, Khargharia S, Kizzire K, Ericson MD, Rice KG. Metabolically stabilized long-circulating PEGylated polyacridine peptide polyplexes mediate hydrodynamically stimulated gene expression in liver. Gene Ther. 2011 Jan;18(1):23-37. doi: 10.1038/gt.2010.117. Epub 2010 Aug 19. PubMed PMID: 20720577; PubMed Central PMCID: PMC2990782.
Anderson K, Fernandez C, Rice KG. N-glycan targeted gene delivery to the dendritic cell SIGN receptor. Bioconjug Chem. 2010 Aug 18;21(8):1479-85. doi: 10.1021/bc1000824. PubMed PMID: 20715853; PubMed Central PMCID: PMC5501274.
Fernandez CA, Baumhover NJ, Anderson K, Rice KG. Discovery of metabolically stabilized electronegative polyacridine-PEG peptide DNA open polyplexes. Bioconjug Chem. 2010 Apr 21;21(4):723-30. doi: 10.1021/bc900514s. PubMed PMID: 20218669; PubMed Central PMCID: PMC2860281.
Baumhover NJ, Anderson K, Fernandez CA, Rice KG. Synthesis and in vitro testing of new potent polyacridine-melittin gene delivery peptides. Bioconjug Chem. 2010 Jan;21(1):74-83. doi: 10.1021/bc9003124. PubMed PMID: 19968269; PubMed Central PMCID: PMC2813064.
Fernandez CA, Rice KG. Engineered nanoscaled polyplex gene delivery systems. Mol Pharm. 2009 Sep-Oct;6(5):1277-89. doi: 10.1021/mp900033j. Review. PubMed PMID: 19385668.
