Todd Skaar
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Genomic Medicine: Translating Genetic Discoveries into Clinical Care
Dr. Todd Skaar is an internationally recognized leader in the field of pharmacogenomics. Dr. Skaar and his research team study ways to improve the success of cancer treatment drug therapies. His work focuses on the impact of genomic variability in how these drugs interact with each other and in the body. Better understanding these drug interactions can improve outcomes and reduce hospitalizations. Dr. Skaar’s competitive translational research was awarded an NIH-funded Maximizing Investigators’ Research Award (MIRA).
Dr. Skaar serves as the leader of the Pharmacogenomics (PGx) Implementation Team working under the larger Precision Health Initiative (PHI) inaugural project awarded in 2016. PGx, which utilizes a patient’s genetics to guide selection and dosing of appropriate medications, has the potential to enhance medication efficacy and minimize toxicity. Dr. Skaar’s team has successfully implemented PGx testing in cardiology, oncology, psychiatry, neurology, and in various transplant disciplines.
Dr. Skaar is passionate about mentoring and encouraging young researchers. Trainees have emerged as leaders in translational medicine, as faculty at academic institutions, as scientists working in the pharmaceutical and biotechnology industries, and as regulators at the U.S. Food and Drug Administration and National Institutes of Health. Dr. Skaar exemplifies a translational scientist through his research, collaborations, mentorship of trainees, and through his positive impact on human health.
Dr. Skaar's translation of research into improved health outcomes for patients taking medications is another excellent example of how IUPUI's faculty members are TRANSLATING their RESEARCH INTO PRACTICE.
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Item Genomic Medicine: Translating Genetic Discoveries into Clinical Care(Center for Translating Research Into Practice, IU Indianapolis, 2022-10-06) Skaar, ToddThe 2022 Bantz-Petronio Translating Research Into Practice Faculty Award recipient is Todd Skaar, PhD. Dr. Skaar, an internationally recognized leader in the field of pharmacogenomics, received this award in recognition of his groundbreaking research and his dedication to mentoring the next generation of translational scholars. Dr. Skaar and his research team study ways to improve the success of cancer treatment drug therapies. His work focuses on the impact of genomic variability in how these drugs interact with each other and in the body. Better understanding these drug interactions can improve outcomes and reduce hospitalizations.Item Opportunity for pharmacogenomic testing in patients with cystic fibrosis(Wiley, 2022-04) Sakon, Colleen; Alicea, Leah A.; Patacca, Heather; Brown, Cynthia D.; Skaar, Todd C.; Tillman, Emma M.; Medicine, School of MedicineBackground Patients with cystic fibrosis (CF) are exposed to many drugs in their lifetime and many of these drugs have Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines that are available to guide dosing. Contemporary CF treatments are targeted to specific mutations in the CF transmembrane conductance regulator (CFTR) gene, and thus, require patients to have genetic testing before initiation of modulator therapy. However, aside from CFTR genetic testing, pharmacogenomic testing is not standard of care for CF patients. Aim The aim of this study is to determine the number of non-CFTR modulator medications with CPIC guidelines that are prescribed to patients with CF. Materials & Methods We identified all patients with a diagnosis of CF and queried our hospital electronic medical records (EMR) for all orders, including inpatient and prescriptions, for all drugs or drug classes that have CPIC actionable guidelines for drug–gene pairs that can be used to guide therapy. Results We identified 576 patients with a diagnosis of CF that were treated at our institution during this 16-year period between June 2005 and May 2021. Of these patients, 504 patients (87.5%) received at least one drug that could have been dosed according to CPIC guidelines if pharmacogenomic results would have been available. Conclusions Patients with CF have high utilization of drugs with CPIC guidelines, therefore preemptive pharmacogenomic testing should be considered in CF patients at the time of CFTR genetic testing.Item Clinical Opportunities for Germline Pharmacogenetics and Management of Drug-Drug Interactions in Patients With Advanced Solid Cancers(ASCO, 2022) Shugg, Tyler; Ly, Reynold C.; Rowe, Elizabeth J.; Philips, Santosh; Hyder, Mustafa A.; Radovich, Milan; Rosenman, Marc B.; Pratt, Victoria M.; Callaghan, John T.; Desta, Zeruesenay; Schneider, Bryan P.; Skaar, Todd C.; Medicine, School of MedicinePURPOSE: Precision medicine approaches, including germline pharmacogenetics (PGx) and management of drug-drug interactions (DDIs), are likely to benefit patients with advanced cancer who are frequently prescribed multiple concomitant medications to treat cancer and associated conditions. Our objective was to assess the potential opportunities for PGx and DDI management within a cohort of adults with advanced cancer. METHODS: Medication data were collected from the electronic health records for 481 subjects since their first cancer diagnosis. All subjects were genotyped for variants with clinically actionable recommendations in Clinical Pharmacogenetics Implementation Consortium guidelines for 13 pharmacogenes. DDIs were defined as concomitant prescription of strong inhibitors or inducers with sensitive substrates of the same drug-metabolizing enzyme and were assessed for six major cytochrome P450 (CYP) enzymes. RESULTS: Approximately 60% of subjects were prescribed at least one medication with Clinical Pharmacogenetics Implementation Consortium recommendations, and approximately 14% of subjects had an instance for actionable PGx, defined as a prescription for a drug in a subject with an actionable genotype. The overall subject-level prevalence of DDIs and serious DDIs were 50.3% and 34.8%, respectively. Serious DDIs were most common for CYP3A, CYP2D6, and CYP2C19, occurring in 24.9%, 16.8%, and 11.7% of subjects, respectively. When assessing PGx and DDIs together, approximately 40% of subjects had at least one opportunity for a precision medicine-based intervention and approximately 98% of subjects had an actionable phenotype for at least one CYP enzyme. CONCLUSION: Our findings demonstrate numerous clinical opportunities for germline PGx and DDI management in adults with advanced cancer.Item Strategies to Integrate Genomic Medicine into Clinical Care: Evidence from the IGNITE Network(MDPI, 2021-07-08) Sperber, Nina R.; Dong, Olivia M.; Roberts, Megan C.; Dexter, Paul; Elsey, Amanda R.; Ginsburg, Geoffrey S.; Horowitz, Carol R.; Johnson, Julie A.; Levy, Kenneth D.; Ong, Henry; Peterson, Josh F.; Pollin, Toni I.; Rakhra-Burris, Tejinder; Ramos, Michelle A.; Skaar, Todd C.; Orlando, Lori A.; Medicine, School of MedicineThe complexity of genomic medicine can be streamlined by implementing some form of clinical decision support (CDS) to guide clinicians in how to use and interpret personalized data; however, it is not yet clear which strategies are best suited for this purpose. In this study, we used implementation science to identify common strategies for applying provider-based CDS interventions across six genomic medicine clinical research projects funded by an NIH consortium. Each project’s strategies were elicited via a structured survey derived from a typology of implementation strategies, the Expert Recommendations for Implementing Change (ERIC), and follow-up interviews guided by both implementation strategy reporting criteria and a planning framework, RE-AIM, to obtain more detail about implementation strategies and desired outcomes. We found that, on average, the three pharmacogenomics implementation projects used more strategies than the disease-focused projects. Overall, projects had four implementation strategies in common; however, operationalization of each differed in accordance with each study’s implementation outcomes. These four common strategies may be important for precision medicine program implementation, and pharmacogenomics may require more integration into clinical care. Understanding how and why these strategies were successfully employed could be useful for others implementing genomic or precision medicine programs in different contexts.Item Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for Codeine Therapy in the Context of Cytochrome P450 2D6 (CYP2D6) Genotype(Wiley, 2012-02) Crews, K.R.; Gaedigk, A.; Dunnenberger, H.M.; Klein, T.E.; Shen, D.D.; Callaghan, J.T.; Kharasch, E.D.; Skaar, Todd C.Codeine is bioactivated to morphine, a strong opioid agonist, by the hepatic cytochrome P450 2D6 (CYP2D6); hence, the efficacy and safety of codeine as an analgesic are governed by CYP2D6 polymorphisms. Codeine has little therapeutic effect in patients who are CYP2D6 poor metabolizers, whereas the risk of morphine toxicity is higher in ultrarapid metabolizers. The purpose of this guideline (periodically updated at http://www.pharmgkb.org) is to provide information relating to the interpretation of CYP2D6 genotype test results to guide the dosing of codeine.Item Polymorphisms in drug-metabolizing enzymes and steady-state exemestane concentration in postmenopausal patients with breast cancer(Springer Nature, 2017-12) Hertz, Daniel L.; Kidwell, Kelley M.; Seewald, Nicholas J.; Gersch, Christina L.; Desta, Zeruesenay; Flockhart, David A.; Storniolo, Ana-Maria; Stearns, Vered; Skaar, Todd C.; Hayes, Daniel F.; Henry, N. Lynn; Rae, James M.; Medicine, School of MedicineDiscovery of clinical and genetic predictors of exemestane pharmacokinetics was attempted in 246 post-menopausal patients with breast cancer enrolled on a prospective clinical study. A sample was collected two hours after exemestane dosing at a 1 or 3 month study visit to measure drug concentration. The primary hypothesis was that patients carrying the low-activity CYP3A4*22 (rs35599367) SNP would have greater exemestane concentration. Additional SNPs in genes relevant to exemestane metabolism (CYP1A1/2, CYP1B1, CYP3A4, CYP4A11, AKR1C3/4, AKR7A2) were screened in secondary analyses and adjusted for clinical covariates. CYP3A4*22 was associated with a 54% increase in exemestane concentration (p<0.01). Concentration was greater in patients who reported White race, had elevated aminotransferases, renal insufficiency, lower body mass index, and had not received chemotherapy (all p<0.05), and CYP3A4*22 maintained significance after adjustment for covariates (p<0.01). These genetic and clinical predictors of exemestane concentration may be useful for treatment individualization in patients with breast cancer.Item Rifampin Regulation of Drug Transporters Gene Expression and the Association of MicroRNAs in Human Hepatocytes(Frontiers Media, 2016-04-26) Benson, Eric A.; Eadon, Michael T.; Desta, Zeruesenay; Liu, Yunlong; Lin, Hai; Burgess, Kimberly S.; Segar, Matthew W.; Gaedigk, Andrea; Skaar, Todd C.; Medicine, School of MedicineMembrane drug transporters contribute to the disposition of many drugs. In human liver, drug transport is controlled by two main superfamilies of transporters, the solute carrier transporters (SLC) and the ATP Binding Cassette transporters (ABC). Altered expression of these transporters due to drug-drug interactions can contribute to differences in drug exposure and possibly effect. In this study, we determined the effect of rifampin on gene expression of hundreds of membrane transporters along with all clinically relevant drug transporters. Methods: In this study, primary human hepatocytes (n = 7 donors) were cultured and treated for 24 h with rifampin and vehicle control. RNA was isolated from the hepatocytes, mRNA expression was measured by RNA-seq, and miRNA expression was analyzed by Taqman OpenArray. The effect of rifampin on the expression of selected transporters was also tested in kidney cell lines. The impact of rifampin on the expression of 410 transporter genes from 19 different transporter gene families was compared with vehicle control. Results: Expression patterns of 12 clinically relevant drug transporter genes were changed by rifampin (FDR < 0.05). For example, the expressions of ABCC2, ABCB1, and ABCC3 were increased 1.9-, 1.7-, and 1.2-fold, respectively. The effects of rifampin on four uptake drug transporters (SLCO1B3, SLC47A1, SLC29A1, SLC22A9) were negatively correlated with the rifampin effects on specific microRNA expression (SLCO1B3/miR-92a, SLC47A1/miR-95, SLC29A1/miR-30d#, and SLC22A9/miR-20; r < -0.79; p < 0.05). Seven hepatic drug transporter genes (SLC22A1, SLC22A5, SLC15A1, SLC29A1, SLCO4C1, ABCC2, and ABCC4), whose expression was altered by rifampin in hepatocytes, were also present in a renal proximal tubular cell line, but in renal cells rifampin did not alter their gene expression. PXR expression was very low in the kidney cells; this may explain why rifampin induces gene expression in a tissue-specific manner. Conclusion: Rifampin alters the expression of many of the clinically relevant hepatic drug transporters, which may provide a rational basis for understanding rifampin-induced drug-drug interactions reported in vivo. The relevance of its effect on many other transporters remains to be studied.Item A SNP in Steroid Receptor Coactivator-1 Disrupts a GSK3β Phosphorylation Site and Is Associated with Altered Tamoxifen Response in Bone(Oxford University Press, 2012-02) Hartmaier, R.J.; Richter, A.S.; Gillihan, R.M.; Sallit, J.Z.; McGuire, S.E.; Wang, J.; Lee, A.V.; Osborne, C.K.; O'Malley, B.W.; Brown, P.H.; Xu, J.; Skaar, Todd C.; Philips, S.; Rae, J.M.; Azzouz, F.; Li, L.; Hayden, J.; Henry, N.L.; Nguyen, A.T.; Stearns, V.; Hayes, D.F.; Flockhart, D.A.; Oesterreich, S.The coregulator steroid receptor coactivator (SRC)-1 increases transcriptional activity of the estrogen receptor (ER) in a number of tissues including bone. Mice deficient in SRC-1 are osteopenic and display skeletal resistance to estrogen treatment. SRC-1 is also known to modulate effects of selective ER modulators like tamoxifen. We hypothesized that single nucleotide polymorphisms (SNP) in SRC-1 may impact estrogen and/or tamoxifen action. Because the only nonsynonymous SNP in SRC-1 (rs1804645; P1272S) is located in an activation domain, it was examined for effects on estrogen and tamoxifen action. SRC-1 P1272S showed a decreased ability to coactivate ER compared with wild-type SRC-1 in multiple cell lines. Paradoxically, SRC-1 P1272S had an increased protein half-life. The Pro to Ser change disrupts a putative glycogen synthase 3 (GSK3)β phosphorylation site that was confirmed by in vitro kinase assays. Finally, knockdown of GSK3β increased SRC-1 protein levels, mimicking the loss of phosphorylation at P1272S. These findings are similar to the GSK3β-mediated phospho-ubiquitin clock previously described for the related coregulator SRC-3. To assess the potential clinical significance of this SNP, we examined whether there was an association between SRC-1 P1272S and selective ER modulators response in bone. SRC-1 P1272S was associated with a decrease in hip and lumbar bone mineral density in women receiving tamoxifen treatment, supporting our in vitro findings for decreased ER coactivation. In summary, we have identified a functional genetic variant of SRC-1 with decreased activity, resulting, at least in part, from the loss of a GSK3β phosphorylation site, which was also associated with decreased bone mineral density in tamoxifen-treated women.Item Genetic Associations With Toxicity-related Discontinuation of Aromatase Inhibitor Therapy for Breast Cancer(Breast Cancer Research and Treatment, 2013-04-02) Henry, N. Lynn; Skaar, Todd C.; Dantzer, Jessica; Li, Lang; Kidwell, Kelley; Gersch, Christina; Nguyen, Anne T.; Rae, James M.; Desta, Zeruesenay; Oesterreich, Steffi; Philips, Santosh; Carpenter, Janet S.; Storniolo, Anna M.; Stearns, Vered; Hayes, Daniel F.; Flockhart, David A.Up to 25 % of patients discontinue adjuvant aromatase inhibitor (AI) therapy due to intolerable symptoms. Predictors of which patients will be unable to tolerate these medications have not been defined. We hypothesized that inherited variants in candidate genes are associated with treatment discontinuation because of AI-associated toxicity. We prospectively evaluated reasons for treatment discontinuation in women with hormone receptor-positive breast cancer initiating adjuvant AI through a multicenter, prospective, randomized clinical trial of exemestane versus letrozole. Using multiple genetic models, we evaluated potential associations between discontinuation of AI therapy because of toxicity and 138 variants in 24 candidate genes, selected a priori, primarily with roles in estrogen metabolism and signaling. To account for multiple comparisons, statistical significance was defined as p < 0.00036. Of the 467 enrolled patients with available germline DNA, 152 (33 %) discontinued AI therapy because of toxicity. Using a recessive statistical model, an intronic variant in ESR1 (rs9322336) was associated with increased risk of musculoskeletal toxicity-related exemestane discontinuation [HR 5.0 (95 % CI 2.1-11.8), p < 0.0002]. An inherited variant potentially affecting estrogen signaling may be associated with exemestane-associated toxicity, which could partially account for intra-patient differences in AI tolerability. Validation of this finding is required.Item The impact of glucocorticoid polymorphisms on markers of neonatal respiratory disease after antenatal betamethasone administration.(Elsevier, 2013-03) Haas, David M.; Dantzer, Jessica; Lehmann, Amalia S.; Philips, Santosh; Skaar, Todd C.; McCormick, Catherine L.; Hebbring, Scott J.; Jung, Jeesun; Li, LangOBJECTIVE: We previously demonstrated that maternal and fetal genotypes are associated independently with neonatal respiratory distress syndrome. The objective of the current study was to determine the impact of maternal and fetal single-nucleotide polymorphisms (SNPs) in key betamethasone pathways on respiratory outcomes that serve as markers for severity of disease. STUDY DESIGN: DNA was obtained from women who were given betamethasone and from their infants. Samples were genotyped for 73 exploratory drug metabolism and glucocorticoid pathway SNPs. Clinical variables and neonatal outcomes were obtained. Logistic regression analysis that controlled for relevant clinical variables to determine SNP impact on bronchopulmonary dysplasia (BPD), the need for respiratory support, and surfactant therapy use was performed. RESULTS: Data from 109 women who delivered 117 infants were analyzed: 14.5% of the infants experienced BPD; 70.8% of the infants needed some respiratory support after birth, and 27.5% of the infants needed surfactant therapy. In a multivariable regression analysis, gestational age at delivery was associated with most neonatal respiratory outcomes (P ≤ .01), and chorioamnionitis was associated with BPD (P < .03). The following genotypes were associated with respiratory severity outcomes: BPD-fetal Importin 13 gene (IPO13; rs4448553; odds ratio [OR], 0.01; 95% confidence interval [CI], 0.00-0.92); surfactant use-maternal IPO13 (rs2428953 and 2486014; OR, 13.8; 95% CI, 1.80-105.5; and OR, 35.5; 95% CI, 1.71-736.6, respectively). CONCLUSION: Several discrete maternal and fetal SNPs in the IPO13 family may be associated with neonatal respiratory outcomes after maternal antenatal corticosteroid treatment for anticipated preterm birth.