Todd Skaar

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https://hdl.handle.net/1805/29766

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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Systematic review of sleep disorders in cancer patients: can the prevalence of sleep disorders be ascertained?
(2014-11) Otte, Julie L.; Carpenter, Janet S.; Manchanda, Shalini; Rand, Kevin L.; Skaar, Todd C.; Weaver, Michael T.; Chernyak, Yelena; Zhong, Xin; Igega, Christele; Landis, Carol
Although sleep is vital to all human functioning and poor sleep is a known problem in cancer, it is unclear whether the overall prevalence of the various types of sleep disorders in cancer is known. The purpose of this systematic literature review was to evaluate if the prevalence of sleep disorders could be ascertained from the current body of literature regarding sleep in cancer. This was a critical and systematic review of peer-reviewed, English-language, original articles published from 1980 through 15 October 2013, identified using electronic search engines, a set of key words, and prespecified inclusion and exclusion criteria. Information from 254 full-text, English-language articles was abstracted onto a paper checklist by one reviewer, with a second reviewer randomly verifying 50% (k = 99%). All abstracted data were entered into an electronic database, verified for accuracy, and analyzed using descriptive statistics and frequencies in SPSS (v.20) (North Castle, NY). Studies of sleep and cancer focus on specific types of symptoms of poor sleep, and there are no published prevalence studies that focus on underlying sleep disorders. Challenging the current paradigm of the way sleep is studied in cancer could produce better clinical screening tools for use in oncology clinics leading to better triaging of patients with sleep complaints to sleep specialists, and overall improvement in sleep quality.
Aromatase inhibitor-induced modulation of breast density: clinical and genetic effects
(NPG - Nature Publishing Group, 2013-10-29) Henry, N. L.; Chan, H-P; Dantzer, J.; Goswami, C. P.; Li, L.; Skaar, Todd C.; Rae, J. M.; Desta, Z.; Khouri, N.; Pinsky, R.; Oesterreich, S.; Zhou, C.; Hadjiiski, L.; Philips, S.; Robarge, J.; Nguyen, A. T.; Storniolo, A. M.; Flockhart, D. A.; Hayes, D. F.; Helvie, M. A.; Stearns, V.; Department of Medicine, School of Medicine
Background: Change in breast density may predict outcome of women receiving adjuvant hormone therapy for breast cancer. We performed a prospective clinical trial to evaluate the impact of inherited variants in genes involved in oestrogen metabolism and signalling on change in mammographic percent density (MPD) with aromatase inhibitor (AI) therapy. Methods: Postmenopausal women with breast cancer who were initiating adjuvant AI therapy were enrolled onto a multicentre, randomised clinical trial of exemestane vs letrozole, designed to identify associations between AI-induced change in MPD and single-nucleotide polymorphisms in candidate genes. Subjects underwent unilateral craniocaudal mammography before and following 24 months of treatment. Results: Of the 503 enrolled subjects, 259 had both paired mammograms at baseline and following 24 months of treatment and evaluable DNA. We observed a statistically significant decrease in mean MPD from 17.1 to 15.1% (P<0.001), more pronounced in women with baseline MPD ⩾20%. No AI-specific difference in change in MPD was identified. No significant associations between change in MPD and inherited genetic variants were observed. Conclusion: Subjects with higher baseline MPD had a greater average decrease in MPD with AI therapy. There does not appear to be a substantial effect of inherited variants in biologically selected candidate genes.
Genome-Wide Discovery of Drug-Dependent Human Liver Regulatory Elements
(PLOS (Public Library of Science), 2014-10-02) Smith, Robin P.; Eckalbar, Walter L.; Morrissey, Kari M.; Luizon, Marcelo R.; Hoffmann, Thomas J.; Sun, Xuefeng; Jones, Stacy L.; Aldred, Shelley Force; Ramamoorthy, Anuradha; Desta, Zeruesenay; Liu, Yunlong; Skaar, Todd C.; Trinklein, Nathan D.; Giacomini, Kathleen M.; Ahituv, Nadav; Department of Medicine, School of Medicine
Inter-individual variation in gene regulatory elements is hypothesized to play a causative role in adverse drug reactions and reduced drug activity. However, relatively little is known about the location and function of drug-dependent elements. To uncover drug-associated elements in a genome-wide manner, we performed RNA-seq and ChIP-seq using antibodies against the pregnane X receptor (PXR) and three active regulatory marks (p300, H3K4me1, H3K27ac) on primary human hepatocytes treated with rifampin or vehicle control. Rifampin and PXR were chosen since they are part of the CYP3A4 pathway, which is known to account for the metabolism of more than 50% of all prescribed drugs. We selected 227 proximal promoters for genes with rifampin-dependent expression or nearby PXR/p300 occupancy sites and assayed their ability to induce luciferase in rifampin-treated HepG2 cells, finding only 10 (4.4%) that exhibited drug-dependent activity. As this result suggested a role for distal enhancer modules, we searched more broadly to identify 1,297 genomic regions bearing a conditional PXR occupancy as well as all three active regulatory marks. These regions are enriched near genes that function in the metabolism of xenobiotics, specifically members of the cytochrome P450 family. We performed enhancer assays in rifampin-treated HepG2 cells for 42 of these sequences as well as 7 sequences that overlap linkage-disequilibrium blocks defined by lead SNPs from pharmacogenomic GWAS studies, revealing 15/42 and 4/7 to be functional enhancers, respectively. A common African haplotype in one of these enhancers in the GSTA locus was found to exhibit potential rifampin hypersensitivity. Combined, our results further suggest that enhancers are the predominant targets of rifampin-induced PXR activation, provide a genome-wide catalog of PXR targets and serve as a model for the identification of drug-responsive regulatory elements.
Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2D6 and CYP2C19 Genotypes and Dosing of Selective Serotonin Reuptake Inhibitors
(Wiley, 2015-08) Hicks, J. Kevin; Bishop, Jeffrey R.; Sangkuhl, Katrin; Müller, Daniel J; Ji, Yuan; Leckband, Susan G.; Leeder, J. Steven; Graham, Rebecca L.; Chiulli, Dana L.; LLerena, Adrián; Skaar, Todd C.; Scott, Stuart A.; Stingl, Julia C.; Klein, Teri E.; Caudle, Kelly E.; Gaedigk, Andrea; Department of Medicine, IU School of Medicine
Selective serotonin reuptake inhibitors (SSRIs) are primary treatment options for major depressive and anxiety disorders. CYP2D6 and CYP2C19 polymorphisms can influence the metabolism of SSRIs, thereby affecting drug efficacy and safety. We summarize evidence from the published literature supporting these associations and provide dosing recommendations for fluvoxamine, paroxetine, citalopram, escitalopram, and sertraline based on CYP2D6 and/or CYP2C19 genotype (updates at www.pharmgkb.org).
A NOVEL APPROACH TO MODELING MENOPAUSAL SYMPTOMS AND THE ROLE OF THE OREXIN SYSTEM
(Office of the Vice Chancellor for Research, 2012-04-13) Federici, Lauren; Fitz, Stephanie D.; Snow, Winter; Skaar, Todd C.; Carpenter, Janet; Shekhar, Anantha; Johnson, Philip L.
Menopausal symptoms become prevalent in conditions associated with depletion of estrogens [e.g., ovariectomy surgery or with breast cancer treatments that block estrogen activity (e.g., tamoxifen or aromatase inhibition therapy)]. The primary menopause associated symptom is cutaneous vasodilation “hot flashes”, but also includes sleep and mood disruption (Freeman et al., 2005; Seritan et al., 2010). Although the cause of menopausal symptoms is poorly understood, it is well-established that the hypothalamus: 1) plays a critical role in thermoregulation, sleep wake activity and emotional responses; and 2) has high and fairly exclusive expression of both estrogen α and β receptors (Laflamme et al., 1998). A recently discovered neuropeptide called Orexin (ORX) is exclusively synthesized in the perifornical hypothalamus (PeF). This neuropeptide plays a critical role in arousal, anxiety (Johnson et al., 2010), and body temperature regulation (Rusyniak et al., 2011), but is also severely elevated in the brain of postmenopausal women (El-Sedeek et al., 2010) and reduced in control subjects following estrogen replacement. Therefore, loss of normal inhibitory control by estrogens of the ORX system may lead to menopausal-related symptoms, and ORX antagonists could constitute a potential novel treatment strategy for adverse menopausal symptoms. In support of this hypothesis, ovariectomized (OVEX), female rats, compared to sham controls, had significantly greater anxiety at baseline which was blocked by administration of an ORX1 receptor (ORX1R) antagonist (SB334867, 25mg/kg ip) or estrogen replacement. Administration of a sub-threshold dose of FG-7142 (a partial inverse GABAA receptor agonist, 3mg/kg ip) caused higher (~6°C) and longer tail skin flushes in OVEX rats, which was attenuated with similar pretreatment with an ORX1R antagonist or with estrogen replacement. These results indicate a novel role for both the GABA and ORX systems in menopausal symptoms and further research aims to elucidate the mechanisms of dysfunction of these systems in the menopausal state.
FDA’s Draft Guidance on Laboratory-Developed Tests Increases Clinical and Economic Risk to Adoption of Pharmacogenetic Testing
(Wiley, 2015-07) Levy, Kenneth D.; Pratt, Victoria M.; Skaar, Todd C.; Vance, Gail H.; Flockhart, David A.; Department of Medicine, IU School of Medicine
Prerequisites to Implementing a Pharmacogenomics Program in a Large Healthcare System
(Nature Publishing Group, 2014-09) Levy, KD; Decker, BS; Carpenter, JS; Flockhart, DA; Dexter, PR; Desta, Z; Skaar, Todd C.; Department of Medicine, Division of Clinical Pharmacology, IU School of Medicine
Cypiripi: exact genotyping of CYP2D6 using high-throughput sequencing data
(Oxford University Press, 2015-06-15) Numanagic, Ibrahim; Malikic, Salem; Pratt, Victoria M.; Skaar, Todd C.; Flockhart, David A.; Sahinalp, S. Cenk; Department of Medicine, IU School of Medicine
MOTIVATION: CYP2D6 is highly polymorphic gene which encodes the (CYP2D6) enzyme, involved in the metabolism of 20-25% of all clinically prescribed drugs and other xenobiotics in the human body. CYP2D6 genotyping is recommended prior to treatment decisions involving one or more of the numerous drugs sensitive to CYP2D6 allelic composition. In this context, high-throughput sequencing (HTS) technologies provide a promising time-efficient and cost-effective alternative to currently used genotyping techniques. To achieve accurate interpretation of HTS data, however, one needs to overcome several obstacles such as high sequence similarity and genetic recombinations between CYP2D6 and evolutionarily related pseudogenes CYP2D7 and CYP2D8, high copy number variation among individuals and short read lengths generated by HTS technologies. RESULTS: In this work, we present the first algorithm to computationally infer CYP2D6 genotype at basepair resolution from HTS data. Our algorithm is able to resolve complex genotypes, including alleles that are the products of duplication, deletion and fusion events involving CYP2D6 and its evolutionarily related cousin CYP2D7. Through extensive experiments using simulated and real datasets, we show that our algorithm accurately solves this important problem with potential clinical implications.
Differential quantification of CYP2D6 gene copy number by four different quantitative real-time PCR assays
(Ovid Technologies (Wolters Kluwer) - Lippincott Williams & Wilkins, 2010-07) Ramamoorthy, Anuradha; Flockhart, David A.; Hosono, Naoya; Kubo, Michiaki; Nakamura, Yusuke; Skaar, Todd C.; Department of Medicine, IU School of Medicine
Copy number variations (CNVs) in the CYP2D6 gene contribute to interindividual variation in drug metabolism. As the most common duplicated allele in Asian populations is the nonfunctional CYP2D6*36 allele, the goal of this study was to identify CNV assays that can differentiate between multiple copies of the CYP2D6*36 allele and multiple copies of other CYP2D6 alleles. We determined CYP2D6 gene copy numbers in 32 individuals with known CYP2D6 CNVs from the Coriell Japanese-Chinese panel using four quantitative real-time PCR assays. These assays target different regions of the CYP2D6 gene: 5'-flanking region, intron 2, intron 6, and exon 9 (Ex9). The specific target site of the Ex9 assay was verified by sequencing the PCR amplicon. Three of the CYP2D6 CNV assays (5'-flanking region, intron 2, and intron 6) estimated CYP2D6 copy numbers that were concordant for all 32 individuals. However, the Ex9 assay was concordant in only 10 of 32 samples. The 10 concordant samples did not contain any CYP2D6*36 alleles and the 22 discordant samples contained at least one CYP2D6*36 allele. In addition, the Ex9 assay accurately quantified all of the non-CYP2D6*36 alleles in all samples. Ex9 amplicon sequencing indicated that it targets a region of CYP2D6 exon 9 that undergoes partial gene-conversion in the CYP2D6*36 allele. In conclusion, CYP2D6 Ex9 CNV assay can be used to determine the copy number of non-CYP2D6*36 alleles. Selective amplification of non-CYP2D6*36 sequence by the Ex9 assay should be useful in determining the number of functional copies of CYP2D6 in Asian populations.
A translational bioinformatic approach in identifying and validating an interaction between Vitamin A and CYP19A1
(Springer (Biomed Central Ltd.), 2015) Philips, Santosh; Zhou, Jing; Li, Zhigao; Skaar, Todd C.; Li, Lang; Department of Medicine, IU School of Medicine
INTRODUCTION: One major challenge in personalized medicine research is to identify the environmental factors that can alter drug response, and to investigate their molecular mechanisms. These environmental factors include co-medications, food, and nutrition or dietary supplements. The increasing use of dietary supplements and their potential interactions with cytochrome P450 (CYP450) enzymes is a highly significant personalized medicine research domain, because most of the drugs on the market are metabolized through CYP450 enzymes. METHODS: Initial bioinformatics analysis revealed a number of regulators of CYP450 enzymes from a human liver bank gene expression quantitative loci data set. Then, a compound-gene network was constructed from the curated literature data. This network consisted of compounds that interact with either CYPs and/or their regulators that influence either their gene expression or activity. We further evaluated this finding in three different cell lines: JEG3, HeLa, and LNCaP cells. RESULTS: From a total of 868 interactions we were able to identify an interesting interaction between retinoic acid (i.e. Vitamin A) and the aromatase gene (i.e. CYP19A1). Our experimental results showed that retinoic acid at physiological concentration significantly influenced CYP19A1 gene expressions. CONCLUSIONS: These results suggest that the presence of retinoic acid may alter the efficacy of agents used to suppress aromatase expression.

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