Personalized medicine: going to the dogs?

Mealey, Katrina L.; Martinez, Stephanie E.; Villarino, Nicolás F.; Court, Michael H.

doi:10.1007/s00439-019-02020-w

Cited by 25 publications

(27 citation statements)

References 117 publications

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“…The Heikkinen study primarily used Beagles from a closed colony in New Jersey (United States), and the Eguchi study used Beagles from Japan, whereas our study used Beagles from multiple sources in the United States. We have previously observed (Court, 2013;Mealey et al, 2019) that the frequencies of the CYP1A2 stop codon mutation is higher in beagles from Japan (37%-39%), than Beagles from Germany (15%) or the United States (13%) (Mise et al, 2004;Tenmizu et al, 2004;Whiterock et al, 2007;Aretz and Geyer, 2011). Beagles in this study had a CYP1A2 stop codon frequency of 22%.…”

Section: Discussionsupporting

confidence: 48%

Absolute Quantitation of Drug-Metabolizing Cytochrome P450 Enzymes and Accessory Proteins in Dog Liver Microsomes Using Label-Free Standard-Free Analysis Reveals Interbreed Variability

et al. 2019

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Dogs are commonly used in human and veterinary pharmaceutical development. Physiologically based pharmacokinetic modeling using recombinant cytochrome P450 (CYP) enzymes requires accurate estimates of CYP abundance, particularly in liver. However, such estimates are currently available for only seven CYPs, which were determined in a limited number of livers from one dog breed (beagle). In this study, we used a label-free shotgun proteomics method to quantitate 11 CYPs (including four CYPs not previously measured), cytochrome P450 oxidoreductase, and cytochrome b5 in liver microsomes from 59 dogs representing four different breeds and mixedbreed dogs. Validation included showing correlation with CYP marker activities, immunoquantified protein, as well as CYP1A2 and CYP2C41 null allele genotypes. Abundance values largely agreed with those previously published. Average CYP abundance was highest (>120 pmol/mg protein) for CYP2D15 and CYP3A12; intermediate (40-89 pmol/mg) for CYP1A2, CYP2B11, CYP2E1, and CYP2C21; and lowest (<12 pmol/mg) for CYP2A13, CYP2A25, CYP2C41, CYP3A26, and CYP1A1. The CYP2C41 gene was detected in 12 of 58 (21%) livers. CYP2C41 protein abundance averaged 8.2 pmol/mg in those livers, and was highest (19 pmol/mg) in the only liver with two CYP2C41 gene copies. CYP1A2 protein was not detected in the only liver homozygous for the CYP1A2 stop codon mutation. Large breed-associated differences were observed for CYP2B11 (P < 0.0001; ANOVA) but not for other CYPs. Research hounds and Beagles had the highest CYP2B11 abundance; mixed-breed dogs and Chihuahua were intermediate; whereas greyhounds had the lowest abundance. These results provide the most comprehensive estimates to date of CYP abundance and variability in canine liver. SIGNIFICANCE STATEMENT This work provides the most comprehensive quantitative analysis to date of the drug-metabolizing cytochrome P450 proteome in dogs that will serve as a valuable reference for physiologically based scaling and modeling used in drug development and research. This study also revealed high interindividual variation and dog breedassociated differences in drug-metabolizing cytochrome P450 expression that may be important for predicting drug disposition variability among a genetically diverse canine population.

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Section: Discussionsupporting

confidence: 48%

Absolute Quantitation of Drug-Metabolizing Cytochrome P450 Enzymes and Accessory Proteins in Dog Liver Microsomes Using Label-Free Standard-Free Analysis Reveals Interbreed Variability

et al. 2019

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“…The situation is also complicated by the issue that there is no clinicallyapproved canine genetic test for c-KIT mutations. Therefore, while toceranib is the closest, evidence-based, precision medicine approach in veterinary medicine, it currently fails to meet important considerations in which human-targeted therapies are based (122).…”

Section: Precision Medicine In Veterinary Clinicsmentioning

confidence: 99%

The Importance of the Tumor Microenvironment and Hypoxia in Delivering a Precision Medicine Approach to Veterinary Oncology

et al. 2020

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Treating individual patients on the basis of specific factors, such as biomarkers, molecular signatures, phenotypes, environment, and lifestyle is what differentiates the precision medicine initiative from standard treatment regimens. Although precision medicine can be applied to almost any branch of medicine, it is perhaps most easily applied to the field of oncology. Cancer is a heterogeneous disease, meaning that even though patients may be histologically diagnosed with the same cancer type, their tumors may have different molecular characteristics, genetic mutations or tumor microenvironments that can influence prognosis or treatment response. In this review, we describe what methods are currently available to clinicians that allow them to monitor key tumor microenvironmental parameters in a way that could be used to achieve precision medicine for cancer patients. We further describe exciting novel research involving the use of implantable medical devices for precision medicine, including those developed for mapping tumor microenvironment parameters (e.g., O 2 , pH, and cancer biomarkers), delivering local drug treatments, assessing treatment responses, and monitoring for recurrence and metastasis. Although these research studies have predominantly focused on and were tailored to humans, the results and concepts are equally applicable to veterinary patients. While veterinary clinical studies that have adopted a precision medicine approach are still in their infancy, there have been some exciting success stories. These have included the development of a receptor tyrosine kinase inhibitor for canine mast cell tumors and the production of a PCR assay to monitor the chemotherapeutic response of canine high-grade B-cell lymphomas. Although precision medicine is an exciting area of research, it currently has failed to gain significant translation into human and veterinary healthcare practices. In order to begin to address this issue, there is increasing awareness that cross-disciplinary approaches involving human and veterinary clinicians, engineers and chemists may be needed to help advance precision medicine toward its full integration into human and veterinary clinical practices.

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“…In human medicine, this approach has been made possible by the preparation of the high-quality human reference genome as a foundation and the large-scale accumulation and integration of disease-related gene annotation and genetic variation information such as Clinvar (Landrum et al 2013). Recent studies have shown in precision medicine in companion animals (Mauler et al, 2017, Mealey et al, 2019. Here, we have constructed a chromosome-level genome assembly for a breed of cat, and are about to launch an information foundation for pet precision medicine for the future of the veterinary care.…”

Section: Implications For Veterinary Medicine and Precision Medicine mentioning

confidence: 99%

AnAms1.0: A high-quality chromosome-scale assembly of a domestic catFelis catusof American Shorthair breed

Isobe

Matsumoto²,

Chung

et al. 2020

Preprint

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The domestic cat (Felis catus) is one of the most popular companion animals in the world.Comprehensive genomic resources will aid the development and application of veterinary medicine including to improve feline health, in particular, to enable precision medicine which is promising in human application. However, currently available cat genome assemblies were mostly built based on the Abyssinian cat breed which is highly inbred and has limited power in representing the vast diversity of the cat population. Moreover, the current reference assembly remains fragmented with sequences contained in thousands of scaffolds.We constructed a reference-grade chromosome-scale genome assembly of a domestic cat, Felis catus genome of American Shorthair breed, Anicom American shorthair 1.0 (AnAms1.0) with high contiguity (scaffold N50 > 120 Mb), by combining multiple advanced genomic technologies, including PacBio long-read sequencing as well as sequence scaffolding by long-range genomic information obtained from Hi-C and optical mapping data.Homology-based and ab initio gene annotation was performed with the Iso-Seq data.Analyzed data is be publicly accessible on Cats genome informatics (Cats-I, https://cat.annotation.jp/), a cat genome database established as a platform to facilitate the accumulation and sharing of genomic resources to improve veterinary care.

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Personalized medicine: going to the dogs?

Cited by 25 publications

References 117 publications

Absolute Quantitation of Drug-Metabolizing Cytochrome P450 Enzymes and Accessory Proteins in Dog Liver Microsomes Using Label-Free Standard-Free Analysis Reveals Interbreed Variability

Absolute Quantitation of Drug-Metabolizing Cytochrome P450 Enzymes and Accessory Proteins in Dog Liver Microsomes Using Label-Free Standard-Free Analysis Reveals Interbreed Variability

The Importance of the Tumor Microenvironment and Hypoxia in Delivering a Precision Medicine Approach to Veterinary Oncology

AnAms1.0: A high-quality chromosome-scale assembly of a domestic catFelis catusof American Shorthair breed

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