Sci Transl Med. 2022 Sep 7;14(661):eabo5987. doi: 10.1126/scitranslmed.abo5987. Epub 2022 Sep 7.

ABSTRACT

Head and neck squamous cell carcinoma (HNSCC) is a common and frequently lethal cancer with few therapeutic options. In particular, there are few effective targeted therapies. Development of highly effective therapeutic strategies tailored to patients with HNSCC remains a pressing challenge. To address this, we present a pharmacogenomic study to facilitate precision treatments for patients with HNSCC. We established a large collection of 56 HNSCC patient-derived cells (PDCs), which recapitulated the molecular features of the original tumors. Pharmacological assessment of HNSCCs was conducted using a three-tiered high-throughput drug screening using 2248 compounds across these PDC models and an additional 18 immortalized cell lines. We integrated genomic, transcriptomic, and pharmacological analysis to predict biomarkers, gene-drug associations, and validated biomarkers. These results supported drug repurposing for multiple HNSCC subtypes, including the JAK2 inhibitor fedratinib, for low KRT18-expressing HNSCC cases, and the topoisomerase inhibitor mitoxantrone, for IL6R-activated HNSCC cases. Our results demonstrated concordance between susceptibility predictions from the PDCs and the matched patients' responses to standard clinical medication. Moreover, we identified and experimentally confirmed that high expression of ITGB1 elicited therapeutic resistance to docetaxel and high SOD1 expression conferred resistance to afatinib. We further validated ITGB1 as a predictive biomarker for the efficacy of docetaxel therapy in a phase 2 clinical trial. In summary, our study shows that this HNSCC cell resource, as well as the resulting pharmacogenomic profiles, is effective for biomarker discovery and for guiding precision oncology therapies in HNSCCs.

PMID:36070368 | DOI:10.1126/scitranslmed.abo5987

Pharmacogenomics. 2022 Sep 7. doi: 10.2217/pgs-2022-0074. Online ahead of print.

ABSTRACT

Aim: A follow-up genome-wide association study (GWAS) in an extended cohort of rheumatoid arthritis (RA) patients starting low-dose methotrexate (MTX) treatment was performed to identify further genetic variants associated with alanine aminotransferase (ALT) elevation. Patients & methods: A GWAS was performed on 346 RA patients. Two outcomes within the first 6 months of MTX treatment were assessed: ALT >1.5-times the upper level of normal (ULN) and maximum level of ALT. Results: SPATA9 (rs72783407) was significantly associated with maximum level of ALT (p = 2.58 × 10-8) and PLCG2 (rs60427389) was tentatively associated with ALT >1.5 × ULN. Conclusion: Associations with SNPs in genes related to male fertility (SPATA9) and inflammatory processes (PLCG2) were identified.

PMID:36070248 | DOI:10.2217/pgs-2022-0074

Antimicrob Agents Chemother. 2022 Sep 7:e0227721. doi: 10.1128/aac.02277-21. Online ahead of print.

ABSTRACT

Tuberculosis is the most common cause of death in HIV-infected individuals. Rifampin and isoniazid are the backbones of the current first-line antitubercular therapy. The aim of the present study was to describe the time-dependent pharmacokinetics and pharmacogenetics of rifampin and isoniazid and to quantitatively evaluate the drug-drug interaction between rifampin and isoniazid in patients coinfected with HIV. Plasma concentrations of isoniazid, acetyl-isoniazid, isonicotinic acid, rifampin, and 25-desacetylrifampin from 40 HIV therapy-naive patients were determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS) after the first dose and at steady state of antitubercular therapy. Patients were genotyped for determination of acetylator status and CYP2C19 phenotype. Nonlinear mixed-effects models were developed to describe the pharmacokinetic data. The model estimated an autoinduction of both rifampin bioavailability (0.5-fold) and clearance (2.3-fold). 25-Desacetylrifampin clearance was 2.1-fold higher at steady state than after the first dose. Additionally, ultrarapid CYP2C19 metabolizers had a 2-fold-higher rifampin clearance at steady state than intermediate or extensive metabolizers. An induction of isonicotinic acid formation from isoniazid dependent on total rifampin dose was estimated. Simulations indicated a 30% lower isoniazid exposure at steady state during administration of standard rifampin doses than isoniazid exposure in noninduced individuals. Rifampin exposure was correlated with CYP2C19 polymorphism, and rifampin administration may increase exposure to toxic metabolites by isoniazid in patients. Both findings may influence the risk of treatment failure, resistance development, and toxicity and require further investigation, especially with regard to ongoing high-dose rifampin trials.

PMID:36069614 | DOI:10.1128/aac.02277-21

Methods Mol Biol. 2022;2547:595-609. doi: 10.1007/978-1-0716-2573-6_21.

ABSTRACT

Genetic ancestry inference can be used to stratify patient cohorts and to model pharmacogenomic variation within and between populations. We provide a detailed guide to genetic ancestry inference using genome-wide genetic variant datasets, with an emphasis on two widely used techniques: principal components analysis (PCA) and ADMIXTURE analysis. PCA can be used for patient stratification and categorical ancestry inference, whereas ADMIXTURE is used to characterize genetic ancestry as a continuous variable. Visualization methods are critical for the interpretation of genetic ancestry inference methods, and we provide instructions for how the results of PCA and ADMIXTURE can be effectively visualized.

PMID:36068478 | DOI:10.1007/978-1-0716-2573-6_21

Methods Mol Biol. 2022;2547:569-593. doi: 10.1007/978-1-0716-2573-6_20.

ABSTRACT

Historically genetics has not been considered when prescribing drugs for children. However, it is clear that genetics are not only an important determinant of disease in children but also of drug response for many important drugs that are core agents used in the therapy of common problems in children. Advances in therapy and in the ethical construct of children's research have made pharmacogenomic assessment for children much easier to pursue. It is likely that pharmacogenomics will become part of the therapeutic decision-making process for children, notably in areas such as childhood cancer where weighing benefits and risks of therapy is crucial.

PMID:36068477 | DOI:10.1007/978-1-0716-2573-6_20

Methods Mol Biol. 2022;2547:527-567. doi: 10.1007/978-1-0716-2573-6_19.

ABSTRACT

Rheumatoid arthritis (RA) is a chronic systemic inflammatory disorder that can lead to severe joint damage and is often associated with a high morbidity and disability. Disease-modifying anti-rheumatic drugs (DMARDs) are the mainstay of treatment in RA. DMARDs not only relieve the clinical signs and symptoms of RA but also inhibit the radiographic progression of disease and reduce the effects of chronic systemic inflammation. Since the introduction of biologic DMARDs in the late 1990s, the therapeutic range of options for the management of RA has significantly expanded. However, patients' response to these agents is not uniform with considerable variability in both efficacy and toxicity. There are no reliable means of predicting an individual patient's response to a given DMARD prior to initiation of therapy. In this chapter, the current published literature on the pharmacogenetics of traditional DMARDS and the newer biologic DMARDs in RA is highlighted. Pharmacogenetics may help individualize drug therapy in patients with RA by providing reliable biomarkers to predict medication toxicity and efficacy.

PMID:36068476 | DOI:10.1007/978-1-0716-2573-6_19

Methods Mol Biol. 2022;2547:505-526. doi: 10.1007/978-1-0716-2573-6_18.

ABSTRACT

Pharmacogenomics can improve pain management by considering individual variations in pain perception and susceptibility and sensitivity to medicines related to genetic diversity. Due to the subjective nature of pain and the fact that people respond differently to medicines, it can be challenging to develop a consistent and successful regimen for pain disorders. Numerous factors influence the outcome of pain treatment programs, but two stand out: altered perception of pain and varying responsiveness to analgesic medicines. Numerous polymorphisms in genes such as CYP2D6, OPRM1, and ABCB1 have been identified, culminating in a heterogeneous response to pain medication in people who have these genetic polymorphisms. Improved treatment regimens that factor in pharmacogenetic differences in patients would help reduce the risk of opioid dependency and help effectively treat postoperative pain.

PMID:36068475 | DOI:10.1007/978-1-0716-2573-6_18

Methods Mol Biol. 2022;2547:491-504. doi: 10.1007/978-1-0716-2573-6_17.

ABSTRACT

Pain affects approximately 100 million Americans. Pain harms quality of life and costs patients billions of dollars per year. Clinically, nonpharmacologic and pharmacologic therapies can alleviate acute and chronic pain suffering. Opioids are one type of medication used to manage pain. However, opioids can potentially create dependence and substance abuse, and the effects are not consistent in all patients. Pharmacogenomics is the study of the genome to understand the effects of drugs on individual patients based on their genetic information. Through pharmacogenomics, researchers can investigate genetic polymorphisms related to pain that maximize individual patient drug responses and minimize toxicity. This chapter discusses the pharmacogenomics of opioids to treat pain, including individual genetic differences to opioid treatments, opioid pharmacokinetics and pharmacodynamics, and the genetic polymorphisms associated with individual opioid medications.

PMID:36068474 | DOI:10.1007/978-1-0716-2573-6_17

Methods Mol Biol. 2022;2547:437-490. doi: 10.1007/978-1-0716-2573-6_16.

ABSTRACT

Drug addiction is a serious relapsing disease that has high costs to society and to the individual addicts. Treatment of these addictions is still in its nascency, with only a few examples of successful therapies. Therapeutic response depends upon genetic, biological, social, and environmental components. A role for genetic makeup in the response to treatment has been shown for several addiction pharmacotherapies with response to treatment based on individual genetic makeup. In this chapter, we will discuss the role of genetics in pharmacotherapies, specifically for cocaine, alcohol, and opioid dependences. The continued elucidation of the role of genetics should aid in the development of new treatments and increase the efficacy of existing treatments.

PMID:36068473 | DOI:10.1007/978-1-0716-2573-6_16

Methods Mol Biol. 2022;2547:427-436. doi: 10.1007/978-1-0716-2573-6_15.

ABSTRACT

ADHD is a common condition in both children and adults. The most prescribed medications for the treatment of ADHD include methylphenidate, mixed amphetamine salts, atomoxetine, guanfacine, and clonidine. While each of these medications have their own distinct pharmacokinetic profile, the extent to which pharmacogenetics effects their pharmacokinetic parameters is best described in atomoxetine, followed by methylphenidate. Atomoxetine is predominantly metabolized by cytochrome p450 2D6 (CYP2D6), while methylphenidate is metabolized by carboxylesterase 1 (CES1). Both CYP2D6 and CES1 have multiple variants resulting in varying levels of enzyme activity; however, to date, the functional consequence of variants and alleles for CYP2D6 is better characterized as compared to CES1. Regarding CYP2D6, individuals who are poor metabolizers prescribed atomoxetine experience up to ten-fold higher exposure as compared to normal metabolizers at comparable dosing. Additionally, individuals prescribed methylphenidate with the rs71647871 variant may experience up to 2.5-fold higher exposure as compared to those without. Having this pharmacogenetic information available may aid clinicians and patients when choosing medications and doses to treat ADHD.

PMID:36068472 | DOI:10.1007/978-1-0716-2573-6_15

Methods Mol Biol. 2022;2547:389-425. doi: 10.1007/978-1-0716-2573-6_14.

ABSTRACT

Antipsychotics are the mainstay treatment for schizophrenia. There is large variability between individuals in their response to antipsychotics, both in efficacy and adverse effects of treatment. While the source of interindividual variability in antipsychotic response is not completely understood, genetics is a major contributing factor. The identification of pharmacogenetic markers that predict antipsychotic efficacy and adverse reactions is a growing area of research and holds the potential to replace the current trial-and-error approach to treatment selection in schizophrenia with a personalized medicine approach.In this chapter, we provide an overview of the current state of pharmacogenetics in schizophrenia treatment. The most promising pharmacogenetic findings are presented for both antipsychotic response and commonly studied adverse reactions. The application of pharmacogenetics to schizophrenia treatment is discussed, with an emphasis on the clinical utility of pharmacogenetic testing and directions for future research.

PMID:36068471 | DOI:10.1007/978-1-0716-2573-6_14

Methods Mol Biol. 2022;2547:275-387. doi: 10.1007/978-1-0716-2573-6_13.

ABSTRACT

Alzheimer's disease (AD) is a priority health problem in developed countries with a high cost to society. Approximately 20% of direct costs are associated with pharmacological treatment. Over 90% of patients require multifactorial treatments, with risk of adverse drug reactions (ADRs) and drug-drug interactions (DDIs) for the treatment of concomitant diseases such as hypertension (>25%), obesity (>70%), diabetes mellitus type 2 (>25%), hypercholesterolemia (40%), hypertriglyceridemia (20%), metabolic syndrome (20%), hepatobiliary disorder (15%), endocrine/metabolic disorders (>20%), cardiovascular disorder (40%), cerebrovascular disorder (60-90%), neuropsychiatric disorders (60-90%), and cancer (10%).For the past decades, pharmacological studies in search of potential treatments for AD focused on the following categories: neurotransmitter enhancers (11.38%), multitarget drugs (2.45%), anti-amyloid agents (13.30%), anti-tau agents (2.03%), natural products and derivatives (25.58%), novel synthetic drugs (8.13%), novel targets (5.66%), repository drugs (11.77%), anti-inflammatory drugs (1.20%), neuroprotective peptides (1.25%), stem cell therapy (1.85%), nanocarriers/nanotherapeutics (1.52%), and other compounds (<1%).Pharmacogenetic studies have shown that the therapeutic response to drugs in AD is genotype-specific in close association with the gene clusters that constitute the pharmacogenetic machinery (pathogenic, mechanistic, metabolic, transporter, pleiotropic genes) under the regulatory control of epigenetic mechanisms (DNA methylation, histone/chromatin remodeling, microRNA regulation). Most AD patients (>60%) are carriers of over ten pathogenic genes. The genes that most frequently (>50%) accumulate pathogenic variants in the same AD case are A2M (54.38%), ACE (78.94%), BIN1 (57.89%), CLU (63.15%), CPZ (63.15%), LHFPL6 (52.63%), MS4A4E (50.87%), MS4A6A (63.15%), PICALM (54.38%), PRNP (80.7059), and PSEN1 (77.19%). There is also an accumulation of 15 to 26 defective pharmagenes in approximately 85% of AD patients. About 50% of AD patients are carriers of at least 20 mutant pharmagenes, and over 80% are deficient metabolizers for the most common drugs, which are metabolized via the CYP2D6, CYP2C9, CYP2C19, and CYP3A4/5 enzymes.The implementation of pharmacogenetics can help optimize drug development and the limited therapeutic resources available to treat AD, and personalize the use of anti-dementia drugs in combination with other medications for the treatment of concomitant disorders.

PMID:36068470 | DOI:10.1007/978-1-0716-2573-6_13

Methods Mol Biol. 2022;2547:255-266. doi: 10.1007/978-1-0716-2573-6_11.

ABSTRACT

Studies of genetic variants and systems biology have indicated that Yin-Yang dynamics are especially meaningful for cardiovascular pharmacogenomics and personalized therapeutic strategies. The comprehensive concepts of Yin-Yang can be used to characterize the dynamical factors in the adaptive microenvironments of the complex cardiovascular systems. The Yin-Yang imbalances in the complex adaptive systems (CAS) at different levels and stages are essential for cardiovascular diseases (CVDs), including atherosclerosis, hypertension, and heart failure (HF). At the molecular and cellular levels, Yin-Yang interconnections have been considered critical for genetic variants and various pathways, mitophagy, cell death, and cholesterol homeostasis. The significance of the adaptive and spatiotemporal factors in the nonlinear Yin-Yang interactions has been identified in different pathophysiological processes such as fibrosis. The Yin-Yang dynamical balances between proinflammatory and anti-inflammatory cytokines have vital roles in the complex reactions to stress and impairments to the heart. Procoagulant and anticoagulant lipids and lipoproteins in plasma have the Yin-Yang roles that increase or decrease thrombin productions and thrombosis. At the systems level, the Yin-Yang type of relationships has been suggested between atrial fibrillation (AF), diastolic dysfunction (DD), and HF. Based on such perceptions, systemic and personalized cardiovascular profiles can be constructed by embracing the features of CAS, especially the microenvironments and the adaptative pathophysiological stages. These features can be integrated into the comprehensive Yin-Yang dynamics framework to identify more accurate biomarkers for better prevention and treatments. The goal of reestablishing ubiquitous Yin-Yang dynamical balances may become the central theme for personalized and systems medicine for cardiovascular diseases.

PMID:36068468 | DOI:10.1007/978-1-0716-2573-6_11

Methods Mol Biol. 2022;2547:241-253. doi: 10.1007/978-1-0716-2573-6_10.

ABSTRACT

Calcium imaging is an invaluable technique to detect and characterize calcium flux in cells. The use of calcium dye provides information on the concentration and spatial distribution of calcium. Calcium imaging is a well-established technique to assess the calcium-induced calcium release mechanism in cardiomyocytes. It can also be used to characterize mutations in genes crucial for this mechanism that frequently causes arrhythmia. Here we describe a high-throughput methodology of calcium imaging that records individual calcium transients in more than 10,000 human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) in less than 30 min.

PMID:36068467 | DOI:10.1007/978-1-0716-2573-6_10

Methods Mol Biol. 2022;2547:201-240. doi: 10.1007/978-1-0716-2573-6_9.

ABSTRACT

Precision medicine exemplifies the emergence of personalized treatment options which may benefit specific patient populations based upon their genetic makeup. Application of pharmacogenomics requires an understanding of how genetic variations impact pharmacokinetic and pharmacodynamic properties. This particular approach in pharmacotherapy is helpful because it can assist in and improve clinical decisions. Application of pharmacogenomics to cardiovascular pharmacotherapy provides for the ability of the medical provider to gain critical knowledge on a patient's response to various treatment options and risk of side effects.

PMID:36068466 | DOI:10.1007/978-1-0716-2573-6_9

Methods Mol Biol. 2022;2547:187-199. doi: 10.1007/978-1-0716-2573-6_8.

ABSTRACT

The SARS-CoV-2 virus has been the subject of intense pharmacological research. Various pharmacotherapeutic approaches including antiviral and immunotherapy are being explored. A pandemic, however, cannot depend on the development of new drugs; the time required for conventional drug discovery and development is far too lengthy. As such, repurposing drugs is being used as a viable approach for identifying pharmacological agents for COVID-19 infections. Evaluation of repurposed drug candidates with pharmacogenomic analysis is being used to identify near-term pharmacological remedies for COVID-19.

PMID:36068465 | DOI:10.1007/978-1-0716-2573-6_8

Methods Mol Biol. 2022;2547:165-185. doi: 10.1007/978-1-0716-2573-6_7.

ABSTRACT

The good clinical results of immune checkpoint inhibitors (ICIs) in recent cancer therapy and the success of RNA vaccines against SARS-nCoV2 have provided important lessons to the scientific community. On the one hand, the efficacy of ICI depends on the number and immunogenicity of tumor neoantigens (TNAs) which unfortunately are not abundantly expressed in many cancer subtypes. On the other hand, novel RNA vaccines have significantly improved both the stability and immunogenicity of mRNA and its efficient delivery, this way overcoming past technique limitations and also allowing a quick vaccine development at the same time. These two facts together have triggered a resurgence of therapeutic cancer vaccines which can be designed to include individual TNAs and be synthesized in a timeframe short enough to be suitable for the tailored treatment of a given cancer patient.In this chapter, we explain the pipeline for the synthesis of TNA-carrying RNA vaccines which encompasses several steps such as individual tumor next-generation sequencing (NGS), selection of immunogenic TNAs, nucleic acid synthesis, drug delivery systems, and immunogenicity assessment, all of each step comprising different alternatives and variations which will be discussed.

PMID:36068464 | DOI:10.1007/978-1-0716-2573-6_7

Methods Mol Biol. 2022;2547:141-163. doi: 10.1007/978-1-0716-2573-6_6.

ABSTRACT

The enormous heterogeneity of cancer systems has made it very challenging to overcome drug resistance and adverse reactions to achieve personalized therapies. Recent developments in systems biology, especially the perception of cancer as the complex adaptive system (CAS), may help meet the challenges by deciphering the interactions at various levels from the molecular, cellular, tissue-organ, to the whole organism. The ubiquitous Yin-Yang interactions among the coevolving components, including the genes and proteins, decide their spatiotemporal features at various stages from cancer initiation to metastasis. The Yin-Yang imbalances across different systems levels, from genetic mutations to tumor cells adaptation, have been related to the intra- and inter-tumoral heterogeneity in the micro- and macro-environments. At the molecular and cellular levels, dysfunctional Yin-Yang dynamics in the cytokine networks, mitochondrial activities, redox systems, apoptosis, and metabolism can contribute to tumor cell growth and escape of immune surveillance. Up to the organism and system levels, the Yin-Yang imbalances in the cancer microenvironments can lead to different phenotypes from breast cancer to leukemia. These factors may be considered the systems-based biomarkers and treatment targets. The features of adaptation and nonlinearity in Yin-Yang dynamical interactions should be addressed by individualized drug combinations, dosages, intensities, timing, and frequencies at different cancer stages. The comprehensive "Yin-Yang dynamics" framework would enable powerful approaches for personalized and systems medicine strategies.

PMID:36068463 | DOI:10.1007/978-1-0716-2573-6_6

Methods Mol Biol. 2022;2547:95-140. doi: 10.1007/978-1-0716-2573-6_5.

ABSTRACT

Pharmacogenomics is a powerful tool to predict individual response to treatment, in order to personalize therapy, and it has been explored extensively in oncology practice. Not only efficacy on the malignant disease has been investigated but also the possibility to predict adverse effects due to drug administration. Chemotherapy-induced peripheral neurotoxicity (CIPN) is one of those. This potentially severe and long-lasting/permanent side effect of commonly administered anticancer drugs can severely impair quality of life (QoL) in a large cohort of long survival patients. So far, a pharmacogenomics-based approach in CIPN regard has been quite delusive, making a methodological improvement warranted in this field of interest: even the most refined genetic analysis cannot be effective if not applied correctly. Here we try to devise why it is so, suggesting how THE "bench-side" (pharmacogenomics) might benefit from and should cooperate with THE "bed-side" (clinimetrics), in order to make genetic profiling effective if applied to CIPN.

PMID:36068462 | DOI:10.1007/978-1-0716-2573-6_5

Methods Mol Biol. 2022;2547:63-94. doi: 10.1007/978-1-0716-2573-6_4.

ABSTRACT

Pharmacogenetic testing in patients with cancer requiring cytotoxic chemotherapy offers the potential to predict, prevent, and mitigate chemotherapy-related toxicities. While multiple drug-gene pairs have been identified and studied, few drug-gene pairs are currently used routinely in the clinical status. Here we review what is known, theorized, and unknown regarding the use of pharmacogenetic testing in cancer.

PMID:36068461 | DOI:10.1007/978-1-0716-2573-6_4