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Signal Transduction and Targeted Therapy Oct 2023Individual variability in drug response (IVDR) can be a major cause of adverse drug reactions (ADRs) and prolonged therapy, resulting in a substantial health and... (Review)
Review
Individual variability in drug response (IVDR) can be a major cause of adverse drug reactions (ADRs) and prolonged therapy, resulting in a substantial health and economic burden. Despite extensive research in pharmacogenomics regarding the impact of individual genetic background on pharmacokinetics (PK) and pharmacodynamics (PD), genetic diversity explains only a limited proportion of IVDR. The role of gut microbiota, also known as the second genome, and its metabolites in modulating therapeutic outcomes in human diseases have been highlighted by recent studies. Consequently, the burgeoning field of pharmacomicrobiomics aims to explore the correlation between microbiota variation and IVDR or ADRs. This review presents an up-to-date overview of the intricate interactions between gut microbiota and classical therapeutic agents for human systemic diseases, including cancer, cardiovascular diseases (CVDs), endocrine diseases, and others. We summarise how microbiota, directly and indirectly, modify the absorption, distribution, metabolism, and excretion (ADME) of drugs. Conversely, drugs can also modulate the composition and function of gut microbiota, leading to changes in microbial metabolism and immune response. We also discuss the practical challenges, strategies, and opportunities in this field, emphasizing the critical need to develop an innovative approach to multi-omics, integrate various data types, including human and microbiota genomic data, as well as translate lab data into clinical practice. To sum up, pharmacomicrobiomics represents a promising avenue to address IVDR and improve patient outcomes, and further research in this field is imperative to unlock its full potential for precision medicine.
Topics: Humans; Precision Medicine; Microbiota; Gastrointestinal Microbiome; Pharmacogenetics; Drug-Related Side Effects and Adverse Reactions
PubMed: 37806986
DOI: 10.1038/s41392-023-01619-w -
JAMA Network Open Oct 2023Limited evidence supports multigenetic pharmacogenomics-guided treatment (MPGT) in schizophrenia. (Randomized Controlled Trial)
Randomized Controlled Trial
IMPORTANCE
Limited evidence supports multigenetic pharmacogenomics-guided treatment (MPGT) in schizophrenia.
OBJECTIVE
To evaluate the clinical effectiveness of MPGT in schizophrenia in a randomized clinical trial (RCT).
DESIGN, SETTING, AND PARTICIPANTS
This RCT was conducted from March 2020 to March 2022. Male Chinese Han inpatients aged 18 to 60 years diagnosed with schizophrenia with a Positive and Negative Symptom Scale (PANSS) score of 60 or more from 2 selected study hospitals were included. Patients and raters were masked to MPGT or treatment as usual (TAU) randomization.
INTERVENTIONS
Participants were randomly assigned in a 1:1 ratio to receive either MPGT or TAU for 12 weeks.
MAIN OUTCOMES AND MEASURES
The primary efficacy outcome was the percentage change in PANSS total scores (range, 30 to 210) from baseline to week 6 analyzed by a modified intention-to-treat mixed model for repeated measures. The secondary outcome included response and symptomatic remission rates.
RESULTS
A total of 210 participants (mean [SD] age, 29.2 [8.8] years) were enrolled and analyzed, with 113 assigned to MPGT and 97 to TAU. Compared with those randomized to TAU, participants randomized to MPGT demonstrated a significantly higher percentage change in PANSS score (74.2% vs 64.9%; adjusted mean difference, 9.2 percentage points; 95% CI, 4.4-14.1 percentage points; P < .001) and a higher response rate (93 of 113 [82.3%] vs 63 of 97 [64.9%]; adjusted odds ratio, 2.48; 95% CI, 1.28-4.80; P = .01) at the end of week 6.
CONCLUSIONS AND RELEVANCE
In this RCT of MPGT, MPGT was more effective than TAU in treating patients with schizophrenia. These findings suggest that multigenetic pharmacogenomic testing could serve as an effective tool to guide the treatment of schizophrenia.
TRIAL REGISTRATION
Chinese Clinical Trial Registry Identifier: ChiCTR2000029671.
Topics: Male; Humans; Adult; Pharmacogenetics; Schizophrenia; Treatment Outcome
PubMed: 37801319
DOI: 10.1001/jamanetworkopen.2023.35518 -
Cancer Cell Apr 2024Inter- and intra-tumor heterogeneity is a major hurdle in primary liver cancer (PLC) precision therapy. Here, we establish a PLC biobank, consisting of 399 tumor...
Inter- and intra-tumor heterogeneity is a major hurdle in primary liver cancer (PLC) precision therapy. Here, we establish a PLC biobank, consisting of 399 tumor organoids derived from 144 patients, which recapitulates histopathology and genomic landscape of parental tumors, and is reliable for drug sensitivity screening, as evidenced by both in vivo models and patient response. Integrative analysis dissects PLC heterogeneity, regarding genomic/transcriptomic characteristics and sensitivity to seven clinically relevant drugs, as well as clinical associations. Pharmacogenomic analysis identifies and validates multi-gene expression signatures predicting drug response for better patient stratification. Furthermore, we reveal c-Jun as a major mediator of lenvatinib resistance through JNK and β-catenin signaling. A compound (PKUF-01) comprising moieties of lenvatinib and veratramine (c-Jun inhibitor) is synthesized and screened, exhibiting a marked synergistic effect. Together, our study characterizes the landscape of PLC heterogeneity, develops predictive biomarker panels, and identifies a lenvatinib-resistant mechanism for combination therapy.
Topics: Humans; Biological Specimen Banks; Pharmacogenetics; Precision Medicine; Liver Neoplasms; Organoids; Phenylurea Compounds; Quinolines
PubMed: 38593780
DOI: 10.1016/j.ccell.2024.03.004 -
Precision Clinical Medicine Dec 2023Inflammatory bowel disease (IBD) is an incurable disease characterized by remission-relapse cycles throughout its course. Both Crohn's disease (CD) and ulcerative... (Review)
Review
Inflammatory bowel disease (IBD) is an incurable disease characterized by remission-relapse cycles throughout its course. Both Crohn's disease (CD) and ulcerative colitis (UC), the two main forms of IBD, exhibit tendency to develop complications and substantial heterogeneity in terms of frequency and severity of relapse, thus posing great challenges to the clinical management for IBD. Current treatment strategies are effective in different ways in induction and maintenance therapies for IBD. Recent advances in studies of genetics, pharmacogenetics, proteomics and microbiome provide a strong driving force for identifying molecular markers of prognosis and treatment response, which should help clinicians manage IBD patients more effectively, and then, improve clinical outcomes and reduce treatment costs of patients. In this review, we summarize and discuss precision medicine in IBD, focusing on predictive markers of disease course and treatment response, and monitoring indices during therapeutic drug monitoring.
PubMed: 38638127
DOI: 10.1093/pcmedi/pbad033 -
Biochemical Pharmacology Nov 2023Ovarian cancer stands as the prevailing gynecologic malignancy, afflicting over 313,959 individuals annually worldwide, accompanied by more than 207,252 fatalities.... (Review)
Review
Ovarian cancer stands as the prevailing gynecologic malignancy, afflicting over 313,959 individuals annually worldwide, accompanied by more than 207,252 fatalities. Perturbations in calcium signaling contribute significantly to the pathogenesis of numerous cancers, including ovarian cancer, wherein alterations in calcium transporter expression have been reported. Overexpression of TRPM7, a prominent calcium transporter, has been linked to adverse prognostic outcomes in various cancer types. The focus of this comprehensive review centers around delineating the oncogenic role of TRPM7 in cancer development and exploring its therapeutic potential as a target in combating this disease. Notably, TRPM7 fosters cancer invasion, metastasis, and uncontrolled cell proliferation, thereby perpetuating the expansion and reinforcement of these malignant entities. Furthermore, this review takes ovarian cancer as an example and summarizes the "dual-mode" regulatory role of TRPM7 in cancer. Within the domain of ovarian cancer, TRPM7 assumes the role of a harsh tyrant, firmly controlling the calcium ion signaling pathway and metabolic reprogramming pathways.
Topics: Humans; Female; TRPM Cation Channels; Calcium; Ovarian Neoplasms; Cell Proliferation; Protein Serine-Threonine Kinases
PubMed: 37839677
DOI: 10.1016/j.bcp.2023.115857 -
Journal of Personalized Medicine Jul 2023Previous studies have documented pain as an important concern for quality of life (QoL) and one of the most challenging manifestations for cancer patients. Thus, cancer... (Review)
Review
BACKGROUND
Previous studies have documented pain as an important concern for quality of life (QoL) and one of the most challenging manifestations for cancer patients. Thus, cancer pain management (CPM) plays a key role in treating pain related to cancer. The aim of this systematic review was to investigate CPM, with an emphasis on personalized medicine, and introduce new pharmacogenomics-based procedures for detecting and treating cancer pain patients.
METHODS
This study systematically reviewed PubMed from 1990 to 2023 using keywords such as cancer, pain, and personalized medicine. A total of 597 publications were found, and after multiple filtering processes, 75 papers were included. In silico analyses were performed using the GeneCards, STRING-MODEL, miRTargetLink2, and PharmGKB databases.
RESULTS
The results reveal that recent reports have mainly focused on personalized medicine strategies for CPM, and pharmacogenomics-based data are rapidly being introduced. The literature review of the 75 highly relevant publications, combined with the bioinformatics results, identified a list of 57 evidence-based genes as the primary gene list for further personalized medicine approaches. The most frequently mentioned genes were CYP2D6, COMT, and OPRM1. Moreover, among the 127 variants identified through both the literature review and data mining in the PharmGKB database, 21 variants remain as potential candidates for whole-exome sequencing (WES) analysis. Interestingly, hsa-miR-34a-5p and hsa-miR-146a-5p were suggested as putative circulating biomarkers for cancer pain prognosis and diagnosis.
CONCLUSIONS
In conclusion, this study highlights personalized medicine as the most promising strategy in CPM, utilizing pharmacogenomics-based approaches to alleviate cancer pain.
PubMed: 37623452
DOI: 10.3390/jpm13081201 -
Annual Review of Pharmacology and... Jan 2024I am deeply honored to be invited to write this scientific autobiography. As a physician-scientist, pediatrician, molecular biologist, and geneticist, I have... (Review)
Review
I am deeply honored to be invited to write this scientific autobiography. As a physician-scientist, pediatrician, molecular biologist, and geneticist, I have authored/coauthored more than 600 publications in the fields of clinical medicine, biochemistry, biophysics, pharmacology, drug metabolism, toxicology, molecular biology, cancer, standardized gene nomenclature, developmental toxicology and teratogenesis, mouse genetics, human genetics, and evolutionary genomics. Looking back, I think my career can be divided into four distinct research areas, which I summarize mostly chronologically in this article: () discovery and characterization of the AHR/CYP1 axis, () pharmacogenomics and genetic prediction of response to drugs and other environmental toxicants, () standardized drug-metabolizing gene nomenclature based on evolutionary divergence, and () discovery and characterization of the gene encoding the ZIP8 metal cation influx transporter. Collectively, all four topics embrace gene-environment interactions, hence the title of my autobiography.
Topics: Humans; Animals; Mice; Genomics; Membrane Transport Proteins; Pharmacogenetics; Physicians
PubMed: 37788491
DOI: 10.1146/annurev-pharmtox-022323-082311 -
Paediatrics & Child Health Jul 2023The past two decades have seen enormous advancements in medical knowledge around the role of genetic factors of variability, both in human disease and drug response.... (Review)
Review
The past two decades have seen enormous advancements in medical knowledge around the role of genetic factors of variability, both in human disease and drug response. This knowledge is increasingly being translated into guidelines that inform drug dosing, monitoring for efficacy and safety, and determining the suitability of specific agents to treat patients. Health Canada and the U.S. Food and Drug Administration have recommended using genetic information to guide dosing for more than 20 drugs. There are no current, comprehensive paediatric guidelines to assist health care professionals in the use of genetics to inform medication dosing, safety, and efficacy in children, and such guidance is urgently needed. This statement helps to guide clinician understanding of the role of pharmacogenetics and how to use this information when prescribing medications in paediatrics.
PubMed: 37287477
DOI: 10.1093/pch/pxad002 -
Pharmaceuticals (Basel, Switzerland) Nov 2023Indiscriminate drug administration may lead to drug therapy results with varying effects on patients, and the proposal of personalized medication can help patients to... (Review)
Review
Indiscriminate drug administration may lead to drug therapy results with varying effects on patients, and the proposal of personalized medication can help patients to receive effective drug therapy. Conventional ways of personalized medication, such as pharmacogenomics and therapeutic drug monitoring (TDM), can only be implemented from a single perspective. The development of pharmacometabolomics provides a research method for the realization of precise drug administration, which integrates the environmental and genetic factors, and applies metabolomics technology to study how to predict different drug therapeutic responses of organisms based on baseline metabolic levels. The published research on pharmacometabolomics has achieved satisfactory results in predicting the pharmacokinetics, pharmacodynamics, and the discovery of biomarkers of drugs. Among them, the pharmacokinetics related to pharmacometabolomics are used to explore individual variability in drug metabolism from the level of metabolism of the drugs in vivo and the level of endogenous metabolite changes. By searching for relevant literature with the keyword "pharmacometabolomics" on the two major literature retrieval websites, PubMed and Web of Science, from 2006 to 2023, we reviewed articles in the field of pharmacometabolomics that incorporated pharmacokinetics into their research. This review explains the therapeutic effects of drugs on the body from the perspective of endogenous metabolites and pharmacokinetic principles, and reports the latest advances in pharmacometabolomics related to pharmacokinetics to provide research ideas and methods for advancing the implementation of personalized medication.
PubMed: 38004434
DOI: 10.3390/ph16111568 -
Biomedicine & Pharmacotherapy =... Aug 2023Prenyltransferases (PTases) are known to play a role in embryonic development, normal tissue homeostasis and cancer by posttranslationally modifying proteins involved in... (Review)
Review
Prenyltransferases (PTases) are known to play a role in embryonic development, normal tissue homeostasis and cancer by posttranslationally modifying proteins involved in these processes. They are being discussed as potential drug targets in an increasing number of diseases, ranging from Alzheimer's disease to malaria. Protein prenylation and the development of specific PTase inhibitors (PTIs) have been subject to intense research in recent decades. Recently, the FDA approved lonafarnib, a specific farnesyltransferase inhibitor that acts directly on protein prenylation; and bempedoic acid, an ATP citrate lyase inhibitor that might alter intracellular isoprenoid composition, the relative concentrations of which can exert a decisive influence on protein prenylation. Both drugs represent the first approved agent in their respective substance class. Furthermore, an overwhelming number of processes and proteins that regulate protein prenylation have been identified over the years, many of which have been proposed as molecular targets for pharmacotherapy in their own right. However, certain aspects of protein prenylation, such as the regulation of PTase gene expression or the modulation of PTase activity by phosphorylation, have attracted less attention, despite their reported influence on tumor cell proliferation. Here, we want to summarize the advances regarding our understanding of the regulation of protein prenylation and the potential implications for drug development. Additionally, we want to suggest new lines of investigation that encompass the search for regulatory elements for PTases, especially at the genetic and epigenetic levels.
Topics: Protein Prenylation; Proteins; Dimethylallyltranstransferase; Enzyme Inhibitors; Terpenes; Prenylation
PubMed: 37236024
DOI: 10.1016/j.biopha.2023.114915