The pharmacoepigenetic paradigm in cancer treatment

Frontiers in Pharmacology, Год журнала: 2024, Номер 15

Опубликована: Апрель 24, 2024

Epigenetic modifications, characterized by changes in gene expression without altering the DNA sequence, play a crucial role development and progression of cancer significantly influencing activity cellular function. This insight has led to novel class therapeutic agents, known as epigenetic drugs. These drugs, including histone deacetylase inhibitors, acetyltransferase methyltransferase aim modulate curb growth uniquely landscape cells. Ongoing research clinical trials are rigorously evaluating efficacy these particularly their ability improve outcomes when used combination with other treatments. Such therapies may more effectively target potentially overcome challenge drug resistance, significant hurdle therapy. Additionally, importance nutrition, inflammation control, circadian rhythm regulation modulating responses been increasingly recognized, highlighting critical modifiers thereby effectiveness pharmacological interventions patient outcomes. drugs represent paradigm shift treatment, offering targeted that promise precise approach treating wide spectrum tumors, fewer side effects compared traditional chemotherapy. progress marks step towards personalized interventions, leveraging unique profiles individual tumors optimize treatment strategies.

Язык: Английский

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Unraveling druggable cancer-driving proteins and targeted drugs using artificial intelligence and multi-omics analyses

Scientific Reports, Год журнала: 2024, Номер 14(1)

Опубликована: Авг. 21, 2024

The druggable proteome refers to proteins that can bind small molecules with appropriate chemical affinity, inducing a favorable clinical response. Predicting through screening and in silico modeling is imperative for drug design. To contribute this field, we developed an accurate predictive classifier cancer-driving using amino acid composition descriptors of protein sequences 13 machine learning linear non-linear classifiers. optimal was achieved the support vector method, utilizing 200 tri-amino descriptors. high performance model evident from area under receiver operating characteristics (AUROC) 0.975 ± 0.003 accuracy 0.929 0.006 (threefold cross-validation). prediction enhanced multi-omics approaches, including target-disease evidence score, shortest pathways cancer hallmarks, structure-based ligandability assessment, unfavorable prognostic analysis, oncogenic variome. Additionally, performed repurposing analysis identify drugs highest affinity capable targeting best predicted proteins. As result, identified 79 key ligandability, 23 them demonstrated significance across 16 TCGA PanCancer types: CDKN2A, BCL10, ACVR1, CASP8, JAG1, TSC1, NBN, PREX2, PPP2R1A, DNM2, VAV1, ASXL1, TPR, HRAS, BUB1B, ATG7, MARK3, SETD2, CCNE1, MUTYH, CDKN2C, RB1, SMARCA4. Moreover, prioritized 11 clinically relevant these This strategy effectively predicts prioritizes biomarkers, therapeutic targets, in-depth studies trials. Scripts are available at https://github.com/muntisa/machine-learning-for-druggable-proteins .

Язык: Английский

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Return of Clinically Actionable Pharmacogenetic Results From Molecular Tumor Board DNA Sequencing Data: Workflow and Estimated Costs

Clinical Pharmacology & Therapeutics, Год журнала: 2025, Номер unknown

Опубликована: Янв. 9, 2025

Pharmacogenetic testing can prevent severe toxicities from several oncology drug therapies; it also has the potential to improve outcomes supportive care drugs. Paired tumor and germline sequencing is increasingly common in practice; these include of pharmacogenes, but pharmacogenetic variants are rarely included clinical reports, despite many being clinically actionable. We established an informatics workflow evaluate results for variants. used Aldy computational tool, which we have previously shown determine variant alleles 14 pharmacogenes data with >99% accuracy, identify whole exome our molecular board. Patients genetic that actionable their individual therapy programs, including both treatment care, referred a pharmacogenetics laboratory confirmation. Through evaluation weekly workflow, determined took approximately 3.25 hours complete analysis 20 patients. Using United States pharmacist's median salary, estimated incremental added cost process be only ~$15 per patient. This adds minor increase patient's safety efficacy treatment.

Язык: Английский

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Allele and genotype frequencies of variants in P450 cytochromes, transports, and DNA repair enzymes in the Dominican Republic population

Frontiers in Pharmacology, Год журнала: 2025, Номер 15

Опубликована: Март 5, 2025

Single-nucleotide variants (SNVs) give rise to important inter-individual and inter-ethnic variabilities in the metabolism disposition of several therapeutic agents may cause differences treatment response clinically drugs like antiarrhythmics, antidepressants, antihistamines, antipsychotics, among others. Information about prevalence Dominican Republic population is still limited. The aim this study was describe frequency distribution 32 SNVs from 14 genes with pharmacogenetic interest within a sample 150 unrelated healthy individuals. Genotype allele frequencies were determined, pairwise Wright's FST statistic evaluated. Hardy-Weinberg equilibrium deviations found seven loci CYP2D6 (rs16947, rs3892097, rs1058164, rs1135840, rs28371725) CYP2C19 (rs12769205 rs4244285) genes. minor ranged 0.01 0.50 values xenobiotic biotransformation enzymes transporter average admixture estimates 51.6%, 39.5%, 8.9% for European, African, Amerindian ancestries, respectively. Pairwise analysis revealed that Dominicans displayed genetic similarity Latin American populations, especially those Afro-Caribbean ancestry, given selected variants. Higher identified East South Asians, Europeans, Africans, which above threshold moderate differentiation CYP2C, CYP3A, CYP1A1, ABCB1, SLC45A2, XRCC1, XRCC3 These results should allow establishing clinical relevance testing variant alleles related drug transport population.

Язык: Английский

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Global analysis of actionable genomic alterations in thyroid cancer and precision-based pharmacogenomic strategies

Frontiers in Pharmacology, Год журнала: 2025, Номер 16

Опубликована: Апрель 14, 2025

Introduction Thyroid cancer, a prevalent endocrine malignancy, has an age-standardized incidence rate of 9.1 per 100,000 people and mortality 0.44 as 2024. Despite significant advances in precision oncology driven by large-scale international consortia, gaps persist understanding the genomic landscape thyroid cancer its impact on therapeutic efficacy across diverse populations. Methods To address this gap, we performed comprehensive data mining silico analyses to identify pathogenic variants driver genes, calculate allele frequencies, assess deleteriousness scores global populations, including African, Amish, Ashkenazi Jewish, East South Asian, Finnish non-Finnish European, Latino, Middle Eastern groups. Additionally, pharmacogenomic profiling, drug prescription, clinical trial were analyzed prioritize targeted strategies. Results Our analysis examined 56,622 40 cancer-driver genes 76,156 human genomes, identifying 5,001 known predicted oncogenic variants. Enrichment revealed critical pathways such MAPK, PI3K-AKT-mTOR, p53 signaling, underscoring their roles pathogenesis. High-throughput validation strategies confirmed actionable alterations RET, BRAF, NRAS, KRAS, EPHA7. Ligandability assessments identified these proteins promising targets. Furthermore, our findings highlight potential inhibitors, vandetanib, dabrafenib, selumetinib, for improving treatment outcomes. Discussion This study underscores significance integrating insights with disparities treatment. The identification population-specific targets provides foundation advancing oncology. Future efforts should focus underrepresented developing prevention strategies, fostering collaboration ensure equitable access testing innovative therapies. These initiatives have transform care align broader goals personalized medicine.

Язык: Английский

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Gastric cancer actionable genomic alterations across diverse populations worldwide and pharmacogenomics strategies based on precision oncology

Frontiers in Pharmacology, Год журнала: 2024, Номер 15

Опубликована: Май 2, 2024

Introduction: Gastric cancer is one of the most prevalent types worldwide. The World Health Organization (WHO), International Agency for Research on Cancer (IARC), and Global Statistics (GLOBOCAN) reported an age standardized global incidence rate 9.2 per 100,000 individuals gastric in 2022, with a mortality 6.1. Despite considerable progress precision oncology through efforts international consortia, understanding genomic features their influence effectiveness anti-cancer treatments across diverse ethnic groups remains essential. Methods: Our study aimed to address this need by conducting integrated silico analyses identify actionable alterations driver genes, assess impact using deleteriousness scores, determine allele frequencies nine populations: European Finnish, non-Finnish, Latino, East Asian, South African, Middle Eastern, Ashkenazi Jewish, Amish. Furthermore, our goal was prioritize targeted therapeutic strategies based pharmacogenomics clinical guidelines, drug prescriptions, trial data. Results: comprehensive analysis examined 275,634 variants within 60 genes from 730,947 exome sequences 76,215 whole-genome unrelated individuals, identifying 13,542 annotated predicted oncogenic variants. We prioritized deleterious subsequent testing. Additionally, we discovered ARID1A, ATM, BCOR, ERBB2, ERBB3, CDKN2A, KIT, PIK3CA, PTEN, NTRK3, TP53 , CDKN2A that could enhance efficacy therapies, as suggested prescription analyses, reviews current evaluations phase III IV trials targeting proteins. Discussion: These findings underline urgency consolidating devise effective prevention measures, invest profiling underrepresented populations, ensure inclusion minorities future research developed countries.

Язык: Английский

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Worldwide analysis of actionable genomic alterations in lung cancer and targeted pharmacogenomic strategies

Heliyon, Год журнала: 2024, Номер 10(17), С. e37488 - e37488

Опубликована: Сен. 1, 2024

Язык: Английский

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Relationship Between Pharmacokinetics and Pharmacogenomics, and Its Impact on Drug Choice and Dose Regimens

Опубликована: Янв. 1, 2024

Plasma drug levels can vary due to various factors associated with medications. These include: Genetic and epigenetic lead individual variations in metabolism, thereby affecting every stage of the ADME process. For instance, a dysfunctional efflux pump enteric membrane increase toxicity certain drugs, alterations protein binding sites impact distribution, gene deletions encoding metabolizing enzymes plasma concentrations, therapeutic outcomes. Conversely, overexpression transporters apical renal tubules rapidly eliminate decreasing their half-life. In this context, pharmacogenomics plays crucial role uncovering variable responses attributed phenotypic changes resulting from genetic variations. are considered pharmacogenetic biomarkers (Quiñones L, Roco Á, Cayún JP et al (2017) Clinical applications pharmacogenomics. Rev Med Chil 145:483–500) ( https://www.fda.gov/drugs/science-and-research-drugs/table-pharmacogenomic-biomarkers-drug-labeling ).

Язык: Английский

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Assessing the Occurrence and Influence of Cancer Chemotherapy-Related Pharmacogenetic Alleles in the Chilean Population

Pharmaceutics, Год журнала: 2024, Номер 16(4), С. 561 - 561

Опубликована: Апрель 19, 2024

Background: Pharmacogenomic knowledge as a biomarker for cancer care has transformed clinical practice, however, current guidelines are primarily derived from Eurocentric populations, this limits their application in Latin America, particularly among Hispanic or Latino groups. Despite advancements, systemic chemotherapy still poses challenges drug toxicity and suboptimal response. This study explores pharmacogenetic markers related to anticancer drugs Chilean cohort, filling gap American research. Notably, the influence of native South Mapuche-Huilliche ancestry. Methods: To explore drugs, we utilized an ethnically Admixed genome-wide association studies (GWAS) dataset 1095 unrelated individuals. were selected PharmGKB, totaling 36 level 1 2 evidence single nucleotide polymorphisms (SNPs) 571 3 SNPs. Comparative analyses involved assessing SNP frequencies across diverse populations 1000 Genomes Project. Haplotypes estimated, linkage disequilibrium was examined. Ancestry-based explored relationships between SNPs European ancestries. Chi-square distribution with p ≤ 0.05 Bonferroni’s multiple adjustment tests determined statistical differences allele frequencies. Results: Our reveals significant disparities frequency within population. dihydropyrimidine dehydrogenase (DPYD) variants (rs75017182 rs67376798), linked increased risk severe fluoropyrimidine toxicity, exhibit exceptionally low (minor (MAF) < 0.005). Nudix hydrolase 15 (NUDT15) rs116855232, associated hematological mercaptopurine is relatively common (MAF = 0.062), further Thiopurine methyltransferase enzyme (TPMT), implicated mercaptopurines, rs1142345 rs1800460 TMPT gene demonstrate higher MAFs Americans population range 0.031–0.057). Finally, variant UDP-glucuronosyltransferase (UGT1A1) rs4148323, correlated irinotecan neutropenia, exhibits highest MAF East Asian 0.136) 0.025) distinguishing them other investigated populations. Conclusions: provides first comprehensive characterization therapy-related highlights findings underscore necessity inclusive research personalized therapeutic strategies ensure equitable effective precision medicine global communities.

Язык: Английский

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Genotype‐driven asthma prescribing of inhaled corticosteroids and long‐acting β2‐agonist: A cost‐effectiveness analysis

Pediatric Pulmonology, Год журнала: 2024, Номер 59(10), С. 2449 - 2456

Опубликована: Апрель 25, 2024

Abstract Introduction Predicting response to inhaled corticosteroids (ICSs) + long‐acting β2‐agonist (LABA) by previously detecting the presence of Arg16Gly ADRB2 genotype is a strategy that could reduce and optimize management asthmatic patients. There need for economic evaluations facilitate implementation such tests. This research aims evaluate cost‐effectiveness screening in children with asthma Colombia. Methods From perspective third‐party payer, we conducted analysis determine cost quality‐adjusted life‐years (QALYs) genotype‐driven prescribing based on versus current treatment no genetic testing. Using four state‐transition models, estimate QALYs employing micro‐simulation modeling time horizon 10 years cycle length 1 week. Cost‐effectiveness was assessed at willingness‐to‐pay (WTP) value US$5180. Results The mean incremental testing US$ −6809. benefit 16 QALYs. net monetary strategic 88,893. Genetic highest expected benefit. outcomes derived from our primary remained robust when subjected variations all underlying assumptions parameter values. Conclusion cost‐effective address requiring ICS+LABA. result should encourage generation more evidence incorporation into clinical practice guidelines pediatric asthma.

Язык: Английский

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