Pharmacogenetic Predictors of Taxane-Induced Peripheral Neuropathy

Peripheral neuropathy is an adverse event of taxane treatment that is related both to the patient's cumulative drug exposure and their inherent sensitivity to neurotoxicity. Discovery and validation of genetic loci that determine neuropathy risk is an important first step towards individualization of taxane treatment with the ultimate goal of maximizing treatment efficacy and minimizing the risk of severe adverse events. Paclitaxel exposure is regulated by enzymes and transporters that have common variants known to influence protein expression or activity. Paclitaxel is primarily metabolized by the CYP2C8 enzyme, and prior research from our group and others suggests that patients who carry a common low-activity variant, CYP2C8*3, may be at increased risk of neuropathy. Using a cohort of paclitaxel-treated breast cancer patients, I was able to confirm the association between CYP2C8*3 and increased risk of paclitaxel-induced peripheral neuropathy. I then attempted to use a genotyping platform that interrogates thousands of variants in hundreds of genes relevant to drug metabolism, elimination, and transport to identify polymorphisms that influence risk of neurotoxicity after accounting for the CYP2C8*3 variant. Surprisingly, I discovered a polymorphism in a gene not thought to be relevant to paclitaxel pharmacokinetics, ABCG1, which was associated with neuropathy risk. Less is known about the clinical or genetic factors that modulate docetaxel-induced neuropathy risk. I performed genome-wide association in a large cohort of docetaxel-treated patients to discover genetic loci that modulate risk of neuropathy. I discovered several candidates, one of which was an intergenic polymorphism that surpassed genome-wide significance after adjustment for relevant clinical covariates. I then attempted, unsuccessfully, to replicate these discoveries in independent cohorts of taxane-treated patients. This inability to replicate indicates that either the associations of these variants are limited to the cohort in which they were discovered or that they were merely spurious discoveries. Replication should be attempted in independent patient cohorts that are more similar to those in which these discoveries were made to validate the influence of these variants on neuropathy risk, enabling translation into routine clinical practice.Doctor of Philosoph

Exploring pharmacogenetics in osteosarcoma

Contains fulltext : 252878.pdf (Publisher’s version ) (Open Access)Radboud University, 06 september 2022Promotor : Brunner, H.G. Co-promotores : Coenen, M.J.H., Loo, D.M.W.M. te221 p

Facilitating precision medicine through analysis of next-generation sequencing projects

Precision medicine constitutes an emerging strategy that aims at the individualization of healthcare by considering the personal molecular features and environmental factors of the patient in question. Genetic biomarkers constitute one dimension of a patient’s molecular phenotype that can allow for treatment stratification. As such, incorporating genetic variability into clinical decision making has raised great interest with drug developers, regulators and in the wider medical community. Importantly however, most studies that evaluated associations of genetic variability with drug reponse or toxicity interrogated only selected, mostly common candidate variants and the prevalence and relevance of rare variants for pharmacogenetics remained largely unexplored. This thesis demonstrates how population-scale Next-Generation Sequencing (NGS) data can be leveraged to map the interindividual and ethnogeographic variability of genes with medical importance. Papers I and II focused on ATP-binding casette (ABC) transporters, as an example of a pharmacogenetically relevant gene family, and show how their variability can have potential predictive value in breast cancer chemotherpy. The human ABC transporter family consists of 48 functionally important membrane proteins which mediate the active transport of a plethora of substrates, including a multitude of endogenous substrates as well as drugs, such as calcium channel blockers and various chemotherapeutics. Because of this physiological and clinical importance, Paper I systematically investigated the interindividual and ethnogeographic variability in the ABC transporter superfamily using NGS data of 138,632 unrelated individuals worldwide, and used an list of sophisticated computational algorithms to estimate their functional relevance. In total, 62,793 exonic variants were discovered, of which 98.5% were rare with minor allele frequencies (MAF) <1.5%. Based on these data, individuals were found to harbor between 9.3 and 13.9 deleterious ABC variants, only 0.3% of which were shared among all populations. As such, this work analyzed the landscape of ABC transporter variability on an unprecedented scale and revealed large interindividual and ethnogeographic variability with potential relevance for the treatment with ABC transporter substrates. Paper II built on these findings by evaluating whether ABC transporter variability was associated with drug response. As drug resistance due to facilitated ABC transporter-mediated efflux of chemotherapeutics constitutes an important cause of morbidity and mortality, ABC transporter variability was evaluated whether it could predict treatment outcomes in breast invasive carcinoma (BRCA), clear cell renal carcinoma (ccRCC) and hepatocellular carcinoma (HCC). In contrast to previous studies, these analyses did not only consider common ABC polymorphisms but considered also rare genetic variants using mutational burden testing. Importantly, variant burden of ABCC1 was found to significantly assoiate with reduced survival in BRCA patients, specifically in those subgroups treated with the MRP1 (the transporter encoded by ABCC1) 2 substrates doxorubicin (p=0.0088) and cyclophosphamide (p=0.0011). In contrast, no association was discovered in tamoxifen-treated patients (p=0.13). Multiple variants enriched in the high mutational burden group affected residues in functionally important transporter domains providing additional mechanistic support. Combined, these results argue for a model in which multiple variants with individually small effect sizes shape drug resistance, thus incentivizing a shift in strategy away from the interrogation of candidate variants and towards the incorporation of germline data for precision cancer medicine. Paper III indicated how publically available sequencing data from individuals can be used to provide accurate estimates of population-specific carrier rates and genetic complexity of 450 human autosomal recessive (AR) diseases. Specifically, population-scale NGS data of individuals free from clinically diagnosed congenital disorders was used to identify disease allele carrier frequencies for 450 AR disorders. Using 85 diseases with known epidemiology, the data showed that our prevalence estimates corresponded well to clinically reported incidences (p<0.001; R=0.68). Furthermore, these data allowed for the first time to evaluate the genetic complexity of the human AR diseasome and estimate population-specific founder effects. As such, these analyses reveal the molecular genetics of AR diseases with unprecedented resolution and provide important insights into epidemiology, complexity and population-specific founder effects, which can provide a powerful resource for clinical geneticists to inform population-adjusted genetic screening programs, particularly in otherwise understudied ethnogeographic groups. In conclusion, by utilizing sophisticated computational methods for the analysis of publically available population-scale sequencing data of >130,000 individuals, this thesis uncovered the landscape of genetic variability in genes with importance for pharmacogenetics and congenital disease. The resulting findings aspire to improve pharmacogenetic interpretations and carrier screening programs and, hopefully, can contribute to the advancement of precision medicine

Integrated Role of Nanotechnology and Pharmacogenetics in Diagnosis and Treatment of Diseases

“One size fits all” is an erroneous paradigm in drug delivery, due to side effects/adverse effects and variability observed in drug response. The variability is a result of geneotypic variations (variability in genomic constitution) which is studied in the branch of science called Pharmacogenomics. The variability in drug response is studied by multigene analysis or profiling of whole-genome single nucleotide polymorphism (SNP) and is recorded in terms of the pharmacokinetic (absorption, distribution, metabolism and elimination) and pharmacodynamic (drug-receptor interaction, immune response, etc.) response of the drug. Therefore, a foray into this research area can provide valuable information for designing of drug therapies, identifying disease etiology, therapeutic targets and biomarkers for application in treatment and diagnosis of diseases. Lately, with the integration of pharmacogenomics and nanotechnology, a new facade for the diagnosis and treatment of diseases has opened up, and the prescription pattern of drugs has moved to pharmacotyping (individualized dose and dosage-form adjusted therapy) using nanoplatforms like nanobioconjugates, nanotheranostics, etc

Clinical Applications of Pharmacogenetics

The rapidly evolving field of Pharmacogenetics aims at identifying the genetic factors implicated in the inter-individual variation of drug response. These factors could enable patient sub-classification based on their treatment needs thus expediting drug development and promoting personalized, safer and more effective treatments. This book presents Pharmacogenetic examples from a broad spectrum of different drugs, for different diseases, which are representative of different stages of evaluation or application. It has been designed so as to serve both the unfamiliar reader through explanations of basic Pharmacogenetic concepts, the clinician with presentation of the latest developments and international guidelines, and the research scientist with examples of Pharmacogenetic applications, discussions on the limitations and an outlook on the new scientific trends in this field

Pharmacogenetics, enzyme probes and therapeutic drug monitoring as potential tools for individualizing taxane therapy

The taxanes are a class of chemotherapeutic agents that are widely used in the treatment of various solid tumors. Although taxanes are highly effective in cancer treatment, their use is associated with serious complications attributable to large interindividual variability in pharmacokinetics and a narrow therapeutic window. Unpredictable toxicity occurrence necessitates close patient monitoring while on therapy and adverse effects frequently require decreasing, delaying or even discontinuing taxane treatment. Currently, taxane dosing is based primarily on body surface area, ignoring other factors that are known to dictate variability in pharmacokinetics or outcome. This article discusses three potential strategies for individualizing taxane treatment based on patient information that can be collected before or during care. The clinical implementation of pharmacogenetics, enzyme probes or therapeutic drug monitoring could enable clinicians to personalize taxane treatment to enhance efficacy and/or limit toxicity

Response and toxicity to cytarabine therapy in leukemia and lymphoma: From dose puzzle to pharmacogenomic biomarkers

Cytarabine is a pyrimidine nucleoside analog, commonly used in multiagent chemotherapy regimens for the treatment of leukemia and lymphoma, as well as for neoplastic meningitis. Ara‐C‐based chemotherapy regimens can induce a suboptimal clinical outcome in a fraction of patients. Several studies suggest that the individual variability in clinical response to Leukemia & Lymphoma treatments among patients, underlying either Ara‐C mechanism resistance or toxicity, appears to be associated with the intracellular accumulation and retention of Ara‐CTP due to genetic variants related to metabolic enzymes. Herein, we reported (a) the latest Pharmacogenomics biomarkers associated with the response to cytarabine and (b) the new drug formulations with optimized pharmacokinetics. The purpose of this review is to provide readers with detailed and comprehensive information on the effects of Ara‐C‐based therapies, from biological to clinical practice, maintaining high the interest of both researcher and clinical hematologist. This review could help clinicians in predicting the response to cytarabine‐based treatments