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PhenoTox: Pharmacometabolomics of early-onset fluoropyrimdine-related toxicity in cancer patients: hunting the missing heritability

English title PhenoTox: Pharmacometabolomics of early-onset fluoropyrimdine-related toxicity in cancer patients: hunting the missing heritability
Applicant Largiadèr Carlo
Number 163205
Funding scheme Project funding
Research institution Institut für Klinische Chemie Inselspital Bern
Institution of higher education University of Berne - BE
Main discipline Clinical Cancer Research
Start/End 01.09.2016 - 28.02.2021
Approved amount 449'437.00
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All Disciplines (2)

Discipline
Clinical Cancer Research
Clinical Pharmacology

Keywords (8)

pharmacometabolomics; fluoropyrimidine toxicity; capecitabine; metabolic phenotyping; microRNA; cancer chemotherapy; pharmacogenomics; 5-fluorouracil

Lay Summary (German)

Lead
Das Projekt befasst sich mit genetischen Faktoren unerwünschter Nebenwirkungen von häufig angewendeten Krebsmedikamenten mit dem Ziel Grundlagen für eine individualisierte Chemotherapie zu erarbeiten.
Lay summary
Bösartige Tumoren, “Krebs”, entstehen aus gesunden Zellen, und solche Tumoren sind eine der häufigsten Todesursachen. Tumorzellen sind gesunden menschlichen Zellen nahe verwandt. Die Bekämpfung der Tumoren mit Medikamenten wie Chemotherapien führt bei einem Teil der Patienten zur Heilung. Für den Erfolg von Chemotherapien ist einerseits die Empfindlichkeit der Tumorzellen ausschlaggebend, andererseits aber die Empfindlichkeit des gesamten Organismus des Erkrankten. So können Chemotherapien gefährliche Nebenwirkungen haben, wenn der Patient bestimmte Medikamente verlangsamt verarbeitet oder ausscheidet. Fluorouracil und Capecitabine sind sehr häufig gebrauchte, wirksame Chemotherapiemedikamente, die besonders bei der Behandlung von Darmkrebs, Magenkrebs und Brustkrebs wichtig sind. Bei manchen Patienten, deren Enzyme in Leber und Darm die Medikamente langsamer abbauen, verursachen Fluorouracil und Capecitabine unvorhersehbare Nebenwirkungen, die sogar tödlich sein können. Der Grund dafür ist – individuell gesehen – eine Überdosis des Medikaments, auch wenn die Dosierung für die Mehrzahl der Patienten korrekt ist. Die Voraussage dieses verlangsamten Medikamentenstoffwechsels und damit der gefährlichen Nebenwirkungen ist Gegenstand des Forschungsprojekts. Die Messung von genetischen Varianten der Enzyme, die Wirkung und Abbau von Fluorouracil und Capecitabine bestimmen, soll erlauben für jeden Patienten vorauszusagen, ob mit einem hohen Risiko von Nebenwirkungen zu rechnen ist und ob allenfalls Anpassungen der Dosis oder gar der Verzicht auf diese Medikamente nötig sind. Solche Mechanismen sind aber bei allen Chemotherapien bedeutsam, so dass dieses Forschungsprojekt in einem weiteren Rahmen zur Sicherheit und optimierten Anwendung der Chemotherapien beitragen wird.
Direct link to Lay Summary Last update: 25.07.2016

Responsible applicant and co-applicants

Employees

Publications

Publication
Haplotype structure defines effects of common DPYD variants c.85T > C (rs1801265) and c.496A > G (rs2297595) on dihydropyrimidine dehydrogenase activity: Implication for 5‐fluorouracil toxicity
Hamzic Seid, Schärer Dominic, Offer Steven M., Meulendijks Didier, Nakas Christos, Diasio Robert B., Fontana Stefano, Wehrli Marc, Schürch Stefan, Amstutz Ursula, Largiadèr Carlo R. (2021), Haplotype structure defines effects of common DPYD variants c.85T > C (rs1801265) and c.496A > G (rs2297595) on dihydropyrimidine dehydrogenase activity: Implication for 5‐fluorouracil toxicity, in British Journal of Clinical Pharmacology, bcp.14742-bcp.14742.
A Novel Nomenclature for Repeat Motifs in the Thymidylate Synthase Enhancer Region and Its Relevance for Pharmacogenetic Studies
Schaerer Dominic, Froehlich Tanja K., Hamzic Seid, Offer Steven M., Diasio Robert B., Joerger Markus, Amstutz Ursula, Largiadèr Carlo R. (2020), A Novel Nomenclature for Repeat Motifs in the Thymidylate Synthase Enhancer Region and Its Relevance for Pharmacogenetic Studies, in Journal of Personalized Medicine, 10(4), 181-181.
Fluoropyrimidine chemotherapy: recommendations for DPYD genotyping and therapeutic drug monitoring of the Swiss Group of Pharmacogenomics and Personalised Therapy
Hamzic Seid, Aebi Stefan, Joerger Markus, Montemurro Michael, Ansari Marc, Amstutz Ursula, Largiadr Carlo (2020), Fluoropyrimidine chemotherapy: recommendations for DPYD genotyping and therapeutic drug monitoring of the Swiss Group of Pharmacogenomics and Personalised Therapy, in Swiss Medical Weekly, 1-9.
Dihydropyrimidine Dehydrogenase Testing prior to Treatment with 5-Fluorouracil, Capecitabine, and Tegafur: A Consensus Paper
Wörmann Bernhard, Bokemeyer Carsten, Burmeister Thomas, Köhne Claus-Henning, Schwab Matthias, Arnold Dirk, Blohmer Jens-Uwe, Borner Markus, Brucker Sara, Cascorbi Ingolf, Decker Thomas, de Wit Maike, Dietz Andreas, Einsele Hermann, Eisterer Wolfgang, Folprecht Gunnar, Hilbe Wolfgang, Hoffmann Jürgen, Knauf Wolfgang, Kunzmann Volker, Largiadèr Carlo R., Lorenzen Sylvie, Lüftner Diana, Moehler Markus, et al. (2020), Dihydropyrimidine Dehydrogenase Testing prior to Treatment with 5-Fluorouracil, Capecitabine, and Tegafur: A Consensus Paper, in Oncology Research and Treatment, 43(11), 628-636.
Evaluating the role of ENOSF1 and TYMS variants as predictors in fluoropyrimidine-related toxicities: An IPD meta-analysis
Hamzic Seid, Kummer Dominic, Froehlich Tanja K., Joerger Markus, Aebi Stefan, Palles Claire, Thomlinson Ian, Meulendijks Didier, Schellens Jan H.M., García-González Xandra, López-Fernández Luis A., Amstutz Ursula, Largiadèr Carlo R. (2020), Evaluating the role of ENOSF1 and TYMS variants as predictors in fluoropyrimidine-related toxicities: An IPD meta-analysis, in Pharmacological Research, 152, 104594-104594.
Genotype-guided fluoropyrimidine dosing: ready for implementation
Amstutz Ursula, Largiadèr Carlo R (2018), Genotype-guided fluoropyrimidine dosing: ready for implementation, in The Lancet Oncology, 19(11), 1421-1422.
Come a long way, still a ways to go: from predicting and preventing fluoropyrimidine toxicity to increased efficacy?
Hamzic Seid, Amstutz Ursula, Largiadèr Carlo R (2018), Come a long way, still a ways to go: from predicting and preventing fluoropyrimidine toxicity to increased efficacy?, in Pharmacogenomics, 19(8), 689-692.
Novel Genetic Variants in Carboxylesterase 1 Predict Severe Early-Onset Capecitabine-Related Toxicity
Hamzic S, Kummer D, Milesi S, Mueller D, Joerger M, Aebi S, Amstutz U, Largiader CR (2017), Novel Genetic Variants in Carboxylesterase 1 Predict Severe Early-Onset Capecitabine-Related Toxicity, in Clinical Pharmacology & Therapeutics, 102(5), 796-804.

Collaboration

Group / person Country
Types of collaboration
Prof. R. B. Diasio, Prof. S. M. Offer / Mayo Clinic Cancer Center United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Prof. Stefan Aebi / Cantonal Hospital Lucerne Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication

Associated projects

Number Title Start Funding scheme
185419 PGXLink -Connecting pharmacogenomics (PGX), pharmacological intermediates, and clinical outcomes. 01.12.2019 Biolink funds
119839 FLOxTox: Assessment of the Polygenic Basis of Adverse Reactions to 5-Flourouracil/ Leucovorin/Oxaliplatin of Colorectal Cancer Patients Using a Pathway Approach 01.06.2008 Project funding
183501 Installing a Hyperion CyTOF mass cytometry platform for high-dimensional single cell analysis at the University of Bern 01.10.2019 R'EQUIP
138285 FLOxTox2: Pharmacogenetics of adverse side effects in cancer patients treated with 5-fluorouracil-based therapies 01.03.2012 Project funding

Abstract

Background: The fluoropyrimidines (FPs) 5-fluorouracil (5FU) and its oral prodrug capecitabine are among the most frequently used anticancer drugs and have a very narrow therapeutic index. Current body surface area (BSA)-based dosing only insufficiently accounts for inter-individual variability in drug exposure, putting susceptible patients at risk of severe and potentially life-threatening FP-related toxicity. We have recently shown that genetic variants in the dihydropyrimidine dehydrogenase (DPD) gene (DPYD), encoding the rate-limiting 5FU catabolism enzyme, are important predictors of early-onset FP toxicity, and that genetic variation in a DPYD-regulatory microRNA (miR-27a) modulates toxicity risk in carriers of DPYD risk variants. In contrast, so far, no relevant associations of genetic variants in genes encoding the main drug target, thymidylate synthase (TYMS) or folate pathway enzymes, which metabolize the required co-factor for thymidylate synthase inhibition, have been found. Working hypotheses: Given that common nonsynonymous variants are known in most folate pathway genes, we hypothesize that combinations of different polymorphisms in multiple genes (multilocus genotypes) may result in similar FP toxicity phenotypes, making associations difficult to detect by classical genetic association studies. To address this limitation, we will leverage a novel pharmacometabolomics-informed approach based on metabolic phenotyping. Given our recent findings, we further hypothesize that regulatory microRNAs may have an important role in FP-catabolic variability. Finally, we hypothesize that current BSA-based dosing hampers the identification of genetic, demographic and clinical factors contributing to individual FP toxicity risk and the quantification of their clinical relevance. Thus, the power of association studies can be improved by accounting for differences in individual drug exposure (i.e. plasma concentrations or area under the curve, AUC). Specific objectives: (A) Assess the quantitative impact of multilocus genotypes on the folate pathway in plasma samples from healthy volunteers to identify candidates for investigation in a cancer patient cohort. (B) Assess relationships between genotypes and FP pharmacokinetics (AUC, steady-state concentrations) in FP-treated cancer patients to infer the impact of BSA-based dosing on variability in FP exposure and genetic associations with FP toxicity. (C) Assess the contribution of miRNA genetic and expression variability to phenotypic variation in the FP-catabolic pathway in healthy volunteers and cell models. Experimental design and methods: For objectives A and C, we will collect plasma, DNA and RNA samples from 300 healthy volunteers. Folate metabolites levels will be semi-quantitatively assessed using targeted LC-MS/MS assays and correlated with multilocus genotypes in folate pathway genes. For objective B, we will correlate dose-adjusted FP-AUC in plasma from 500 FP-treated cancer patients with candidate genotypes in FP catabolism (identified in our previous research) and the folate pathway (identified in objective A). For objective C, microRNA expression profiles and genetic variation will be assessed using high-throughput sequencing in samples from healthy volunteers, and correlated with plasma concentrations of endogenous metabolites to identify variants of potential regulatory importance for FP catabolism. Candidate variants will subsequently be functionally characterized in cell models. Expected value of the proposed project: This project will address important potential contributors to inter-individual variability in FP toxicity using pharmacometabolomics-informed pharmacogenomics to further advance our understanding of the underlying mechanisms and improve the identification of patients at risk of potentially life-threatening adverse events from FP-based chemotherapy. In addition, this project will provide novel insights into the phenotypic impact of genetic variation in the folate pathway and microRNA variability that are of wide relevance in the context of variability in the response to other important drugs, as well as health and disease in general.
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