Leiden University Scholarly Publications

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Diekstra, M.H.M. (2017)

Pharmacogenetics of sunitinib in metastatic renal cell carcinoma

Doctoral Thesis

Sunitinib treatment requires a personalized approach, since patients can respond very differently to this drug. Pharmacogenetics may improve our ability to provide a tailored therapy by studying how genetic variations could influence drug response. The objective of this thesis was to find genetic markers that can predict toxicity and efficacy of sunitinib in patients with metastatic renal cell carcinoma. This research builds upon previous findings from candidate gene studies by testing a selection of SNPs based on plausible involvement in pharmacokinetics or pharmacodynamics of the drug of interest. We observed that SNPs located in genes involved in metabolism and drug absorption (CYP3A4, CYP3A5, and ABCB1) are potentially associated with the clearance of sunitinib and its active metabolite. In analogy to this, we confirmed SNP associations from previous studies for SNPs in CYP3A5 and ABCB1 that predict the need for dose...

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Sunitinib treatment requires a personalized approach, since patients can respond very differently to this drug. Pharmacogenetics may improve our ability to provide a tailored therapy by studying how genetic variations could influence drug response. The objective of this thesis was to find genetic markers that can predict toxicity and efficacy of sunitinib in patients with metastatic renal cell carcinoma. This research builds upon previous findings from candidate gene studies by testing a selection of SNPs based on plausible involvement in pharmacokinetics or pharmacodynamics of the drug of interest. We observed that SNPs located in genes involved in metabolism and drug absorption (CYP3A4, CYP3A5, and ABCB1) are potentially associated with the clearance of sunitinib and its active metabolite. In analogy to this, we confirmed SNP associations from previous studies for SNPs in CYP3A5 and ABCB1 that predict the need for dose reductions and improvement of PFS on sunitinib. Sunitinib-induced toxicity is possibly related to SNPs in CYP3A4 and CYP3A5, and in interleukin genes IL8 and IL13. VEGFR-2 (KDR) rs34231037 G-allele variant carriers were potentially associated with a favorable response to sunitinib. A GWAS learned us that SNPs in chromosome 21 are involved in sunitinib efficacy, probably by influencing drug resistance mechanisms.

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Pharmacogenetics
Sunitinib
Oncology
Renal cell carcinoma
SNP
Pharmacokinetics
Personalized medicine
All authors
Diekstra, M.H.M.
Editor(s)
Diekstra M.H.M.
Supervisor
Guchelaar, H.-J.; Gelderblom, A.J.
Co-supervisor
Swen, J.J.
Committee
Veelken, J.H.; Knibbe, C.A.J.; Kiemeney, L.A.L.M.; Gietema, J.A.
Qualification
Doctor (dr.)
Awarding Institution
Medicine, Leiden University
Date
2017-09-13
ISBN (print)
9789492026125

Funding

Sponsorship
The research presented in this thesis was performed at the department of Clinical Pharmacy and Toxicology of Leiden University Medical Center, Leiden, The Netherlands. Financial support for the publication of this thesis was provided by Afdelingsfonds Klinische Farmacie & Toxicologie The research leading to these results has received funding from the European Union’s Seventh Framework Programme (FP7/2007-2013) under grant agreement no 259939.