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... Show moreSunitinib 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. Show less
Both tyrosine kinase inhibitors (tki) and mammalian target of rapamycin (mTOR) inhibitors are oral targeted therapies that are used for the treatment of a variety of malignancies. Due to the... Show moreBoth tyrosine kinase inhibitors (tki) and mammalian target of rapamycin (mTOR) inhibitors are oral targeted therapies that are used for the treatment of a variety of malignancies. Due to the growing evidence for drug exposure-response relationships, in combination with their high interpatient variability in pharmacokinetics (pk) and a fixed dosing regimen, it is hypothesized that dose individualization of oral targeted therapies may lead to better treatment outcomes both in terms of efficacy as well as toxicity. This thesis describes the results of different studies that investigated dose optimization strategies of oral targeted therapies used in oncology, with a focus on the TKIs pazopanib and sunitinib and the mTOR inhibitor everolimus. Show less
Wit, D. de; Gelderblom, H.; Sparreboom, A.; Hartigh, J. den; Hollander, M. den; Konig-Quartel, J.M.C.; ... ; Erp, N.P. van 2014
