Colon cancer is the third most frequent malignancy in the Western world. Average 5 year-survival is around 70% and depends on the stage of the disease being very poor (under 10% 5-year survival)... Show moreColon cancer is the third most frequent malignancy in the Western world. Average 5 year-survival is around 70% and depends on the stage of the disease being very poor (under 10% 5-year survival) for stage IV patients and excellent (more than 90% 5 year survival) for stage I patients. The prognosis of patients with stage II varies between 80 and 60% 5-year survival. The causes of this variation remain unclear. Furthermore, the prognosis of patients with stage III has improved significantly, reaching 70% 5-year survival, since the introduction of adjuvant chemotherapy. However, still 30% of the patients with stage III disease that do not respond to chemotherapy. Therefore, reliable predictive and prognostic markers in stage II and III colon carcinoma are necessary to be able to elucidate whether a patient is going to respond to therapy or not and to be able to offer personalized treatment. In this research project, we aimed to identify predictive markers of therapy response in stage III disease and prognostic markers in stage II and III colon carcinoma. The first three chapters focus on the value of known single nucleotide polymorphisms (SNP) in genes involved in the activation, metabolism of chemotherapeutic drugs like 5-fluorouracil and oxaliplatin as well as in the repair of DNA damage caused by these drugs as predictive markers for therapy response. In the remaining chapters , the focus is placed on the identification of molecular prognostic markers in stages II and III. Several mutations in known cancer driver genes and genes involved in signal transduction have been studied. Show less
Swen, J.J.; Straaten, T. van der; Wessels, J.A.M.; Bouvy, M.L.; Vlassak, E.E.W.; Assendelft, W.J.J.; Guchelaar, H.J. 2012
Nausea and vomiting are well known side effects related to chemotherapy. Indeed, nausea and vomiting are the most distressing side effects of chemotherapy in cancer patients. Dopamine, serotonin... Show moreNausea and vomiting are well known side effects related to chemotherapy. Indeed, nausea and vomiting are the most distressing side effects of chemotherapy in cancer patients. Dopamine, serotonin and neurokinin1 are thought to be the neurotransmitters that play role in the pathophysiology of Chemotherapy Induced Nausea Vomiting (CINV). Thus, the antagonists of those neurotransmitters are considered as prophylactic antiemetics for CINV. In the 1990s, the use of 5-Hydroxytriptamine receptor antagonists (5-HT3RAs) highly improved the patients__ response rate to antiemetic drugs. In addition, the combination of a neurokinin 1 antagonist, a 5HT3RA and a corticosteroid can further increase the response rate up by 15% in acute phase and 20% in delayed phase. Thus, the international guideline of clinical oncology recommend this combination as prophylactic antiemetic drugs in the acute phase and a combination of dexamethasone __ metoclopramide as prophylactic antiemetics in the delayed phase. However, when the standard antiemetic drug regimens are administered to patients, there are still 20-30% patients in the acute phase and 40% patients in the delayed phase experiencing CINV. Thus, there is a high interindividual variability in response to antiemetic drugs in oncology patients. Some patient characteristics such as female gender, younger patients and history of alcohol drinking could increase the risk of CINV from 20% to 70%. Therefore, individualizing of the use of antiemetics could start by considering the patient characteristics. This thesis focuses on determining the impact of CINV on QoL in Indonesian cancer patients and optimizing the prevention and treatment of CINV by exploration of pharmacogenetic biomarkers. Show less
In many patients drugs do not show the expected efficacy, whereas in other patients they cause toxic effects, sometimes even at low dose. Response rates to major classes of drugs range from 25 to... Show moreIn many patients drugs do not show the expected efficacy, whereas in other patients they cause toxic effects, sometimes even at low dose. Response rates to major classes of drugs range from 25 to 60 percent. For some patients, the reason for this variability may be explained by genetic variation. Pharmacogenetics is the study of variations in DNA sequence as related to drug response. The ultimate goal of pharmacogenetics is to predict and thereby improve drug response in the individual patient. The concept of interindividual differences in drug response was proposed as early as 1909. With the completion of the Human Genome Project in 2003 hope was raised that pharmacogenetics could be implemented in clinical practice in the near future. However, the clinical use of pharmacogenetic testing remained limited. Yet, the body of evidence supporting its usefulness is growing continuously. The research presented in this thesis aims to identify the reasons for the slow clinical translation of pharmacogenetics and to explore and expand possible solutions to address these obstacles. The thesis is divided into four parts. First, obstacles and possible solutions for the clinical implementation of pharmacogenetics are identified. In the second part, issues related to the quality control of pharmacogenetic testing are discussed. In the third part, the influence of genetic variation on the response to sulfonylureas is used as a case model to investigate the possibilities for pharmacogenetics in primary care. The fourth part contains the general discussion and a future outlook. Show less
Steeghs, N.; Mathijssen, R.H.J.; Wessels, J.A.M.; Graan, A.J. de; Straaten, T. van der; Mariani, M.; ... ; Guchelaar, H.J. 2011
Even though treatment of several types of solid tumors has improved in the past few years with the introduction of the monoclonal antibodies against the epidermal growth factor receptor (EGFR) and... Show moreEven though treatment of several types of solid tumors has improved in the past few years with the introduction of the monoclonal antibodies against the epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF), the clinical benefit of these targeted therapies is modest. Pharmacogenetics has the potential to select patients with higher chance of response to agents that target these pathways. In the thesis, we describe the association of the FCGR3A Phe158Val polymorphism with progression-free survival in advanced colorectal cancer patients treated with cetuximab added to chemotherapy and bevacizumab. Following this finding, we found that cetuximab activates type 2 macrophages, which could have a negative effect on the clinical efficacy of cetuximab. Furthermore, we detected a genetic interaction profile consisting of the VEGF +405G>C and TYMS TSER polymorphisms, that was associated with the efficacy of capecitabine, oxaliplatin and bevacizumab in advanced colorectal cancer patients. Finally, we performed a genome wide association study with the same treatment, in which polymorphisms in the proximity of the AGPAT5 gene were associated with progression-free survival Show less
Calcineurin inhibitors are crucial in the prevention of acute rejection in the first year after renal transplantation. Unfortunately, these drugs (ciclosporin A, tacrolimus) are characterized by... Show moreCalcineurin inhibitors are crucial in the prevention of acute rejection in the first year after renal transplantation. Unfortunately, these drugs (ciclosporin A, tacrolimus) are characterized by serious clinical toxicity and between patient variability in their effect. Therefore, the dose of these drugs should be individualized in order to reach a balance between rejection and toxicity. This thesis aimed to describe the variability between and within patients using mathematical models and subsequently to explain this variability. Genetic and non-genetic factors were used to explain variability and several factors were identified (polymorphism in metabolism enzyme CYP3A5, body weight, concomitant prednisolone dose). For this purpose drug concentrations in blood are measured as a concentration biomarker. Furthermore, another biomarker the activity ot the target enzyme calcineurin was determined in leukocytes, but was found to be more variable within patients than between patients. This response biomarker was not found to be clinically useful to individualize the drug dosage. Finally, pharmacological determinants for subclinical acute rejection at 6 months were determined in patients treated with ciclosporin. Although ciclosporin exposure and several genetic variants were not found to relate, a previous acute rejection period and a kidney from a deceased donor increased the risk of rejection 5-fold. Show less
Wilffert, B.; Swen, J.; Mulder, H.; Touw, D.; Maitland-Van der Zee, A.H.; Deneer, V.; KNMP Working Grp Pharmacogenetics 2011
Results from this thesis have elucidated potential genetic markers, which were associated with treatment outcome to MTX and adalimumab. Furthermore, a model for predicting the efficacy of MTX in... Show moreResults from this thesis have elucidated potential genetic markers, which were associated with treatment outcome to MTX and adalimumab. Furthermore, a model for predicting the efficacy of MTX in patients with RA was validated in two cohorts indicating that predicting efficacy by a pharmacogenetic model is feasible in RA patients treated with MTX. Importantly, definitive conclusions about the role of genetic predictive factors in treatment outcome to DMARDS could not be drawn, since these results have to be further validated and replicated in future pharmacogenetic studies. Large randomized prospective studies should be planned to demonstrate its legitimate predictive and cost-effective value before a genetically individualized approach is applicable in daily clinical practice. The potential role of pharmacogenetics in the prediction of efficacy and adverse events in RA patients treated with DMARDs is presented in this thesis. Hereby, new knowledge is added to the relatively young research field of pharmacogenetics, which may hopefully lead to a better treatment strategy for RA patients Show less
This thesis focuses on targeted anticancer agents. An important class of these agents are the tyrosine kinase inhibitors (TKIs). One of the first steps in TKI treatment development is defining... Show moreThis thesis focuses on targeted anticancer agents. An important class of these agents are the tyrosine kinase inhibitors (TKIs). One of the first steps in TKI treatment development is defining whether a specific type of cancer, for example the sarcomas in chapter 3 of this thesis, express the receptors that are targeted. Once a TKI is developed, phase I studies are conducted to characterize the safety and side effects of the drug when administered to patients. When relevant side effects emerge, studies investigating the underlying mechanisms leading to these side effects are called for. Also pharmacogenetic studies can be performed to investigate whether certain heritable genetic variations influence efficacy or safety of the drug. After the phase I studies have proven the drug to be safe, the drug can be further developed. This includes the investigation of the TKI when combined with other anticancer agents. Items of all the described steps in TKI development are described in this thesis. Show less
In this thesis, we focus on the palliative treatment of advanced colorectal carcinoma with capecitabine, irinotecan and oxaliplatin. We investigated the potential associations of germline genetic... Show moreIn this thesis, we focus on the palliative treatment of advanced colorectal carcinoma with capecitabine, irinotecan and oxaliplatin. We investigated the potential associations of germline genetic variations with the efficacy or toxicity of treatment. We genotyped a selection of SNPs in paired tumor tissue and blood samples of colorectal cancer patients (Chapter 3). Next, we present an overview of clinical and pharmacogenetic factors that have been described to influence irinotecan toxicity (Chapter 4). We investigated the association of febrile neutropenia and drug efficacy with the UGT1A1 genotype in Chapter 5. In Chapter 6, we investigated the GSTP1 Ile105Val SNP with regard to irinotecan efficacy in terms of progression-free survival. We also provide an overview of pharmacogenetic, pharmacokinetic and pharmacodynamic data on this platinum derivative (Chapter 7). In Chapter 8, we transfected ERCC1 negative cells with an ERCC1 gene, containing either the codon 118C or 118T genotype, in order to establish differences in cell survival or DNA repair. In chapter 9 we describe our investigations on the cumulative neurotoxicity and efficacy of oxaliplatin. In chapter 10, an explorative study is described that investigates associations of survival and toxicity in patients receiving oxaliplatin, using a SNP array. Show less
