Colorectal cancer (CRC) is often treated with chemotherapy. However, it is well known that treatment with chemotherapy comes with challenges, such as (severe) adverse events leading to loss of... Show moreColorectal cancer (CRC) is often treated with chemotherapy. However, it is well known that treatment with chemotherapy comes with challenges, such as (severe) adverse events leading to loss of quality of life, treatment discontinuation and sometimes even death. Moreover, chances for curation in the metastatic setting are low. Therefore, a large window of opportunity to improve both safety as well as efficacy of chemotherapeutic treatment for the individual patient exists. A possible approach to improve chemotherapeutic treatment for CRC patients could be the discovery, validation and implementation of new genetic biomarkers. The use of genetic biomarkers allows to identify patients that are at higher risk for severe adverse drug events and to select patients which will benefit the most from chemotherapy. The aim of this thesis was therefore to improve the safety and efficacy of chemotherapeutic drugs in patients with colorectal cancer by individualising drug dosing and choice of drug based on germline genetic biomarkers. The described studies in this thesis brought us a few steps closer to safe and effective use of chemotherapeutic drugs in the individual colorectal cancer patient. Irinotecan should no longer be administered without a UGT1A1 genotype test and a start has been made towards personalised medicine for colorectal cancer patients with peritoneal metastases. Show less
Rheumatoid arthritis (RA) is a chronic, symmetrical, autoimmune disease characterized by inflammation of the joints, as well as damage to a variety of body systems, including the skin, eyes, lungs,... Show moreRheumatoid arthritis (RA) is a chronic, symmetrical, autoimmune disease characterized by inflammation of the joints, as well as damage to a variety of body systems, including the skin, eyes, lungs, heart and blood vessels. Therefore, to prevent (potential) damage with a more favorable course of the disease, it is important to intervene both early and agressively with medication in the treatment of RA. Typically, methotrexate is used as the first treatment, possibly in conjuction with other disease-modifying antirheumatic drugs, or with prednisolone to reduce inflammation rapidly. While the treatment of RA has improved considerably in recent decades, drug treatment does not work for everyone due to toxicity or lack of responsiveness. Therefore, it is suspected that genetics plays a major role in the both efficacy and toxicity of current RA medication. The goal of this thesis is to identify the genetic factors that influence the effectiveness or toxicity of the drugs used in RA. Show less
For more than 40 years, the selective estrogen receptor modulator tamoxifen has been the cornerstone of the endocrine therapy for hormone receptor-positive breast cancer patients. However, a wide... Show moreFor more than 40 years, the selective estrogen receptor modulator tamoxifen has been the cornerstone of the endocrine therapy for hormone receptor-positive breast cancer patients. However, a wide variability in response to therapy is still observed since disease recurrence happens in nearly 30 % of breast cancer patients. Tamoxifen has a complex metabolism and it is mainly metabolized by CYP2D6 enzyme, among others, into endoxifen, the most active metabolite of tamoxifen.In the search of a manner in order to individualize endocrine therapy with tamoxifen, CYP2D6 genotyping and therapeutic drug monitoring based on endoxifen serum concentrations were proposed as potential manners to individualize tamoxifen efficacy. Both approaches have been an ongoing discussion and many studies have been published claiming both negative and positive associations. This thesis mainly focusses on CYP2D6 genotyping and endoxifen concentrations and their impact on clinical survival outcome in early breast cancer patients treated with tamoxifen. Show less
The primary objective of this thesis is to investigate the role of pharmacogenetics in predicting drug response in treatments for the autoimmune diseases: RA and SLE. For this reason, this thesis... Show moreThe primary objective of this thesis is to investigate the role of pharmacogenetics in predicting drug response in treatments for the autoimmune diseases: RA and SLE. For this reason, this thesis is divided in two parts: pharmacogenetics related with drugs used in RA and pharmacogenetics of rituximab used in SLE and other autoimmune diseases. Part 1: Pharmacogenetics of drugs used in RA MTX is the most common DMARD used in RA. However, its use is hampered by frequent adverse drug events among which gastrointestinal toxicity is most frequent. Hepatotoxicity is a relatively rare but serious adverse event related to the use of MTX and is largely unpredictable. In chapter 2 an overview is presented of the previously performed studies concerning pharmacogenetic predictive biomarkers for MTX-induced hepatotoxicity. Treatment with anti-TNF agents results in a reduction of disease activity in most RA patients. However, a substantial part of patients does not respond to this therapy for unknown reasons. It would be highly beneficial to be able to predict whether or not an individual patient responds to treatment. Chapters 4 and 5 describe the investigations on the role of different candidate SNPs related to the efficacy of the treatment with different anti-TNFs in RA. In addition, in chapter 3 a replication study is presented based on 4 polymorphisms that were found associated with anti-TNF response in RA in a previously published genomewide association study. Part 2: Pharmacogenetics of rituximab used in SLE and other autoimmune diseases In chapters 6–8 the role of different genetic variants related to the pharmacodynamics of the drug or of the diseases are evaluated to study the contribution to differences in the response to rituximab in patients with SLE and other systemic autoimmune diseases. In chapter 6, the possible involvement of the -174 IL-6 polymorphism in the clinical response to rituximab in different systemic autoimmune diseases is assessed. In chapter 7, the aim is to investigate the possible involvement of the FCGR3A-158F/V polymorphism in the clinical response to rituximab in Spanish patients with different systemic autoimmune diseases. In chapter 8, the role of G/T polymorphism at the IL2–IL21 region in the rituximab response in a cohort of SLE patient and different autoimmune disorders is analyzed. Chapter 9 provides a summary of this thesis, chapter 10 the Dutch summary (Nederlandse samenvatting), and chapter 11 the general discussion and future perspective of this thesis. Show less
Pharmacogenomics (PGx) utilizes an individual’s germline genetic profile to identify those who are at higher risk for ADRs or lack of efficacy. This information can be used by healthcare... Show morePharmacogenomics (PGx) utilizes an individual’s germline genetic profile to identify those who are at higher risk for ADRs or lack of efficacy. This information can be used by healthcare professionals (HCPs) to guide dose and drug selection before drug initiation in an effort to optimize drug therapy through precision medicine. Despite both the promise of and the progress in the field of PGx to achieve precision medicine, it is still not routinely applied in patient care. As such, a number of barriers preventing implementation have been identified. These include the undetermined model for delivering PGx, the lack of evidence supporting a PGx panel approach and the lack of tools supporting implementation. Therefore, the work of this thesis aims to support the implementation of precision medicine using PGx panel testing. It reports on generating evidence for PGx panel testing (Part I) and the development of tools facilitating implementation (Part II), evaluates the implementation process utilizing these tools (Part III) and quantifies the impact of PGx implementation on patient outcomes and cost-effectiveness (Part IV). Show less
This thesis on systemic treatment options in soft tissue sarcomas consists of two parts. In part I, the pharmacogenetics of systemic gastro-intestinal stromal tumors (GIST) treatment is... Show moreThis thesis on systemic treatment options in soft tissue sarcomas consists of two parts. In part I, the pharmacogenetics of systemic gastro-intestinal stromal tumors (GIST) treatment is investigated. SNPs related to the pharmacokinetics and pharmacodynamics of imatinib and sunitinib have been associated to survival and to toxicity. SNPs in VEGFA and SLCO1B3 have been associated to worse progression free survival during imatinib treatment of advanced GIST. SNPs in ABCG2 and CYP1A2 have been associated with the need for dose reduction in patients receiving imatinib for GIST. A SNP in POR was associated with better progression free survival during sunitinib treatment of advanced GIST . In part II the usage of trabectedin is soft tissue sarcomas (STS) in the Netherlands is studied. Trabectedin as second line treatment of soft tissue sarcoma was compared to ifosfamide monotherapy. The Incremental Cost-Effectiveness Ratio for leiomyosarcomas and liposarcomas was at the top end of what is considered acceptable in the Netherlands. For other soft tissue sarcomas subtypes, ifosfamide dominated trabectedin. The venous access related adverse events of trabectedin have been described. The research in this thesis contributes towards personalised treatment for advanced soft tissue sarcomas. Show less
Fluoropyrimidines, such as 5-fluorouracil (5-FU) and capecitabine, are among the most frequently prescribed anticancer drugs. They are inactivated by the enzyme dihydropyrimidine dehydrogenase (DPD... Show moreFluoropyrimidines, such as 5-fluorouracil (5-FU) and capecitabine, are among the most frequently prescribed anticancer drugs. They are inactivated by the enzyme dihydropyrimidine dehydrogenase (DPD). Up to 5% of the population is DPD deficient and these patients have a significantly increased risk of severe and potentially lethal toxicity when treated with regular doses of 5-FU or capecitabine. DPD is encoded by the gene DPYD and variants in DPYD can lead to a decreased DPD activity. Although prospective DPYD genotyping is a valuable tool to identify patients with DPD deficiency, and thus those at risk for severe and potential life-threatening toxicity, prospective genotyping has not yet been implemented in daily clinical care.With this thesis we improved knowledge on different aspects of DPYD genotyping and DPD phenotyping, in order to better predict DPD deficient patients and personalize their therapy. In addition, we improved clinical implementation of DPYD genotyping, and reduced the risk of severe fluoropyrimidine-induced toxicity in DPYD variant allele carriers. Show less
This thesis examines how both genetic and more conventional epidemiological endeavors may complement research into effects of statin therapy. These include a pharmacogenetic GWAS meta-analysis... Show moreThis thesis examines how both genetic and more conventional epidemiological endeavors may complement research into effects of statin therapy. These include a pharmacogenetic GWAS meta-analysis on statin-induced HDL-C response by the Genomic Investigation of consortium, which identified CETP as a loci of interest, and two-sample Mendelian randomization studies utilizing summary level data from the GIST and other GWAS consortia on fasted blood lipids and type 2 diabetes. We additionally examine the issue of survival bias in Mendelian randomization studies. Finally, we show that intra-individual lipid variability associates with worse neurocognitive outcomes in older individuals at high risk for vascular disease, discuss its interplay with lipid-lowering treatment, and describe the literature regarding genetic factors of possible interest. Show less
Electroconvulsive therapy (ECT) is the transcutaneous application of small electrical stimuli to the brain to produce generalized seizure for the treatment of selected psychiatric disorders, mostly... Show moreElectroconvulsive therapy (ECT) is the transcutaneous application of small electrical stimuli to the brain to produce generalized seizure for the treatment of selected psychiatric disorders, mostly treatment resistant depression, acute mania, and schizophrenic syndromes. Safety of ECT increases the efficacy of therapy and provides fulfillment of a series of required treatments resulting in longer treatment effect of ECT. During the last few decades, researchers have been attempting to improve the effectiveness of ECT, to learn how and why it works, and to understand its risks and adverse side effects. As a result, the safety and efficacy of ECT has been improved and its indications have been relatively defined to increase the efficiency of outcome of therapy. While there has been considerable improvement in safety features, further investigation have been done to promote both the safety and efficacy of the treatment. Such efforts could increase our knowledge on the biological mechanisms involved in effectiveness of ECT that might result in discovery of new treatments. In this dissertation, we investigate how preprocedural medications could improve the safety and efficacy of ECT and further investigated the potential role of pharmacogenetics in the efficacy of ECT and procedural side effects such as cognitive disorders. Show less
Treatment for advanced colorectal cancer (ACC) consists primarily of systemic treatment, mostly without curative intent. Systemic therapies are associated with potentially severe side effects.... Show moreTreatment for advanced colorectal cancer (ACC) consists primarily of systemic treatment, mostly without curative intent. Systemic therapies are associated with potentially severe side effects. Furthermore, treatment is not effective in all patients. Currently, pre-treatment predictors for efficacy and toxicity in systemic treatment of ACC are scarce. Germline genetic variation in genes encoding for enzymes involved in pharmacokinetics or pharmacodynamics of cytotoxic drugs could explain intra-patient differences in treatment effects. Pharmacogenetic studies aim at finding such germline genetic predictors. This thesis focusses on pharmacogenetics of capecitabine and oxaliplatin in treatment of ACC. First, it is established that results derived from DNA in archived tumor samples can be reliably compared to those using DNA from peripheral blood leukocytes. Then, germline genetic markers in MTHFR and MTRR, as well as markers derived from an in vitro genome-wide association study (GWAS) are tested for their association with capecitabine toxicity. Next, effects of ERCC1 genotype on oxaliplatin cytotoxicity in vitro and in clinical association analysis are addressed. The influence of genetic variation in organic cation transporters on oxaliplatin-induced neurotoxicity is examined. Lastly, the results of a GWAS searching for germline predictors of treatment efficacy of capecitabine, oxaliplatin and bevacizumab, with or without cetuximab, are presented. Show less
Aim of this thesis was to investigate pharmacogenetic effects on response to statin treatment and the genetics of lipid metabolism and cardiovascular disease. In chapter 4 the first results of the... Show moreAim of this thesis was to investigate pharmacogenetic effects on response to statin treatment and the genetics of lipid metabolism and cardiovascular disease. In chapter 4 the first results of the Genomic investigation of Statin Therapy (GIST) consortium are presented. We identified and validated two new GWAS loci to be associated with LDL-cholesterol response after statin treatment. In addition, we confirmed two previous identified loci. In chapter 5 we showed that we were not able to identify any loci associated with differential event reduction after statin therapy within the PROSPER study. The results presented in chapter 8 show that even at old age a genetic predisposition to high LDL-cholesterol is a risk factor for mortality. The results of this thesis show that currently the possibilities to personalize statin treatment based on genetic variants is limited. New research methods will hopefully give new opportunities to improve cardiovascular disease treatment and give more insight into the biological mechanisms of statin treatment. Show less
Model based approaches, integrating physiological parameters or linking exposure with response, are powerful tools to quantify and evaluate the impact of genetic differences that are reflected as... Show moreModel based approaches, integrating physiological parameters or linking exposure with response, are powerful tools to quantify and evaluate the impact of genetic differences that are reflected as variability of drug exposure and/or clinical response(s). This thesis __Pharmacogenomics in Drug Development: Implementation and Application of PKPD Model Based Approaches__ focused on genotype differences in explaining inter-individual variability in drug metabolism and clinical response. Population pharmacokinetic and pharmacodynamic models were developed to evaluate the relationship between exposure differences resulting from UGT2B15 genotype and their effects on both fasting plasma glucose and glycosylated haemoglobin for the type 2 diabetes drug, Sipoglitazar__. The model was used to quantify the optimal dose and regime (Single treatment/genotyped-based or titrated based upon response) for future clinical trials. Evaluating the potential impact of genetic differences early during development is important to appropriately design future clinical studies and to ensure that exposure response relationships for efficacy and safety can be identifed for all genetic subgroups. Ultimately, these model-based approaches can be used to determine if covariate-based dose individualization would be advantageous/beneficial to normalize exposure and minimize variability in clinical outcomes across heterogeneous clinical populations. Show less
The aim of this thesis was to optimize immunosuppressive therapy, especially everolimus therapy in renal transplantation recipients by identifying pharmacological and pharmacogenetic risk factors... Show moreThe aim of this thesis was to optimize immunosuppressive therapy, especially everolimus therapy in renal transplantation recipients by identifying pharmacological and pharmacogenetic risk factors influencing pharmacokinetics, and dynamics such as side effects and patient outcome. Therapeutic Drug Monitoring (TDM) of oral immunosuppressive agents is essential to prevent toxicity and or rejection; therefore it is very important to use a reliable and accurate bioanalytical assay. Differences between the most used analytical assays of measuring everolimus in whole blood and its effect on dosing advice were investigated. TDM is performed based on either trough or AUC monitoring and pharmacogenetics might be a valuable addition to TDM. Therefore the population pharmacokinetics of everolimus in a calcineurin free regimen was investigated and predictive factors such as pharmacogenetics were evaluated. In addition a limited sampling model was developed. MTOR inhibitors are known for a variety of side effects and high dropout rates. In this thesis a comprehensive analysis was performed aimed at identifying risk factors for discontinuation and a number of serious side effects. This thesis also describes an analysis aimed at identifying risk factor associated with delayed graft function, acute rejection and subclinical rejection in patients on a cyclosporine based immunosuppressive regimen. Show less
Not all hormone receptor positive breast cancer patients benefit from tamoxifen treatment, but may be nonetheless exposed to its side effects (e.g. hot flashes). Tamoxifen needs bioactivation by... Show moreNot all hormone receptor positive breast cancer patients benefit from tamoxifen treatment, but may be nonetheless exposed to its side effects (e.g. hot flashes). Tamoxifen needs bioactivation by formation of the metabolite endoxifen, which is mainly catalyzed by the enzyme CYP2D6. In this thesis, we studied the variation in tamoxifen metabolism in relation to endoxifen serum concentration, tamoxifen efficacy and side effects, focusing on CYP2D6 activity and pharmacogenetics. The importance of good methodology for genotyping and endoxifen measurement was exemplified. In a large trial population, no association between CYP2D6 genotype and disease free survival or the occurence of hot flashes was found, although polymorphisms in the estrogen receptor-1 and UGT2B15 might be related to clinical outcome. Adherence, but not the concomitant use of CYP2D6 inhibiting medication was associated with breast cancer recurrence. CYP2D6 genotype and endoxifen-guided tamoxifen dose escalation led to an increase in endoxifen serum levels and a new 13C-Dextromethorphan breath test was used for phenotyping CYP2D6, which correlated well with CYP2D6 genotype and endoxifen levels. Finally, the CYP2D6 phenotype and endoxifen serum levels are currently prospectively related to breast cancer recurrence. This may lead to therapeutic drug monitoring and selection of patients who benefit most from tamoxifen. Show less
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
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
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
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
