Pharmacogenetics research on chemotherapy resistance in colorectal cancer over the last 20 years

During the past two decades the first sequencing of the human genome was performed showing its high degree of inter-individual differentiation,as a result of large international research projects(Human Genome Project,the 1000 Genomes Project International HapMap Project,and Programs for Genomic Applications NHLBI-PGA).This period was also a time of intensive development of molecular biology techniques and enormous knowledge growth in the biology of cancer.For clinical use in the treatment of patients with colorectal cancer(CRC),in addition to fluoropyrimidines,another two new cytostatic drugs were allowed:irinotecan and oxaliplatin.Intensive research into new treatment regimens and a new generation of drugs used in targeted therapy has also been conducted.The last 20years was a time of numerous in vitro and in vivo studies on the molecular basis of drug resistance.One of the most important factors limiting the effectiveness of chemotherapy is the primary and secondary resistance of cancer cells.Understanding the genetic factors and mechanisms that contribute to the lack of or low sensitivity of tumour tissue to cytostatics is a key element in the currently developing trend of personalized medicine.Scientists hope to increase the percentage of positive treatment response in CRC patients due to practical applications of pharmacogenetics/pharmacogenomics.Over the past 20 years the clinical usability of different predictive markers has been tested among which only a few have been confirmed to have high application potential.This review is a synthetic presentation of drug resistance in the context of CRC patient chemotherapy.The multifactorial nature and volume of the issues involved do not allow the author to present a comprehensive study on this subject in one review.     

Recent applications of chemosensitivity tests for colorectal cancer treatment

The evaluation of therapeutic efficacy is necessary to predict the outcome of patients with metastatic colorectal cancer(CRC). In these patients, there is a critical need for predictive chemosensitivity assays and biomarkers to optimize efficacy and minimize toxicity. The introduction of targeted agents has improved the progression-free survival and overall survival of patients with metastatic disease. However, approximately 50% of patients do not show a positive response to chemotherapy and the selection of patients likely to respond to a specific regimen remains challenging. Cell culturebased chemosensitivity tests use autologous viable tumor cells to evaluate susceptibility to specific agents in vitro and predict their direct effects. Adenosine triphosphate-based assays and methyl thiazolyl-diphenyltetrazolium bromide-based assays are used widely as sensitivity tests because of their short assay period, technical simplicity, and the requirement of small amount of specimen. Among protein- and gene-based chemosensitivity assays, assessment of KRAS mutation status predicts the response to epidermal growth factor receptor-targeted therapy in CRC patients. The validation of predictive and prognostic markers enables the selection of therapeutic regimens with optimal efficacy and minimal toxicity for each patient, which has been termed personalized treatment. This review summarizes currently available predictive and prognostic chemosensitivity tests for metastatic CRC.     

Pharmacogenetics in inflammatory bowel disease

Pharmacogenetics is the study of the association between variability in drug response and (or) drug toxicity and polymorphisms in genes. The goal of this field of science is to adapt drugs to a patient's specific genetic background and therefore make them more efficacious and safe. In this article we describe the variants in genes that influence either the efficacy or toxicity of common drugs used in the treatment of inflammatory bowel diseases (IBD), ulcerative colitis (UC), and Crohn's disease (CD) including sulfasalazine and mesalazine, azathioprine (AZA) and 6-mercaptopurine (6-MP), methotrexate (MIX), glucocorticosteroids (CSs) and infliximab. Furthermore, difficulties with pharmacogenetic studies in general and more specifically in IBD are described. Although pharmacogenetics is a promising field that already contributed to a better understanding of some of the underlying mechanisms of action of drugs used in IBD, the only discovery translated until now into daily practice is the relation between thiopurine S-methyltransferase (TPMT) gene polymorphisms and hematological toxicity of thiopurine treatment. In the future it is necessary to organize studies in well characterized patient cohorts who have been uniformly treated and systematically evaluated in order to quantitate drug response more objectively. An effort should be made to collect genomic DNA from all patients enrolled in clinical drug trials after appropriate informed consent for pharmacogenetic studies.     

FOLFOX/FOLFIRI pharmacogenetics:The call for a personalized approach in colorectal cancer therapy

While 5-fluorouracil used as single agent in patients with metastatic colorectal cancer has an objective response rate around 20%,the administration of combinations of irinotecan with 5-fluorouracil/folinic acid or oxaliplatin with 5-fluorouracil/folinic acid results in significantly increased response rates and improved survival.However,the side effects of systemic therapy such as myelotoxicity,neurotoxicity or gastrointestinal toxicity may lead to life-threatening complications and have a major impact on the quality of life of the patients.Therefore,biomarkers that would be instrumental in the choice of optimal type,combination and dose of drugs for an individual patient are urgently needed.The efficacy and toxicity of anticancer drugs in tumor cells is determined by the effective concentration in tumor cells,healthy tissues and by the presence and quantity of the drug targets.Enzymes active in drug metabolism and transport represent important determinants of the therapeutic outcome.The aim of this review was to summarize published data on associations of gene and protein expression,and genetic variability of putative biomarkers with response to therapy of colorectal cancer to 5-fluorouracil/leucovorin/oxaliplatin and 5-fluorouracil/leukovorin/irinotecan regimens.Gaps in the knowledge identified by this review may aid the design of future research and clinical trials.     

Novel targeting approaches and signaling pathways of colorectal cancer: An insight

Colorectal cancer(CRC) is the third most common cancer of mortality in the world. Chemotherapy based treatment leads to innumerable side effects as it delivers the anticancer drug to both normal cells besides cancer cells. Sonic Hedgehog(SHH), Wnt wingless-type mouse mammary tumor virus/β-catenin, transforming growth factor-β/SMAD, epidermal growth factor receptor and Notch are the main signaling pathways involved in the progression of CRC. Targeted therapies necessitate information regarding the particular aberrant pathways. Advancements in gene therapies have resulted in the recognition of novel therapeutic targets related with these signal-transduction cascades. CRC is a stepwise process where mutations occur over the time and activation of oncogenes and deactivation of tissue suppressor genes takes place. Genetic changes which are responsible for the induction of carcinogenesis include loss of heterozygosity in tumor suppressor genes such as adenomatous polyposis coli, mutation or deletion of genes like p53 and K-ras. Therefore, many gene-therapy approaches like gene correction, virusdirected enzyme-prodrug therapy, immunogenetic manipulation and virotherapy are currently being explored. Development of novel strategies for the safe and effective delivery of drugs to the cancerous site is the need of the hour. This editorial accentuates different novel strategies with emphasis on gene therapy and immunotherapy for the management of CRC.     

Update on hepatitis B virus infection

Chronic infection with hepatitis B virus(HBV) leads to the development of hepatocellular carcinoma and/or chronic liver failure. Despite extensive research, the immunopathogenesis is not completely understood. Viral persistence and clinical outcomes following HBV infection depend on viral factors and host factors; including genetic factors that determine a host’s immune mechanisms. The primary goal of chronic hepatitis B(CHB)treatment is to eradicate HBV or to at least maintain suppression of HBV replication. Despite recent advances in anti-viral agents for chronic HBV infection, complete eradication of the virus has been difficult to achieve.Agents for the treatment of CHB are divided mainly into two groups: immunomodulating agents and antiviral nucleos(t)ide analogues(NAs). Although NAs are safe,effective and easily administered orally, their long-term use poses the risk of drug resistance. Currently, international evidence-based guidelines have been developed to support physicians in managing CHB patients.However, treatment of patients with drug resistance is still challenging, as only a few classes of anti-HBV drugs are available and cross-resistance between drugs can occur. In addition, as the currently available genotypictest for detection of drug resistance still has limitations in identifying the different substitutions present in the same viral genome, the development of a new virologic test to overcome this limitation is necessary. Among the predictive factors associated with response to pegylated interferon(PEG-IFN) therapy, hepatitis B surface antigen quantification is considered to be a surrogate marker for monitoring response to PEG-IFN. Current practice guidelines stress the importance of profound and durable HBV viral suppression in the treatment of CHB patients. To this end, it is essential to choose a potent antiviral drug with a low risk of resistance for initial treatment of CHB to achieve sustained virological response. This review highlights recent advances in the understanding of the immunopathogenesis of HBV and currently available and developing treatment strategies against HBV infection.     

Role of receptor tyrosine kinases in gastric cancer： New targets for a selective therapy

Receptor tyrosine kinases (RTKs) such as the epidermal growth factor receptor family participate in several steps of tumor formation including proliferation and metastatic spread. Several known RTKs are upregulated in gastric cancer being prime targets of a tailored therapy. Only preliminary data exist, however, on the use of the currently clinically available drugs such as trastuzumab, cetuximab, bevacizumab, gefitinib, erlotinib, and imatinib in the setting of gastric cancer. Preclinical data suggest a potential benefit of their use, especially in combination with "conventional" cytostatic therapy. This review summarizes the current knowledge about their use in cancer therapy as well as new approaches and drugs to optimize treatment success.     

Chemotherapy for colorectal cancer in the elderly

Colorectal cancer(CRC) is one of the leading causes of cancer-related death in the elderly.However,elderly patients with CRC tend to be under-presented in clinical trials and undertreated in clinical practice.Advanced age alone should not be the only criteria to preclude effective therapy in elderly patients with CRC.The best guide about optimal cancer treatment can be provided by comprehensive geriatric assessment.Elderly patients with stage Ⅲ colon cancer can enjoy the same benefit from adjuvant chemotherapy with 5-fluorouracil/leucovorin or capecitabine as younger patients,without a substantial increase in toxicity.With conflicting results of retrospective studies and a lack of data available from randomized studies,combined modality treatment should be used with great caution in elderly patients with locally advanced rectal cancer.Combination chemotherapy can be considered for older patients with metastatic CRC.For elderly patients who are frail or vulnerable,however,monotherapy or a stopand-go strategy may be desirable.The use of targeted therapies in older patients with metastatic CRC appears to be promising in view of their better efficacy and toxicity.Treatment should be individualized based on the nature of the disease,the physiologic or functional status,and the patient's preference.     

Therapeutic drug monitoring in patients with inflammatory bowel disease

Thiopurine analogs and anti-tumor necrosis factor(TNF)agents have dramatically changed the therapeutics of inflammatory bowel diseases(IBD),improving short and long-term outcomes.Unfortunately some patients do not respond to therapy and others lose response over time.The pharmacokinetic properties of these drugs are complex,with high inter-patient variability.Thiopurine analogs are metabolized through a series of pathways,which vary according to the patients’pharmacogenetic profile.This profile largely determines the ratios of metabolites,which are in turn associated with likelihoods of clinical efficacy and/or toxicity.Understanding these mechanisms allows for manipulation of drug dose,aiming to reduce the development of toxicity while improving the efficacy of treatment.The efficacy of anti-TNF drugs is influenced by many pharmacodynamic variables.Several factors may alter drug clearance,including the concomitant use of immunomodulators(thiopurine analogs and methotrexate),systemic inflammation,the presence of anti-drug antibodies,and body mass.The treatment of IBD has evolved with the understanding of the pharmacologic profiles of immunomodulating and TNF-inhibiting medications,with good evidence for improvement in patient outcomesobserved when measuring metabolic pathway indices.The role of routine measurement of metabolite/drug levels and antibodies warrants further prospective studies as we enter the era of personalized IBD care.     

Micelles as potential drug delivery systems for colorectal cancer treatment

Despite the significant progress in cancer therapy, colorectal cancer (CRC) remains one of the most fatal malignancies worldwide. Chemotherapy is currently the mainstay therapeutic modality adopted for CRC treatment. However, the long-term effectiveness of chemotherapeutic drugs has been hampered by their low bioavailability, non-selective tumor targeting mechanisms, non-specific biodistribution associated with low drug concentrations at the tumor site and undesirable side effects. Over the last decade, there has been increasing interest in using nanotechnology-based drug delivery systems to circumvent these limitations. Various nanoparticles have been developed for delivering chemotherapeutic drugs among which polymeric micelles are attractive candidates. Polymeric micelles are biocompatible nanocarriers that can bypass the biological barriers and preferentially accumulate in tumors via the enhanced permeability and retention effect. They can be easily engineered with stimuli-responsive and tumor targeting moieties to further ensure their selective uptake by cancer cells and controlled drug release at the desirable tumor site. They have been shown to effectively improve the pharmacokinetic properties of chemotherapeutic drugs and enhance their safety profile and anticancer efficacy in different types of cancer. Given that combination therapy is the new strategy implemented in cancer therapy, polymeric micelles are suitable for multidrug delivery and allow drugs to act concurrently at the action site to achieve synergistic therapeutic outcomes. They also allow the delivery of anticancer genetic material along with chemotherapy drugs offering a novel approach for CRC therapy. Here, we highlight the properties of polymeric micelles that make them promising drug delivery systems for CRC treatment. We also review their application in CRC chemotherapy and gene therapy as well as in combination cancer chemotherapy.     

Molecular markers to predict clinical outcome and radiation induced toxicity in lung cancer

The elucidation of driver mutations involved in the molecular pathogenesis of cancer has led to a surge in the application of novel targeted therapeutics in lung cancer. Novel oncologic research continues to lead investigators towards targeting personalized tumor characteristics rather than applying targeted therapy to broad patient populations. Several driver genes, in particular epidermal growth factor receptor (EGFR) and ALK fusions, are the earliest to have made their way into clinical trials. The avant-garde role of genomic profiling has led to important clinical challenges when adapting current standard treatments to personalized oncologic care. This new frontier of medicine requires newer biomarkers for toxicity that will identify patients at risk, as well as, new molecular markers to predict and assess clinical outcomes. Thus far, several signature genes have been developed to predict outcome as well as genetic factors related to inflammation to predict toxicity.KEYWORDS : Lung cancer, biomarkers, toxicity, novel therapies     

One hundred and fifty years of the Journal of Internal Medicine (JIM)

Systemic therapeutic efficacy is central to determining the outcome of patients with metastatic colorectal cancer (CRC). In these patients, there is a critical need for predictive biomarkers to optimize efficacy whilst minimizing toxicity. The integration of a new generation of molecularly targeted drugs into the treatment of CRC, coupled with the development of sophisticated technologies for individual tumours as well as patient molecular profiling, underlines the potential for personalized medicine. In this review, we focus on the latest progress made within the genomic and proteomic fields, concerning predictive biomarkers for individualized therapy in metastatic CRC.     

Antihypertensive pharmacogenetics: getting the right drug into the right patient

Pharmacogenetic investigation seeks to identify genetic factors that contribute to interpatient and interdrug variation in responses to antihypertensive drug therapy. Classical studies have characterized single gene polymorphisms of drug metabolizing enzymes that are responsible for large interindividual differences in pharmacokinetic responses to several antihypertensive drugs. Progress is being made using candidate gene and genome scanning approaches to identify and characterize many additional genes influencing pharmacodynamic mechanisms that contribute to interindividual differences in responses to antihypertensive drug therapy. Knowledge of polymorphic variation in these genes will help to predict individual patients' blood pressure responses to antihypertensive drug therapy and may also provide new insights into molecular mechanisms responsible for elevation of blood pressure.     

Gastro-intestinal toxicity of chemotherapeutics in colorectal cancer:The role of inflammation

Chemotherapy-induced diarrhea(CID)is a common and often severe side effect experienced by colorectal cancer(CRC)patients during their treatment.As chemotherapy regimens evolve to include more efficacious agents,CID is increasingly becoming a major cause of dose limiting toxicity and merits further investigation.Inflammation is a key factor behind gastrointestinal(GI)toxicity of chemotherapy.Different chemotherapeutic agents activate a diverse range of pro-inflammatory pathways culminating in distinct histopathological changes in the small intestine and colonic mucosa.Here we review the current understanding of the mechanisms behind GI toxicity and the mucositis associated with systemic treatment of CRC.Insights into the inflammatory response activated during this process gained from various models of GI toxicity are discussed.The inflammatory processes contributing to the GI toxicity of chemotherapeutic agents are increasingly being recognised as having an important role in the development of anti-tumor immunity,thus conferring added benefit against tumor recurrence and improving patient survival.We review the basic mechanisms involved in the promotion of immunogenic cell death and its relevance in the treatment of colorectal cancer.Finally,the impact of CID on patient outcomes and therapeutic strategies to prevent or minimise the effect of GI toxicity and mucositis are discussed.     

Pharmacogenetics: an opportunity for a safer and more efficient pharmacotherapy

Drug treatment is in many cases ineffective. Besides patients who do not respond to the treatment despite receiving expensive drugs, adverse drug reactions (ADRs) as a consequence of the treatment, is estimated to cost the US society 100 billion USD and over 100,000 deaths per year. Pharmacogenetics is the discipline which takes the patient's genetic information of drug transporters, drug metabolizing enzymes and drug receptors into account to allow for an individualized drug therapy leading to optimal choice and dose of the drugs in question. It is believed that much cost for the society can be saved in this manner. Many drug transporters are polymorphic. In addition, the majority of phase I and phase II dependent drug metabolism is carried out by polymorphic enzymes which can cause abolished, quantitatively or qualitatively altered or enhanced drug metabolism. Stable duplication, multiduplication or amplification of active genes, most likely in response to dietary components that have resulted in a selection of alleles with multiple noninducible genes, has been described. Several examples exist where subjects carrying certain alleles suffer from a lack of drug efficacy because of ultrarapid metabolism caused by multiple genes or by induction of gene expression, or, alternatively, adverse effects from the drug treatment as a result of the presence of defective alleles. The information about the role of polymorphic drug receptors for efficiency of drug therapy is more scarce, although promising examples are seen in drug treatment of asthma where the efficiency can be severely enhanced by predictive genotyping of the drug targets. In addition, certain polymorphic genes can be used as markers for optimization of the drug therapy. It is likely that predictive genotyping is of benefit in 10-20% of drug treatment and thereby allows for prevention of causalities as a cause of ADRs and thus improves the health for a significant fraction of the patients. In 15-40% of the cases, the penetrance of genetic polymorphism is of less importance because of the polygenic influence on the outcome of drug treatment and in 50% of the cases, pharmacogenetics would be without influence because of other more important physiological and environmental factors. In the present contribution an overview about our present knowledge how polymorphic genes can influence the drug efficacy is presented. Some emphasis will be given to different forms of cytochrome P450 which are of importance for drug metabolism.     

Targeted therapeutic agents for colorectal cancer

The treatment of colorectal cancer (CRC) has evolved substantially during the past decade with the advent of molecular targeted therapies. Inhibitors to the vascular endothelial growth factor and epidermal growth factor receptor (EGFR) pathways have been shown to enhance the efficacy of cytotoxic chemotherapy in patients with advanced CRC, and anti-EGFR antibodies demonstrate modest activity as monotherapeutic agents. These biologic agents have improved patient outcomes and survival and have been incorporated into routine clinical practice establishing a new standard of care. Molecular markers have recently been adopted into clinical practice with the finding that the KRAS oncogene is a predictive biomarker for anti-EGFR therapy, whereby the therapeutic benefit of anti-EGFR treatment is restricted to tumors with wild-type KRAS. The use of molecular targeted agents has fewer yet more specific toxicities compared with conventional cytotoxic drugs and enables a more personalized approach to cancer therapy. In contrast to the results for advanced CRC, targeted therapies have not shown a benefit in the adjuvant setting for patients with resected colon cancer. The goal of this review is to provide an update on the medical management of CRC, with a focus on the use of targeted therapy.