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pharmacogenetics of the systemic treatment in advanced hepatocellular carcinoma

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World Journal of Gastroenterology 2019年第29期25卷 3870-3896页

作者： Elena De Mattia Erika Cecchin Michela Guardascione Luisa Foltran Tania Di Raimo Francesco Angelini Mario D’Andrea Giuseppe Toffoli Clinical and Experimental Pharmacology Centro di Riferimento Oncologico di Aviano (CRO) IRCCS Aviano (PN) 33081 Italy Department of Medical Oncology Centro di Riferimento Oncologico di Aviano (CRO) IRCCS Aviano (PN) 33081 Italy Medical Oncology and Anatomic Pathology Unit “San Filippo Neri Hospital” Rome 00135 Italy Department of Oncology “San Filippo Neri Hospital” Rome 00135 Italy

Hepatocellular carcinoma (HCC) accounts for the majority of primary liver cancers. To date, most patients with HCC are diagnosed at an advanced tumor stage, excluding them from potentially curative therapies (i.e., resection, liver transplantation, percutaneous ablation). Treatments with palliative intent include chemoembolization and systemic therapy. Among systemic treatments, the small-molecule multikinase inhibitor sorafenib has been the only systemic treatment available for advanced HCC over 10 years. More recently, other smallmolecule multikinase inhibitors (e.g., regorafenib, lenvatinib, cabozantinib) have been approved for HCC treatment. The promising immune checkpoint inhibitors (e.g., nivolumab, pembrolizumab) are still under investigation in Europe while in the US nivolumab has already been approved by FDA in sorafenib refractory or resistant patients. Other molecules, such as the selective CDK4/6inhibitors (e.g., palbociclib, ribociclib), are in earlier stages of clinical development, and the c- MET inhibitor tivantinib did not show positive results in a phase III study. However, even if the introduction of targeted agents has led to great advances in patient response and survival with an acceptable toxicity profile, a remarkable inter-individual heterogeneity in therapy outcome persists and constitutes a significant problem in disease management. Thus, the identification of biomarkers that predict which patients will benefit from a specific intervention could significantly affect decision-making and therapy planning. Germ-line variants have been suggested to play an important role in determining outcomes of HCC systemic therapy in terms of both toxicity and treatment efficacy. Particularly, a number of studies have focused on the role of genetic polymorphisms impacting the drug metabolic pathway and membrane translocation as well as the drug mechanism of action as predictive/prognostic markers of HCC treatment. The aim of this review is to summarize and

关键词： Hepatocellular carcinoma pharmacogenetics Genetic markers Sorafenib Regorafenib Immune checkpoint inhibitors Cytochromes UDP glucuronosyltransferase 1A

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

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World Journal of Gastroenterology 2014年第29期20卷 9775-9827页

作者： Mariusz Panczyk Laboratory of Molecular Diagnostics and Pharmacogenomics Department of Pharmaceutical BiochemistryMedical University of Lodz Division of Teaching and Outcomes of Education Faculty of Health ScienceMedical University of Warsaw

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 *** clinical use in the treatment of patients with colorectal cancer(CRC),in addition to fluoropyrimidines,another two new cytostatic drugs were allowed:irinotecan and *** research into new treatment regimens and a new generation of drugs used in targeted therapy has also been *** last 20years was a time of numerous in vitro and in vivo studies on the molecular basis of drug *** of the most important factors limiting the effectiveness of chemotherapy is the primary and secondary resistance of cancer *** 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 *** hope to increase the percentage of positive treatment response in CRC patients due to practical applications of pharmacogenetics/*** 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 *** review is a synthetic presentation of drug resistance in the context of CRC patient *** multifactorial nature and volume of the issues involved do not allow the author to present a comprehensive study on this subject in one review.

关键词： pharmacogenetics Pharmacogenomics Drug resistance Colorectal cancer Chemoresistance Individualized medicine

pharmacogenetics, pharmacogenomics and ecogenetics

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Journal of Zhejiang University-Science B(Biomedicine & Biotechnology) 2006年第2期7卷 169-170页

作者： MOTULSKY Amo G. QI Ming Department of Medicine （Medical Genetics） and Genome Sciences University of Washington Seattle WA 98195 USA School of Medicine Zhejiang University Hangzhou 310003 China Beijing Genome Institute CAS Beijing 101300 China University of Rochester NY 14642 USA

pharmacogenetics and pharmacogenomics deal with the role of genetic factors in drug effectiveness and adverse drug reactions. The promise of a personalized medicine is beginning to be explored but requires much more clinical and translational research. Specific DNA abnormalities in some cancers already have led to effective targeted treatments. Racially determined frequency differences in pharmacogenetic traits may affect choice of treatment requiring specific testing rather than basing treatments according to racial designation. The role of genes in variable responses to foreign chemicals (xenobiotics) has been termed ecogenetics or toxicogenetics raising problems in public health and occupational medicine. Nutrigenetics refers to genetic variation in response to nutrients and may affect nutritional requirements and predisposition to chronic disease.

关键词： pharmacogenetics Pharmacogenomics Ecogenetics Nutrigenetics Adverse drug reactions

pharmacogenetics of anticancer monoclonal antibodies

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Cancer Drug Resistance 2019年第1期2卷 69-81页

作者： Dmitrii Shek Scott ARead Golo Ahlenstiel Irina Piatkov Blacktown Clinical School Western Sydney UniversityBlacktownNSW 2148Australia Storr Liver Centre The Westmead Institute for Medical ResearchThe University of SydneyWestmeadNSW 2145Australia Blacktown Hospital BlacktownNSW 2148Australia

pharmacogenetics is the study of therapeutic and adverse responses to drugs based on an individual’s genetic *** antibodies(mAbs)are a rapidly evolving field in cancer therapy,however a number of newly developed and highly effective mAbs(e.g.,anti-CTLA-4 and anti-PD-1)possess pharmacogenomic profiles that remain largely *** the first chemotherapeutic mAb Rituximab was approved in 1997 by the US Food and Drug Administration for cancer treatment,a broad number of other mAbs have been successfully developed and implemented into oncological ***,mAbs are considered as one of the most promising new approaches for cancer *** efficacy of mAb treatment can however be significantly affected by genetic background,where genes responsible for antibody presentation and metabolism,for example,can seriously affect patient *** review will focus on current anticancer mAb treatments,patient genetics that shape their efficacy,and the molecular pathways that bridge the two.

关键词： pharmacogenetics pharmacogenomics immune-checkpoint proteins monoclonal antibodies cancer immunotherapy personalized medicine

Effects of testosterone replacement and its pharmacogenetics on physical performance and metabolism

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Asian Journal of Andrology 2008年第3期10卷 364-372页

作者： Michael Zitzmann Institute of Reproductive Medicine of the University of Münster Münster D-48129 Germany

In men, testosterone （T） deficiency is associated with decreased physical performance, as defined by adverse traits in body composition, namely increased body fat content and reduced muscle mass. Physical abilities in androgen-deficient men are further attenuated by lower oxygen supply due to decreased hemoglobin concentrations and by poor glucose utilization. Dysthymia and a lack of necessary aggressiveness also contribute to deteriorate physical effectiveness. Substitution of T can improve lipid and insulin metabolism as well as growth of muscle fibers and decreasing fat depots, which consequently will result in changes of body composition. Increment of bone density will further contribute to increase physical fitness. The effects of T replacement therapy （TRT） are strongly influenced by age, training, and also pharmacogenetics： the CAG repeat polymorphism in exon 1 of the androgen receptor （AR） gene modulates androgen effects. In vitro, transcription of androgen-dependent target genes is attenuated with increasing length of triplet residues, Clinically, the CAG repeat polymorphism causes significant modulations of androgenicity in healthy eugonadal men as well as efficacy of TRT. Thresholds at which T treatment should be initiated, as well as androgen dosage, could be tailored according to this polymorphism.

关键词： testosterone androgens hypogonadism pharmacogenetics androgen receptor physical performance metabolism

Studies on abacavir-induced hypersensitivity reaction:a successful example of translation of pharmacogenetics to personalized medicine

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Science China(Life Sciences) 2013年第2期56卷 119-124页

作者： GUO YongLi SHI LeMing HONG HuiXiao SU ZhenQiang FUSCOE James NING BaiTang Division of Systems Biology National Center for Toxicological Researchthe US Food and Drug Administration Division of Bioinformatics and Biostatistics National Center for Toxicological Researchthe US Food and Drug Administration

Abacavir is an effective nucleoside analog reverse transcriptase inhibitor used to treat human immunodeficiency virus(HIV) infected *** main side effect is hypersensitivity reaction(HSR).The incidence of the HSR is associated with ethnicity among patients exposed to abacavir,and retrospective and prospective studies show a significantly increased risk of abacavir-induced HSR in human leukocyte antigen(HLA)-B*57:01-carrying *** studies indicated that abacavir interacts specifically with HLA-B*57:01 and changed the binding specificity between the HLA molecule and the HLA-presented endogenous peptide repertoire,leading to a systemic autoimmune ***-B*57:01 screening,combined with patch testing,had clinically predictive value and cost-effective impact in reducing the incidence of abacavir-induced HSR regardless of the HLA-B*57:01 prevalence in the ***,the US Food and Drug Administration(FDA) and international HIV treatment guidelines recommend a routine HLA-B*57:01 screening prior to abacavir treatment to decrease false positive diagnosis and prevent abacavir-induced *** studies of abacavir-induced HSR and the implementation of the HLA-B*57:01 screening in the clinic represent a successful example of the use of pharmacogenetics for personalized diagnosis and therapy.

关键词： personalized medicine pharmacogenetics drug safety abacavir hypersensitivity reaction (HSR) HLA-B*57:01 HLA-B*57-01 screening

Predicting(side) effects for patients with inflammatory bowel disease: The promise of pharmacogenetics

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World Journal of Gastroenterology 2019年第21期25卷 2539-2548页

作者： Michiel Dirk Voskuil Amber Bangma Rinse Karel Weersma Eleonora Anna Margaretha Festen Department of Gastroenterology and Hepatology University of Groningen and University Medical Center GroningenGroningen 9713 GZthe Netherlands Department of Genetics University of Groningen and University Medical Center GroningenGroningen 9713 GZthe Netherlands

Inflammatory bowel disease (IBD) is a chronic and heterogeneous intestinal inflammatory disorder. The medical management of IBD aims for long-lasting disease remission to prevent complications and disease progression. Early introduction of immunosuppression forms the mainstay of medical IBD management. Large inter-individual variability in drug responses, in terms of both efficacy and toxicity, leads to high rates of therapeutic failure in the management of IBD. Better patient stratification is needed to maximize patient benefit and minimize the harm caused by adverse events. Pre-treatment pharmacogenetic testing has the potential to optimize drug selection and dose, and to minimize harm caused by adverse drug reactions. In addition, optimizing the use of cheap conventional drugs, and avoiding expensive ineffective drugs, will lead to a significant reduction in costs. Genetic variation in both TPMT and NUDT15, genes involved in thiopurine metabolism, is associated to an increased risk of thiopurine-induced myelosuppression. Moreover, specific HLA haplotypes confer risk to thiopurine-induced pancreatitis and to immunogenicity to tumor necrosis factor-antagonists, respectively. Falling costs and increased availability of genetic tests allow for the incorporation of pre-treatment genetic tests into clinical IBD management guidelines. In this paper, we review clinically useful pharmacogenetic associations for individualized treatment of patients with IBD and discuss the path from identification of a predictive pharmacogenetic marker to implementation into IBD clinical care.

关键词： Inflammatory bowel disease Crohn’s disease Ulcerative colitis pharmacogenetics Personalized medicine

The use of pharmacogenetics to increase the safety of colorectal cancer patients treated with fluoropyrimidines

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Cancer Drug Resistance 2019年第1期2卷 116-130页

作者： Elena De Mattia Rossana Roncato Chiara Dalle Fratte Fabrizio Ecca Giuseppe Toffoli Erika Cecchin Experimental and Clinical Pharmacology Unit Centro di Riferimento Oncologico di Aviano(CRO)IRCCSAviano 33081Italy

Fluoropyrimidines(FP)are given in the combination treatment of the advanced disease or as monotherapy in the neo-adjuvant and adjuvant treatment of colorectal cancerand other solid tumors including breast,head and neck and gastric *** present a narrow therapeutic index with 10 to 26% of patients experiencing acute severe or life-threatening *** the high number of patients receiving FP-based therapies,and the significant effects of toxicities on their quality of life,the prevention of FP-related adverse events is of major clinical *** genetic variants in the rate limiting enzyme dihydropyrimidine dehydrogenase(DPYD)gene are related to the occurrence of extremely severe,early onset toxicity in FP treated *** pre-treatment diagnostic test of 4 DPYD genetic polymorphisms is suggested by the currently available pharmacogenetic *** prospective implementation projects are ongoing to support the introduction of up-front genotyping of the patients in clinical *** pharmacogenetic studies tried to assess the predictive role of other polymorphisms in genes involved in the FP pharmacokinetics/pharmacodynamic pathways,TYMS and MTHFR,but no additional clinically validated genetic markers of toxicity are available to *** development of next-generation sequencing platforms opens new possibilities to highlight previously unreported genetic ***,the investigation of the genetic variation in the patients immunological system,a pivotal target in cancer treatment,could bring notable advances in the *** review will describe the most recent literature on the use of pharmacogenetics to increase the safety of a treatment based on FP administration in colorectal cancer patients.

关键词： Fluoropyrimidines pharmacogenetics colorectal cancer toxicity DPYD TYMS MTHFR

pharmacogenetics as a tool to tailor antiretroviral therapy: A review

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World Journal of Virology 2015年第3期4卷 198-208页

作者： Antonio Aceti Laura Gianserra Lara Lambiase Alfredo Pennica Elisabetta Teti Clinical Infectious Diseases Sant’Andrea HospitalSapienza University of Rome

Highly active antiretroviral therapy(HAART) has substantially changed human immunodeficiency virus(HIV) infection from an inexorably fatal condition into a chronic disease with a longer life expectancy. This means that HIV patients should receive antiretroviral drugs lifelong, and the problems concerning with a chronic treatment(tolerability, side effects, adherence to treatment) have now become dominant. In this context, strategies for the treatment personalization have taken a central role in optimizing the therapeutic response and prevention of adverse drug reactions. In this setting, the study of pharmacogenetics features could be a very useful tool in clinical practice; moreover, nowadays the study of genetic profiles allows optimizations in the therapeutic management of People Living With HIV(PLWH) through the use of test introduced into clinical practice and approved by international guidelines for the adverse effects prevention such as the genetic test HLA-B*5701 to detect hypersensitivity to Abacavir. For other tests further studies are needed: CYP2B6 516 G > T testing may be able to identify patients at higher risk of Central Nervous System side effects following standard dosing of Efavirenz, UGT1A1*28 testing before initiation of antiretroviral therapy containing Atazanavir may aid in identifying individuals at risk of hyperbilirubinaemia. pharmacogenetics represents a research area with great growth potential which may be useful to guide the rational use of antiretrovirals.

关键词： pharmacogenetics Pharmacogenomics Single nucleotide polymorphism Pharmacokinetics Highly active antiretroviral therapy Polymorphism Phenotype Pharmacodynamic