Early changes in plasma DNA levels of mutant KRAS as a sensitive marker of response to chemotherapy in pancreatic cancer.

Sci Rep. 2017 Aug 11;7(1):7931

Authors: Del Re M, Vivaldi C, Rofi E, Vasile E, Miccoli M, Caparello C, d'Arienzo PD, Fornaro L, Falcone A, Danesi R

Abstract
Pancreatic cancer (PDAC) is still lacking of reliable markers to monitor tumor response. CA 19-9 is the only biomarker approved, despite it has several limitations in sensitivity and specificity. Since mutations of KRAS occur in more than 90% of tumors, its detection in circulating free tumor DNA (cftDNA) could represent a biomarker to monitor chemotherapy response. Twenty-seven advanced PDAC patients given first-line 5-fluorouracil, irinotecan and oxaliplatin or gemcitabine and nab-paclitaxel were enrolled. Three ml of plasma were collected: 1) before starting chemotherapy (baseline); 2) at day 15 of treatment; and 3) at each clinical follow-up. cftDNA was extracted and analysed for KRAS mutations ((mut)KRAS) by digital droplet PCR. Nineteen patients displayed a (mut)KRAS in baseline plasma samples. There was a statistically significant difference in progression-free survival (PFS) and overall survival (OS) in patients with increase vs. stability/reduction of cftDNA in the sample collected at day 15 (median PFS 2.5 vs 7.5 months, p = 0.03; median OS 6.5 vs 11.5 months, p = 0.009). The results of this study demonstrate that cftDNA (mut)KRAS changes are associated with tumor response to chemotherapy and support the evidence that (mut)KRAS in plasma may be used as a new marker for monitoring treatment outcome and disease progression in PDAC.

PMID: 28801547 [PubMed - in process]

Analysis of Separation of White Blood Cells in Peripheral Blood as an Indicator of MPO Deficiency.

Ann Clin Lab Sci. 2017 Aug;47(4):422-431

Authors: Rośniak-Bąk K, Jeleń A, Bąk M

Abstract
The purpose of this study was to analyze the white blood cell (WBC) percentage pattern of patients with myeloperoxidase disorder. During the 18 months of routine work, 36 blood samples were found with disorders of myeloperoxidase activity: 12 cases of total myeloperoxidase (MPOt) deficiency and 24 cases of partial myeloperoxidase (MPOp) deficiency. In the group with MPOp, according to the results, monocytes (MONO) were the dominant population 33.2%±21.3; however, the microscopic evaluation of leucocytes showed the dominance of neutrophil (NEUT). The average NEUT value was 66.63%±12.31; LYMPH 23.33%±10.08; MONO 6.00%±3.20; EOS 2.04%±2.20; BASO 0.29%±0.62; ATYP 0.83%±1.09. In the group with MPOt, the results of automated leukocyte analysis showed that the dominant group consisted of large unstained cells (LUC) 72.6%±8.64. LUC category reflects large immature cells such as blusts. In the microscopic evaluation: NEUT 67% ±11.40; LYMPH 23%±8.94; MONO 6.17%±3.47; EOS 1.25%±1.06; BASO 0.08%±0.29; ATYP 0.92%±1.38. During microscopic verification, no LUC cells were found. Results of the evaluation of automatic WBC separation according to morphology and functionality of cells led to the conclusion that monocyte dominance in the differential WBC count is associated with a high likelihood of MPOp, and the domination of large unstained cells with MPOt.

PMID: 28801368 [PubMed - in process]

Reply to Ugo De Giorgi, Vincenza Conteduca, and Emanuela Scarpi's Letter to the Editor re: Marzia Del Re, Elisa Biasco, Stefania Crucitta, et al. The Detection of Androgen Receptor Splice Variant 7 in Plasma-derived Exosomal RNA Strongly Predicts Resistance to Hormonal Therapy in Metastatic Prostate Cancer Patients. Eur Urol 2017;71:680-7.

Eur Urol. 2017 Aug 08;:

Authors: Del Re M, Biasco E, Crucitta S, Derosa L, Rofi E, Orlandini C, Miccoli M, Galli L, Falcone A, Jenster GW, van Schaik RH, Danesi R

PMID: 28801127 [PubMed - as supplied by publisher]

Rae1-mediated nuclear export of Rnc1 is an important determinant in controlling MAPK signaling.

Curr Genet. 2017 Aug 10;:

Authors: Satoh R, Hagihara K, Sugiura R

Abstract
In eukaryotic cells, RNA binding proteins (RBPs) play critical roles in regulating almost every aspect of gene expression, often shuttling between the nucleus and the cytoplasm. They are also key determinants in cell fate via controlling the target mRNAs under the regulation of various signaling pathways in response to environmental stresses. Therefore, understanding the mechanisms that couple the location of mRNA and RBPs is a major challenge in the field of gene expression and signal responses. In fission yeast, a KH-type RBP Rnc1 negatively regulates MAPK signaling activation via mRNA stabilization of the dual-specificity MAPK phosphatase Pmp1, which dephosphorylates MAPK Pmk1. Rnc1 also serves as a target of MAPK phosphorylation, which makes a feedback loop mediated by an RBP. We recently discovered that the nuclear export of Rnc1 requires mRNA-binding ability and the mRNA export factor Rae1. This strongly suggested the presence of an mRNA-export system, which recognizes the mRNA/RBP complex and dictates the location and post-transcriptional regulation of mRNA cargo. Here, we briefly review the known mechanisms of general nuclear transporting systems, with an emphasis on our recent findings on the spatial regulation of Rnc1 and its impact on the regulation of the MAPK signal transduction cascade.

PMID: 28799069 [PubMed - as supplied by publisher]

CYP2C19*2 and CYP2C19*17 variants and effect of tamoxifen on breast cancer recurrence: Analysis of the International Tamoxifen Pharmacogenomics Consortium dataset.

Sci Rep. 2017 Aug 10;7(1):7727

Authors: Damkier P, Kjærsgaard A, Barker KA, Cronin-Fenton D, Crawford A, Hellberg Y, Janssen EAM, Langefeld C, Ahern TP, Lash TL

Abstract
The role of cytochrome P450 drug metabolizing enzymes in the efficacy of tamoxifen treatment of breast cancer is subject to substantial interest and controversy. CYP2D6 have been intensively studied, but the role of CYP2C19 is less elucidated, and we studied the association of CYPC19 genotype and recurrence of breast cancer. We used outcome and genotyping data from the large publicly available International Tamoxifen Pharmacogenomics Consortium (ITPC) dataset. Cox regression was used to compute the hazard ratios (HRs) for recurrence. CYP2C19 genotype data was available for 2 423 patients and the final sample cohort comprised 2 102 patients. CYP2C19*2 or *19 alleles did not influence DFS. For the CYP2C19*2 allele, the HR was 1.05 (CI 0.78-1.42) and 0.79 (CI 0.32-1.94) for hetero- and homozygote carriers, respectively. The corresponding HR for hetero- and homozygote carriers of the CYP2C19*17 allele were 1.02 (CI 0.71-1.46) and 0.57 (CI 0.26-1.24), respectively. Accounting for CYP2D6 genotype status did not change these estimates. We found no evidence to support a clinically meaningful role of CYP2C19 polymorphisms and response to tamoxifen in breast cancer patients and, consequently, CYP2C19 genotype status should not be included in clinical decisions on tamoxifen treatment.

PMID: 28798474 [PubMed - in process]

Towards personalized medicine for patients with autoimmune diseases: Opportunities and challenges.

Immunol Lett. 2017 Aug 07;:

Authors: Tavakolpour S

Abstract
There is generally no cure for autoimmune disorders, but the symptoms can be managed. Currently available drugs/treatments are more potent than those in the past decades. However, finding the right drug and right patients has remained a serious problem. We should revise our diagnosis criteria to more accurate ones. During the recent years, personalized medicine has attracted much attention. However, it needs to be well-explained for autoimmune diseases. Personalized medicine aims to find the most optimum drugs for a patient. Hence, recognizing the drugs based on genetics and molecular profile of patients, needs a comprehensive protocol. This study attempted to discuss the most practical and effective ways for identifying right patient and right drug. Patients should be divided into subpopulations. According to the last diagnosis criteria and therapeutic options, it was attempted to highlight the gaps or contradictions in current understanding and suggest what the future of research in this area may hold. Various factors could be considered, including genes variants, genes expression, epigenetic alterations, immune responses, and also basic and obvious characteristics (sex, age, ethnic, etc.). Moreover, advantages, disadvantages, obstacles, and opportunities during the personalized medicine for autoimmune diseases have been discussed in great detail. Finally, creation of a global library that covers all the aspects of personalized medicines for different types of autoimmune disease was suggested. In conclusion, revising diagnosis and treatments of autoimmune diseases toward personalized medicine could be the revolutionary step for having more effective and safer therapeutic options.

PMID: 28797806 [PubMed - as supplied by publisher]

Regulation of hepatic stellate cell proliferation and activation by glutamine metabolism.

PLoS One. 2017;12(8):e0182679

Authors: Li J, Ghazwani M, Liu K, Huang Y, Chang N, Fan J, He F, Li L, Bu S, Xie W, Ma X, Li S

Abstract
Liver fibrosis is the excessive accumulation of extracellular matrix proteins, which is mainly caused by accumulation of activated hepatic stellate cells (HSCs). The mechanisms of activation and proliferation of HSCs, two key events after liver damage, have been studied for many years. Here we report a novel pathway to control HSCs by regulating glutamine metabolism. We demonstrated that the proliferation of HSCs is critically dependent on glutamine that is used to generate α-ketoglutarate (α-KG) and non-essential amino acid (NEAA). In addition, both culture- and in vivo-activated HSCs have increased glutamine utilization and increased expression of genes related to glutamine metabolism, including GLS (glutaminase), aspartate transaminase (GOT1) and glutamate dehydrogenase (GLUD1). Inhibition of these enzymes, as well as glutamine depletion, had a significant inhibitory effect on HSCs activation. In addition to providing energy expenditure, conversion of glutamine to proline is enhanced. The pool of free proline may also be increased via downregulation of POX expression. Hedgehog signaling plays an important role in the regulation of glutamine metabolism, as well as TGF-β1, c-Myc, and Ras signalings, via transcriptional upregulation and repression of key metabolic enzymes in this pathway. Finally, changes in glutamine metabolism were also found in mouse liver tissue following CCl4-induced acute injury.
CONCLUSION: Glutamine metabolism plays an important role in regulating the proliferation and activation of HSCs. Strategies that are targeted at glutamine metabolism may represent a novel therapeutic approach to the treatment of liver fibrosis.

PMID: 28797105 [PubMed - in process]

Gender difference in NASH susceptibility: Roles of hepatocyte Ikkβ and Sult1e1.

PLoS One. 2017;12(8):e0181052

Authors: Matsushita N, Hassanein MT, Martinez-Clemente M, Lazaro R, French SW, Xie W, Lai K, Karin M, Tsukamoto H

Abstract
Myeloid cell and hepatocyte IKKβ may mediate the genesis of obesity and insulin resistance in mice fed high fat diet. However, their gender-specific roles in the pathogenesis of non-alcoholic steatohepatitis (NASH) are not known. Here we demonstrate myeloid IKKβ deficiency prevents Western diet-induced obesity and visceral adiposity in females but not in males, and attenuates hyperglycemia, global IR, and NASH in both genders. In contrast, all metabolic sequela including NASH are aggravated by hepatocyte IKKβ deficiency (IkbkbΔhep) in male but not female mice. Gene profiling identifies sulfotransferase family 1E (Sult1e1), which encodes a sulfotransferase E1 responsible for inactivation of estrogen, as a gene upregulated in NASH in both genders and most conspicuously in male IkbkbΔhep mice having worst NASH and lowest plasma estradiol levels. LXRα is enriched to LXRE on Sult1e1 promoter in male WT and IkbkbΔhep mice with NASH, and a Sult1e1 promoter activity is increased by LXRα and its ligand and augmented by expression of a S32A mutant of IκBα. These results demonstrate striking gender differences in regulation by IKKβ of high cholesterol saturated fat diet-induced metabolic changes including NASH and suggest hepatocyte IKKβ is protective in male due at least in part to its ability to repress LXR-induced Sult1e1. Our findings also raise a caution for systemic IKK inhibition for the treatment of NASH as it may exacerbate the disease in male patients.

PMID: 28797077 [PubMed - in process]

New Pharmacogenomics Research Network: An Open Community Catalyzing Research and Translation in Precision Medicine.

Clin Pharmacol Ther. 2017 Aug 10;:

Authors: Relling MV, Krauss RM, Roden DM, Klein TE, Fowler DM, Terada N, Lin L, Riel-Mehan M, Do TP, Kubo M, Yee SW, Johnson GT, Giacomini KM

Abstract
The goal of pharmacogenomics research is to discover genetic polymorphisms that underlie variation in drug response. Increasingly, pharmacogenomics research involves large numbers of patients and the application of new technologies and methodologies to enable discovery. The Pharmacogenomics Research Network (PGRN) has become a community-driven network of investigators spanning scientific and clinical disciplines. Here, we highlight the activities and types of resources that enable PGRN members to enhance and drive basic and translational research in pharmacogenomics.

PMID: 28795399 [PubMed - as supplied by publisher]

Impaired lymphocyte trafficking in mice deficient in the kinase activity of PKN1.

Sci Rep. 2017 Aug 09;7(1):7663

Authors: Mashud R, Nomachi A, Hayakawa A, Kubouchi K, Danno S, Hirata T, Matsuo K, Nakayama T, Satoh R, Sugiura R, Abe M, Sakimura K, Wakana S, Ohsaki H, Kamoshida S, Mukai H

Abstract
Knock-in mice lacking PKN1 kinase activity were generated by introducing a T778A point mutation in the catalytic domain. PKN1[T778A] mutant mice developed to adulthood without apparent external abnormalities, but exhibited lower T and B lymphocyte counts in the peripheral blood than those of wild-type (WT) mice. T and B cell development proceeded in an apparently normal fashion in bone marrow and thymus of PKN1[T778A] mice, however, the number of T and B cell counts were significantly higher in the lymph nodes and spleen of mutant mice in those of WT mice. After transfusion into WT recipients, EGFP-labelled PKN1[T778A] donor lymphocytes were significantly less abundant in the peripheral circulation and more abundant in the spleen and lymph nodes of recipient mice compared with EGFP-labelled WT donor lymphocytes, likely reflecting lymphocyte sequestration in the spleen and lymph nodes in a cell-autonomous fashion. PKN1[T778A] lymphocytes showed significantly lower chemotaxis towards chemokines and sphingosine 1-phosphate (S1P) than WT cells in vitro. The biggest migration defect was observed in response to S1P, which is essential for lymphocyte egress from secondary lymphoid organs. These results reveal a novel role of PKN1 in lymphocyte migration and localization.

PMID: 28794483 [PubMed - in process]

Optogenetics and Pharmacogenetics: Principles and Applications.

Am J Physiol Regul Integr Comp Physiol. 2017 Aug 09;:ajpregu.00091.2017

Authors: Jiang J, Cui H, Rahmouni K

Abstract
Remote and selective spatiotemporal control of the activity of neurons to regulate behavior and physiological functions has been a long-sought goal in system neuroscience. Identification and subsequent bioengineering of light-sensitive ion channels (e.g., channelrhodopsins, halorhodopsin and archaerhodopsins) from the bacteria has made it possible to utilize light to artificially modulate neuronal activity, namely optogenetics. Recent advance in genetics has also allowed development of novel pharmacological tools to selectively and remotely control neuronal activity using engineered G-protein coupled receptors which can be activated by otherwise inert drug-like small molecules such as the Designer Receptors Exclusively Activated by Designer Drug (DREADD) - a form of chemogenetics. The cutting-edge optogenetics and pharmacogenetics are powerful tools in neuroscience which allow selective and bidirectional modulation of the activity of defined populations of neurons with unprecedented specificity. These novel toolboxes are enabling significant advances in deciphering how the nervous system works and its influence on various physiological processes in health and disease. Here, we discuss the fundamental elements of optogenetics and chemogenetics approaches and some of the applications that yielded significant advances in various areas of neuroscience and beyond.

PMID: 28794102 [PubMed - as supplied by publisher]

Corticotropin-Releasing Factor Receptor 1 Antagonism Is Ineffective for Women With Posttraumatic Stress Disorder.

Biol Psychiatry. 2017 Jul 04;:

Authors: Dunlop BW, Binder EB, Iosifescu D, Mathew SJ, Neylan TC, Pape JC, Carrillo-Roa T, Green C, Kinkead B, Grigoriadis D, Rothbaum BO, Nemeroff CB, Mayberg HS

Abstract
BACKGROUND: Medication and psychotherapy treatments for posttraumatic stress disorder (PTSD) provide insufficient benefit for many patients. Substantial preclinical and clinical data indicate abnormalities in the hypothalamic-pituitary-adrenal axis, including signaling by corticotropin-releasing factor, in the pathophysiology of PTSD.
METHODS: We conducted a double-blind, placebo-controlled, randomized, fixed-dose clinical trial evaluating the efficacy of GSK561679, a corticotropin-releasing factor receptor 1 (CRF1 receptor) antagonist in adult women with PTSD. The trial randomized 128 participants, of whom 96 completed the 6-week treatment period.
RESULTS: In both the intent-to-treat and completer samples, GSK561679 failed to show superiority over placebo on the primary outcome of change in Clinician-Administered PTSD Scale total score. Adverse event frequencies did not significantly differ between GSK561679- and placebo-treated subjects. Exploration of the CRF1 receptor single nucleotide polymorphism rs110402 found that response to GSK561679 and placebo did not significantly differ by genotype alone. However, subjects who had experienced a moderate or severe history of childhood abuse and who were also GG homozygotes for rs110402 showed significant improvement after treatment with GSK561679 (n = 6) but not with placebo (n = 7) on the PTSD Symptom Scale-Self-Report.
CONCLUSIONS: The results of this trial, the first evaluating a CRF1 receptor antagonist for the treatment of PTSD, combined with other negative trials of CRF1 receptor antagonists for major depressive disorder, generalized anxiety disorder, and social anxiety disorder, suggest that CRF1 receptor antagonists lack efficacy as monotherapy agents for these conditions.

PMID: 28793974 [PubMed - as supplied by publisher]

Unlocking the mystery of biomarkers: A brief introduction, challenges and opportunities in Parkinson Disease.

Parkinsonism Relat Disord. 2017 Jul 22;:

Authors: Tropea TF, Chen-Plotkin AS

Abstract
First described 200 years ago, Parkinson Disease (PD) exhibits considerable heterogeneity in clinical presentation, as well as trajectory of motor and non-motor decline. This heterogeneity, in turn, complicates the planning of clinical research, particularly trials of disease-modifying therapies, as well as the care of PD patients. While clinical features have been used to delineate subgroups of PD patients, clinical subtyping is hampered by change in features over time, and clinical subtyping may fail to capture the biological processes underlying heterogeneity. In contrast, biomarkers - objective measures that serve as indicators of normal biological processes, pathogenic processes, or pharmacologic responses to therapeutic interventions - have promise to delineate molecularly-defined subgroups of PD patients who may be most likely to benefit from specific therapeutic interventions. Here we review the present role of genetic and biochemical biomarkers in PD. Moreover, we highlight areas where the use of biomarkers may benefit clinical trial planning, as well as clinical care through the application of a "precision medicine" approach, in the near term.

PMID: 28793971 [PubMed - as supplied by publisher]

Pharmacogenetic Approach to Toxicity in Breast Cancer Patients Treated with Taxanes.

Anticancer Res. 2017 05;37(5):2633-2639

Authors: Angelini S, Botticelli A, Onesti CE, Giusti R, Sini V, Durante V, Strigari L, Gentile G, Cerbelli B, Pellegrini P, Sgroi V, Occhipinti M, DI Pietro FR, Rossi A, Simmaco M, Mazzuca F, Marchetti P

Abstract
BACKGROUND: Taxanes are widely used to treat breast cancer patients. Taxanes are metabolized in human liver by the cytochrome CYP3A and are substrate of ATP-binding cassette multidrug transporters ABCB1. Single-nucleotide polymorphisms (SNPs) in genes involved in taxanes' metabolism could affect the inter-individual variability in reported toxicities.
MATERIALS AND METHODS: In this retrospective study, 152 women, affected by breast cancer and receiving a taxane-based chemotherapy, were enrolled. A peripheral blood sample was taken for genotyping the following polymorphisms: CYP3A4* 1B (A>G), CYP3A5 *3 (G>A) and ABCB1 (C1236T; C3435T).
RESULTS: We observed an association between ABCB1 3435 T/T and lower grade of toxicities (p=0.05). No other association were found for CYP 3A4 *1B, 3A5*3 and ABCB1 C1236T.
CONCLUSION: ABCB1 3435 T/T seems to be associated to lower rate of toxicity in patients receiving taxanes. Further prospective and larger studies should be performed to clarify the role of this polymorphism.

PMID: 28476838 [PubMed - indexed for MEDLINE]

Curcumin Targets Circulating Cancer Stem Cells by Inhibiting Self-Renewal Efficacy in Non-Small Cell Lung Carcinoma.

Anticancer Agents Med Chem. 2017;17(6):859-864

Authors: Mirza S, Vasaiya A, Vora H, Jain N, Rawal R

Abstract
BACKGROUND: The ultimate goal of the study was to find a role of curcumin in targeting lung cancer stem cells by reducing their self-renewal efficiency causing DNA damage.
MATERIALS AND METHODS: Circulating lung cancer stem cells were isolated by sphere formation assay and further analysed by flow-cytometry and qRT-PCR for the presence of stem cell and stem cell transcription markers. The IC50 values of gemcitabine and curcumin were analysed by MTT assay, while curcumin induced DNA damage was scrutinized by single cell gel electrophoresis assay.
RESULTS AND CONCLUSION: Our results demonstrated that curcumin significantly affect the self-renewal ability of circulating lung cancer stem cells. The no. of spheres formed in the presence of curcumin was shown to be significantly decreased. Additionally, our results depicted that 4.52±0.72 % and 95.47±0.72 % (p < 0.0001) of DNA material was found to be present in head and tail, respectively, suggesting curcumin's functional potential to cause DNA damage. Thus, we can conclude that curcumin can be used to target lung cancer stem cells which is responsible for the disease progression and metastasis by causing DNA damage or inhibiting their DNA repair mechanisms.

PMID: 27671306 [PubMed - indexed for MEDLINE]

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pharmacogenomics

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pharmacogenomics

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Unmet needs in Schizophrenia.

CNS Neurol Disord Drug Targets. 2017 Aug 03;:

Authors: Pompili M, Meltzer HY

Abstract
The objectives of this article are to describe current trends in the treatment of schizophrenia and the most interesting new approaches to optimizing outcome and fostering the development of new schizophrenia treatments.
RESULTS: Increasing utilization of diverse types of atypical antipsychotic drugs (AAPDs), e.g. clozapine-type serotonin (5-HT)2A and weak dopamine (DA) D2 antagonist, amisulpride, a D2/D3/5-HT7 antagonist, and cariprazine, a D3 partial agonist with additional neurotransmitter targets, is occurring as their advantages in efficacy, especially for cognitive impairment and mood symptoms, and side effects is becoming appreciated. Typical APDs, e.g. haloperidol, are diminishing in favor because of their EPS, especially, tardive dyskinesia (T D) and appreciation that reducing D2 receptor stimulation is not the only means to treat psychosis. Some of the mechanisms inherent in various AAPDs, e.g. 5-HT2A inverse agonism, and D3 receptor partial agonism, are now recognized as effective treatments for psychosis. A new focus on treating the cognitive impairment associated with schizophrenia (CIAS) has emerged via mechanisms such as stimulation of acetyldraline receptor with muscarinic and nicotinic receptor agonists, but demonstrating their efficacy in trials is proving elusive. Pharmacogenetic strategies which may lead to personalized treatment of schizophrenia is emerging but has not yet succeeded in being widely reimbursable. Transcranial stimulation and cognitive enhancement therapy are more common but more evidence for their efficacy is needed.
CONCLUSION: The heterogeneity of the pathophysiology of the various domains of schizophrenia require a diversity of treatments that are best met by the expert use of AAPDs at the current time. Pharmacogenetic efforts are consistent with new evidence that multiple genes are involved in the risk for schizophrenia and the effectiveness of AAPDs.

PMID: 28782490 [PubMed - as supplied by publisher]

In this issue of Pharmacogenomics.

Pharmacogenomics. 2017 Aug;18(12):1117

Authors: Jones S

PMID: 28782463 [PubMed - in process]

Severe sunitinib-induced myelosuppression in a patient with a CYP 3A4 polymorphism.

J Oncol Pharm Pract. 2017 Jan 01;:1078155217724863

Authors: Patel ND, Chakrabory K, Messmer G, Krishnan K, Bossaer JB

Abstract
Sunitinib, an oral vascular endothelial growth factor receptor, is a first-line option for metastatic renal cell carcinoma and widely used in clinical practice. Despite the proven benefit of sunitnib in metastatic renal cell carcinoma, patients may suffer from a variety of adverse events including hypertension, fatigue, hypothyroidism, hand-foot skin reactions, rash, depigmentation, and myelosuppression. Myelosuppression is usually mild, transient and resolves during the two weeks at the end of each cycle where no drug is taken. We present a case of severe and early grade 3 neutropenia and thrombocytopenia occurring two weeks into a six-week cycle. Because of the extreme nature of the toxicity, CYP 3A4 polymorphisms were explored. The patient was found to be heterozygous for CYP 3A4*22, at least partially explaining the early-onset and severity of myelosuppression. This pharmacogenetics information resulted in a rechallenge of dose-reduced sunitinib, which was well tolerated by the patient. The current state of pharmacogenomics concerning sunitinb is also presented, and the need for greater research in this area is highlighted.

PMID: 28782406 [PubMed - as supplied by publisher]