Personalized medicine, pharmacogenomic and companion biomarker

Manceau, Hana; Amrani, K.; Peoc’h, Katell

doi:10.1684/abc.2017.1306

Cited by 4 publications

(6 citation statements)

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“…A major obstacle in the identi cation of a drug target or tumor biomarker using the patient samples is the variability across donors, including genetic diversity, lifestyle, disease state, and therapeutic history of each patient [41]. To overcome this, a large number of specimens as well as precise statistical analysis is needed, but this not always possible in pancreatic cancer research [42].…”

Section: Discussionmentioning

confidence: 99%

Antibody-Mediated Blockade for Galectin-3 Binding Protein in Tumor Secretome Abrogates PDAC Metastasis

Choi¹,

Kim²,

Ea³

et al. 2021

Preprint

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Background One of the major challenges in pancreatic ductal adenocarcinoma (PDAC) management is a local or distant metastasis and limited targeted therapeutics to prevent the process. We aimed to identify a druggable target by screening abnormally secreted protein from PDAC and explore its therapeutic intervention. Methods A LC-MS/MS-based proteomics was carried out for TIF (Tumor Interstitial Fluids) obtained from patient derived xenograft (PDX) models of PDAC. To develop a blocking antibody for selected target protein, antibody phage-display technology was used. Results The proteomic screening of PDAC secretome identified Galectin-3 binding protein (Gal-3BP hereafter) as a top candidate. The Gal-3BP is highly expressed and secreted in PDAC tumors and primary cells. Subsequent functional tests by stable knockdown revealed the Gal-3BP is required for PDAC cell proliferation, migration and invasion. In addition, the depletion of Gal-3BP significantly abrogated in vivo tumor formation and metastasis of pancreatic cancer cells. Mechanistically, we found Gal-3BP enhances the galectin-3 mediated EGFR signaling, leading to the activation of cMyc and its target genes related to EMT. To examine the clinical usability of these findings, we screened a Gal-3BP-immunized chicken antibody library using phage display technique. The two isolated blocking antibody clones against Gal-3BP profoundly inhibited the metastasis of PDAC cells in vivo. Conclusions Altogether, our data demonstrates the Gal-3BP is an important therapeutic target in PDAC and proposed its blockade by antibody as a novel, therapeutic option for the inhibition of PDAC metastasis.

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Section: Discussionmentioning

confidence: 99%

Antibody-Mediated Blockade for Galectin-3 Binding Protein in Tumor Secretome Abrogates PDAC Metastasis

Choi¹,

Kim²,

Ea³

et al. 2021

Preprint

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“…Published data in adults indicate that inflammation has an impact on cytochromes P450 (CYP) activity, the major enzymes involved in drug metabolism, in an isoform-specific manner, and as a result of pre-transcriptional and post-transcriptional mechanisms that are cytokine specific [2][3][4][5][6][7]. Indeed, CYP activity is influenced by the interaction of genetic, environmental, and physiological factors through a wide variety of ligand-activated transcription factors and mediators regulating hepatic CYP content [6,8]. Understanding the impact of inflammation on CYP activity is important to understand in order to personalize drug use, as many diseases such as infection, cancer, diabetes mellitus, autoimmune disease, surgery, or trauma are associated with inflammation [1,9,10].…”

Section: Introductionmentioning

confidence: 99%

Impact of Inflammation on Cytochromes P450 Activity in Pediatrics: A Systematic Review

et al. 2021

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Background and Objective Cytochromes P450 (CYP) are the major enzymes involved in hepatic metabolism of drugs. Personalization of treatment in pediatrics is a major challenge, as it must not only take into account genetic, environmental, and physiological factors but also ontogeny. Published data in adults show that inflammation had an isoform-specific impact on CYP activities and we aimed to evaluate this impact in the pediatric population. Methods Articles listed in PubMed through 7 January, 2021 that studied the impact of inflammation on CYP activities in pediatrics were included in this systematic review. Sources of inflammation, victim drugs (CYP involved), effect of drugdisease interactions, number and age of subjects, and study design were extracted. Results Twenty-seven studies and case reports were included. The impact of inflammation on CYP activities appeared to be age dependent and isoform-specific, with some drug-disease interactions having significant pharmacokinetic and clinical impact. For example, midazolam clearance decreases by 70%, while immunosuppressant and theophylline concentrations increase three-fold and two-fold with intensive care unit admission and infection. Cytochrome P450 activity appears to return to baseline level when the disease is resolved. Conclusions Studies that have assessed the impact of inflammation on CYP activity are lacking in pediatrics, yet it is a major factor to consider to improve drug efficacy or safety. The scarce current data show that the impact of inflammation is isoform and age dependent. An effort must be made to improve the understanding of the impact of inflammation on CYP activities in children to better individualize treatment.

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“…1 Indeed, these factors are unique to each individual and/or may change over time and cause disparity in the safety and efficacy of treatments. 1 Precision medicine is a leading approach in the transformation of medicine, aiming to tailor treatments according to the biological and genetic characteristics of individuals. 2 By using the "five rights of medication administration," personalized medicine supports optimization of therapy in terms of efficacy and safety and thus public health and healthcare costs.…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…The interplay of genetic, physiological, and environmental factors leads to interindividual and intraindividual variability in response to treatment 1 . Indeed, these factors are unique to each individual and/or may change over time and cause disparity in the safety and efficacy of treatments 1 . Precision medicine is a leading approach in the transformation of medicine, aiming to tailor treatments according to the biological and genetic characteristics of individuals 2 .…”

Section: Introductionmentioning

confidence: 99%

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Prediction of cytochromes P450 3A and 2C19 modulation by both inflammation and drug interactions using physiologically based pharmacokinetics

Lenoir

Niederer

Rollason

et al. 2021

CPT Pharmacom & Syst Pharma

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Xenobiotics can interact with cytochromes P450 (CYPs), resulting in drug-drug interactions, but CYPs can also contribute to drug-disease interactions, especially in the case of inflammation, which downregulates CYP activities through pretranscriptional and posttranscriptional mechanisms. Interleukin-6 (IL-6), a key proinflammatory cytokine, is mainly responsible for this effect. The aim of our study was to develop a physiologically based pharmacokinetic (PBPK) model to foresee the impact of elevated IL-6 levels in combination with drug interactions with esomeprazole on CYP3A and CYP2C19. Data from a cohort of elective hip surgery patients whose CYP3A and CYP2C19 activities were measured before and after surgery were used to validate the accurate prediction of the developed models. Successive steps were to fit models for IL-6, esomeprazole, and omeprazole and its metabolite from the literature and to validate them. The models for midazolam and its metabolite were obtained from the literature. When appropriate, a correction factor was applied to convert drug concentrations from whole blood to plasma. Mean ratios between simulated and observed areas under the curve for omeprazole/5-hydroxy omeprazole, esomeprazole, and IL-6 were 1.53, 1.06, and 0.69, respectively, indicating an accurate prediction of the developed models. The impact of IL-6 and esomeprazole on the exposure to CYP3A and CYP2C19 probe substrates and respective metabolites were correctly predicted. Indeed, the ratio between predicted and observed mean concentrations were <2 for all observations (ranging from 0.51 to 1.7).The impact of IL-6 and esomeprazole on CYP3A and CYP2C19 activities after a hip surgery were correctly predicted with the developed PBPK models. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?There is high interindividual variability in cytochrome P450 (CYP) activities due to genetic, environmental, and physiological factors, including drug-drug and | 31

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Personalized medicine, pharmacogenomic and companion biomarker

Cited by 4 publications

References 0 publications

Antibody-Mediated Blockade for Galectin-3 Binding Protein in Tumor Secretome Abrogates PDAC Metastasis

Antibody-Mediated Blockade for Galectin-3 Binding Protein in Tumor Secretome Abrogates PDAC Metastasis

Impact of Inflammation on Cytochromes P450 Activity in Pediatrics: A Systematic Review

Prediction of cytochromes P450 3A and 2C19 modulation by both inflammation and drug interactions using physiologically based pharmacokinetics

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