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https://www.readbyqxmd.com/read/29765526/esophageal-cancer-cells-resistant-to-t-dm1-display-alterations-in-cell-adhesion-and-the-prostaglandin-pathway
#1
Juliette Sauveur, Eva-Laure Matera, Kamel Chettab, Philippe Valet, Jerome Guitton, Ariel Savina, Charles Dumontet
Trastuzumab-emtansine (T-DM1) is an antibody-drug conjugate that specifically targets HER2 thanks to its antibody component trastuzumab. In spite of responses to this novel agent, acquired resistance to treatment remains a major obstacle. Prolonged in vitro exposure of the gastroesophageal junction cancer cell line OE-19 to T-DM1, in the absence or presence of ciclosporin A resulted in the selection of two resistant cell lines to T-DM1. T-DM1-resistant cells presented an increased expression of adhesion genes, altered spreading and higher sensitivity to anoikis than parental cells...
April 20, 2018: Oncotarget
https://www.readbyqxmd.com/read/29739815/impact-of-hormone-receptor-status-on-the-efficacy-of-her2-targeted-treatment
#2
Bin Zhao, Hong Zhao, Jiaxin Zhao
The introduction of human epidermal growth factor receptor 2 (HER2)-targeted drugs into routine clinical practice has a dramatic effect on the outlook for patients with HER2-positive breast cancer (BC). However, the association between efficacy of HER2-targeted therapy and hormone receptor (HR) status is still unclear. Here we conducted a meta-analysis of randomized controlled trials (RCTs) to address this issue in both neoadjuvant and adjuvant settings. PubMed and EMBASE were searched from inception to October 2017 for studies involving trastuzumab, lapatinib, pertuzumab, trastuzumab emtansine and neratinib...
June 2018: Endocrine-related Cancer
https://www.readbyqxmd.com/read/29720111/cancer-derived-exosomes-from-her2-positive-cancer-cells-carry-trastuzumab-emtansine-into-cancer-cells-leading-to-growth-inhibition-and-caspase-activation
#3
Mark Barok, Maija Puhka, Gyorgy Vereb, Janos Szollosi, Jorma Isola, Heikki Joensuu
BACKGROUND: Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate that carries a cytotoxic drug (DM1) to HER2-positive cancer. The target of T-DM1 (HER2) is present also on cancer-derived exosomes. We hypothesized that exosome-bound T-DM1 may contribute to the activity of T-DM1. METHODS: Exosomes were isolated from the cell culture medium of HER2-positive SKBR-3 and EFM-192A breast cancer cells, HER2-positive SNU-216 gastric cancer cells, and HER2-negative MCF-7 breast cancer cells by serial centrifugations including two ultracentrifugations, and treated with T-DM1...
May 2, 2018: BMC Cancer
https://www.readbyqxmd.com/read/29719406/cardiotoxic-effects-of-the-novel-approved-anti-erbb2-agents-and-reverse-cardioprotective-effects-of-ranolazine
#4
Claudia De Lorenzo, Rolando Paciello, Gennaro Riccio, Domenica Rea, Antonio Barbieri, Carmela Coppola, Nicola Maurea
Purpose: Pertuzumab, a novel anti-epidermal growth factor receptor 2 humanized monoclonal antibody, and trastuzumab-emtansine (TDM1), a novel antibody-drug conjugate made up of trastuzumab covalently linked to the highly potent microtubule inhibitory agent DM1, have been recently approved by the US Food and Drug Administration for increasing the efficiency and safety of breast cancer therapy with trastuzumab. We investigated for the first time the potential cardiotoxic effects of pertuzumab and TDM1, which are not yet fully elucidated, and we tested whether ranolazine could blunt their cardiotoxicity...
2018: OncoTargets and Therapy
https://www.readbyqxmd.com/read/29700710/her2-genomic-amplification-in-circulating-tumor-dna-and-estrogen-receptor-positivity-predict-primary-resistance-to-trastuzumab-emtansine-t-dm1-in-patients-with-her2-positive-metastatic-breast-cancer
#5
Hitomi Sakai, Junji Tsurutani, Tsutomu Iwasa, Yoshifumi Komoike, Kazuko Sakai, Kazuto Nishio, Kazuhiko Nakagawa
BACKGROUND: Trastuzumab emtansine (T-DM1) is approved for the treatment of patients with human epidermal growth factor receptor 2 (HER2)-positive advanced breast cancer (ABC), and has high efficacy. However, some patients exhibit primary resistance to T-DM1, and thus methods that can predict resistance in clinical practice are needed. Genomic analysis of circulating tumor DNA (ctDNA) in plasma is a non-invasive and reproducible method. This study aimed to predict primary resistance to T-DM1 by combining genomic analysis of ctDNA and other clinicopathological features of patients with HER2-positive ABC...
April 26, 2018: Breast Cancer: the Journal of the Japanese Breast Cancer Society
https://www.readbyqxmd.com/read/29695635/mechanisms-of-acquired-resistance-to-trastuzumab-emtansine-in-breast-cancer-cells
#6
Guangmin Li, Jun Guo, Ben-Quan Shen, Daniela Bumbaca Yadav, Mark X Sliwkowski, Lisa M Crocker, Jennifer A Lacap, Gail D Lewis Phillips
The receptor tyrosine kinase HER2 is overexpressed in approximately 20% of breast cancer, and its amplification is associated with reduced survival. Trastuzumab emtansine (Kadcyla®, T-DM1), an antibody-drug conjugate that is comprised of trastuzumab covalently linked to the anti-mitotic agent DM1 through a stable linker, was designed to selectively deliver DM1 to HER2-overexpressing tumor cells. T-DM1 is approved for the treatment of patients with HER2-positive metastatic breast cancer following progression on trastuzumab and a taxane...
April 25, 2018: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/29680236/chimeric-small-antibody-fragments-as-strategy-to-deliver-therapeutic-payloads
#7
Sandra Aguiar, Joana Dias, Ana M Manuel, Roberto Russo, Pedro M P Gois, Frederico A da Silva, Joao Goncalves
Antibody-drug conjugates (ADCs) represent an innovative class of biopharmaceuticals, which aim at achieving a site-specific delivery of cytotoxic agents to the target cell. The use of ADCs represents a promising strategy to overcome the disadvantages of conventional pharmacotherapy of cancer or neurological diseases, based on cytotoxic or immunomodulatory agents. ADCs consist of monoclonal antibodies attached to biologically active drugs by means of cleavable chemical linkers. Advances in technologies for the coupling of antibodies to cytotoxic drugs promise to deliver greater control of drug pharmacokinetic properties and to significantly improve pharmacodelivery applications, minimizing exposure of healthy tissue...
2018: Advances in Protein Chemistry and Structural Biology
https://www.readbyqxmd.com/read/29675616/a-pharmacometric-analysis-of-patient-reported-outcomes-in-breast-cancer-patients-through-item-response-theory
#8
Emilie Schindler, Lena E Friberg, Bertram L Lum, Bei Wang, Angelica Quartino, Chunze Li, Sandhya Girish, Jin Y Jin, Mats O Karlsson
PURPOSE: An item response theory (IRT) pharmacometric framework is presented to characterize Functional Assessment of Cancer Therapy-Breast (FACT-B) data in locally-advanced or metastatic breast cancer patients treated with ado-trastuzumab emtansine (T-DM1) or capecitabine-plus-lapatinib. METHODS: In the IRT model, four latent well-being variables, based on FACT-B general subscales, were used to describe the physical, social/family, emotional and functional well-being...
April 19, 2018: Pharmaceutical Research
https://www.readbyqxmd.com/read/29670855/current-therapies-for-human-epidermal-growth-factor-receptor-2-positive-metastatic-breast-cancer-patients
#9
REVIEW
Alexey A Larionov
The median survival of patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) has more than doubled, since the discovery of HER2-targeted treatments: it rose from less than 2 years in 2001 (prior introduction of trastuzumab) to more than 4 years in 2017. The initial generation of HER2-targeted therapies included trastuzumab with taxanes in the first line, followed by the addition of lapatinib and by a switch to another cytotoxic agent after progression. Results of CLEOPATRA, EMILIA, and TH3RESA trials have changed this clinical practice...
2018: Frontiers in Oncology
https://www.readbyqxmd.com/read/29624378/mofi-a-software-tool-for-annotating-glycoprotein-mass-spectra-by-integrating-hybrid-data-from-the-intact-protein-and-glycopeptide-level
#10
Wolfgang Skala, Therese Wohlschlager, Stefan Senn, Gabriel E Huber, Christian G Huber
Hybrid mass spectrometry (MS) is an emerging technique for characterizing glycoproteins, which typically display pronounced microheterogeneity. Since hybrid MS combines information from different experimental levels, it crucially depends on computational methods. Here, we describe a novel software tool, MoFi, which integrates hybrid MS data to assign glycans and other post-translational modifications (PTMs) in deconvoluted mass spectra of intact proteins. Its two-stage search algorithm first assigns monosaccharide/PTM compositions to each peak and then compiles a hierarchical list of glycan combinations compatible with these compositions...
April 6, 2018: Analytical Chemistry
https://www.readbyqxmd.com/read/29615304/corneal-changes-in-trastuzumab-emtansine-treatment
#11
Elke O Kreps, Thierry Derveaux, Hannelore Denys
No abstract text is available yet for this article.
March 12, 2018: Clinical Breast Cancer
https://www.readbyqxmd.com/read/29508628/drug-associated-pulmonary-arterial-hypertension
#12
Michael McGee, Nicholas Whitehead, Jennifer Martin, Nicholas Collins
INTRODUCTION: While pulmonary arterial hypertension remains an uncommon diagnosis, various therapeutic agents are recognized as important associations. These agents are typically categorized into "definite", "likely", "possible", or "unlikely" to cause pulmonary arterial hypertension, based on the strength of evidence. OBJECTIVE: This review will focus on those therapeutic agents where there is sufficient literature to adequately comment on the role of the agent in the pathogenesis of pulmonary arterial hypertension...
March 6, 2018: Clinical Toxicology
https://www.readbyqxmd.com/read/29500444/metformin-induced-caveolin-1-expression-promotes-t-dm1-drug-efficacy-in-breast-cancer-cells
#13
Yuan-Chiang Chung, Ching-Ming Chang, Wan-Chen Wei, Ting-Wei Chang, King-Jen Chang, Wei-Ting Chao
Trastuzumab emtansine (T-DM1) is an antibody drug conjugate (ADC) that was recently approved for the treatment of HER-2-positive metastatic breast cancer. The drug sensitivity of ADCs depends mainly on the internalization efficiency of the drug. Caveolin-1 was shown to promote T-DM1 internalization and enhance drug sensitivity. Whether caveolin-1 can be overexpressed to improve T-DM1 efficacy is interesting and has the potential for clinical application. In this study, diabetes drug metformin was investigated in terms of induction of caveolin-1 expression for increased efficacy of subsequent T-DM1 application...
March 2, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29496986/in-vivo-characterization-of-platinum-ii-based-linker-technology-lx-for-the-development-of-antibody-drug-conjugates-taking-advantage-of-dual-labeling-with-195m-pt-and-89-zr
#14
Joey A Muns, Veronica Montserrat, Hendrik-Jan Houthoff, Karlijn Codee-van der Schilden, Oene Zwaagstra, Niels J Sijbrandi, Eugen Merkul, Guus A M S van Dongen
Introduction: Linker instability and impaired tumor targeting can affect tolerability and efficacy of antibody-drug conjugates (ADCs). In order to improve these ADC characteristics, we recently described the use of a metal-organic linker, [ethylenediamineplatinum(II)]2+, herein called "Lx®". Initial therapy studies in xenograft bearing mice revealed that trastuzumab-Lx-auristatin F (trastuzumab-Lx-AF) outperformed its maleimide benchmark trastuzumab-mal-AF and the FDA-approved ado-trastuzumab emtansine, both containing conventional linkers...
March 1, 2018: Journal of Nuclear Medicine: Official Publication, Society of Nuclear Medicine
https://www.readbyqxmd.com/read/29489698/never-too-old-to-fight-breast-cancer-a-case-report
#15
Monica Zuradelli, Giovanna Masci, Emanuela Ferraro, Agnese Losurdo, Rita De Sanctis, Rosalba Torrisi, Armando Santoro
RATIONALE: Breast cancer is the most common cancer affecting females worldwide and its lifetime risk increases with age. Human epidermal growth factor receptor gene-2 (HER-2) positive breast cancer represents about 20% of all breast cancers, 1 out of 10 is diagnosed in women over 70 years of age. It tends to be more aggressive and to spread more quickly than other subtypes, but the introduction in clinical practice of new anti-HER-2 agents combined with chemotherapy has significantly improved progression free and overall survival...
March 2018: Medicine (Baltimore)
https://www.readbyqxmd.com/read/29456473/adverse-events-of-trastuzumab-emtansine-t-dm1-in-the-treatment-of-her2-positive-breast-cancer-patients
#16
REVIEW
Lidia Kowalczyk, Rupert Bartsch, Christian F Singer, Alex Farr
The human epidermal growth factor receptor 2 (HER2) is commonly associated with poor prognosis and is overexpressed in approximately 15-20% of all breast cancers. The introduction of HER2-targeted therapies led to significant improvement in the prognosis of patients with HER2-positive breast cancer, for both early and advanced disease. These targeted therapies include the antibodies trastzumab and pertuzumab, the tyrosine kinase inhibitor lapatinib, and the antibody-drug conjugate trastuzumab emtansine (T-DM1)...
December 2017: Breast Care
https://www.readbyqxmd.com/read/29433963/pertuzumab-and-trastuzumab-with-or-without-metronomic-chemotherapy-for-older-patients-with-her2-positive-metastatic-breast-cancer-eortc-75111-10114-an-open-label-randomised-phase-2-trial-from-the-elderly-task-force-breast-cancer-group
#17
Hans Wildiers, Konstantinos Tryfonidis, Lissandra Dal Lago, Peter Vuylsteke, Giuseppe Curigliano, Simon Waters, Barbara Brouwers, Sevilay Altintas, Nathan Touati, Fatima Cardoso, Etienne Brain
BACKGROUND: Despite the high incidence of metastatic breast cancer and its related mortality in the elderly population, our knowledge about optimal treatment for older patients with cancer is far from adequate. We aimed to evaluate the efficacy of dual anti-HER2 treatment with or without metronomic chemotherapy in older patients with HER2-positive metastatic breast cancer. METHODS: We did a multicentre, open-label, randomised, phase 2 trial in 30 centres from eight countries in Europe, in patients with histologically proven, HER2-positive metastatic breast cancer, without previous chemotherapy for metastatic disease, who were 70 years or older, or 60 years or older with confirmed functional restrictions defined by protocol, and had a life expectancy of more than 12 weeks and a performance status according to WHO scale of 0-3...
March 2018: Lancet Oncology
https://www.readbyqxmd.com/read/29414262/antibody-drug-conjugates-for-cancer-treatment
#18
John M Lambert, Anna Berkenblit
The concept of exploiting the specific binding properties of monoclonal antibodies as a mechanism for selective delivery of cytotoxic agents to tumor cells is an attractive solution to the challenge of increasing the therapeutic index of cell-killing agents for treating cancer. All three parts of an antibody-drug conjugate (ADC)-the antibody, the cytotoxic payload, and the linker chemistry that joins them together-as well as the biologic properties of the cell-surface target antigen are important in designing an effective anticancer agent...
January 29, 2018: Annual Review of Medicine
https://www.readbyqxmd.com/read/29391599/targeting-plk1-overcomes-t-dm1-resistance-via-cdk1-dependent-phosphorylation-and-inactivation-of-bcl-2-xl-in-her2-positive-breast-cancer
#19
Özge Saatci, Simone Borgoni, Özge Akbulut, Selvi Durmuş, Umar Raza, Erol Eyüpoğlu, Can Alkan, Aytekin Akyol, Özgür Kütük, Stefan Wiemann, Özgür Şahin
Trastuzumab-refractory, HER2 (human epidermal growth factor receptor 2)-positive breast cancer is commonly treated with trastuzumab emtansine (T-DM1), an antibody-drug conjugate of trastuzumab and the microtubule-targeting agent, DM1. However, drug response reduces greatly over time due to acquisition of resistance whose molecular mechanisms are mostly unknown. Here, we uncovered a novel mechanism of resistance against T-DM1 by combining whole transcriptome sequencing (RNA-Seq), proteomics and a targeted small interfering RNA (siRNA) sensitization screen for molecular level analysis of acquired and de novo T-DM1-resistant models of HER2-overexpressing breast cancer...
April 2018: Oncogene
https://www.readbyqxmd.com/read/29387480/sequential-her2-blockade-as-effective-therapy-in-chemorefractory-her2-gene-amplified-ras-wild-type-metastatic-colorectal-cancer-learning-from-a-clinical-case
#20
Erika Martinelli, Teresa Troiani, Vincenzo Sforza, Giulia Martini, Claudia Cardone, Pietro Paolo Vitiello, Davide Ciardiello, Anna Maria Rachiglio, Nicola Normanno, Andrea Sartore-Bianchi, Silvia Marsoni, Alberto Bardelli, Salvatore Siena, Fortunato Ciardiello
Background: Constitutive activation of HER2-dependent intracellular signalling by HER2 gene amplification or by HER2 mutations has been demonstrated as a mechanism of primary and secondary cancer resistance to cetuximab or panitumumab in preclinical and clinical models of metastatic colorectal cancer (mCRC). Both HER2 Amplification for Colorectal Cancer Enhanced Stratification (HERACLES) cohort A and My Pathway clinical trials provided clinical evidence that anti-HER2 therapies could be active in these patients...
2018: ESMO Open
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