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Your search keyword '"Roxanis, Ioannis"' showing total 5 results
Start Over Author "Roxanis, Ioannis" Topic antineoplastic agents
5 results on '"Roxanis, Ioannis"'

1. Integrated Pharmacodynamic Analysis Identifies Two Metabolic Adaption Pathways to Metformin in Breast Cancer.

Author

Lord SR, Cheng WC, Liu D, Gaude E, Haider S, Metcalf T, Patel N, Teoh EJ, Gleeson F, Bradley K, Wigfield S, Zois C, McGowan DR, Ah-See ML, Thompson AM, Sharma A, Bidaut L, Pollak M, Roy PG, Karpe F, James T, English R, Adams RF, Campo L, Ayers L, Snell C, Roxanis I, Frezza C, Fenwick JD, Buffa FM, and Harris AL

Subjects
Adult, Aged, Antineoplastic Agents therapeutic use, Breast Neoplasms genetics, Breast Neoplasms metabolism, Female, Gene Expression Regulation, Neoplastic drug effects, Glucose analogs & derivatives, Glucose metabolism, Humans, Hypoglycemic Agents therapeutic use, Metformin therapeutic use, Middle Aged, Mitochondria drug effects, Mitochondria genetics, Mitochondria metabolism, Positron Emission Tomography Computed Tomography, Transcriptome drug effects, Antineoplastic Agents pharmacology, Breast Neoplasms drug therapy, Hypoglycemic Agents pharmacology, Metabolic Networks and Pathways drug effects, Metformin pharmacology
Abstract

Late-phase clinical trials investigating metformin as a cancer therapy are underway. However, there remains controversy as to the mode of action of metformin in tumors at clinical doses. We conducted a clinical study integrating measurement of markers of systemic metabolism, dynamic FDG-PET-CT, transcriptomics, and metabolomics at paired time points to profile the bioactivity of metformin in primary breast cancer. We show metformin reduces the levels of mitochondrial metabolites, activates multiple mitochondrial metabolic pathways, and increases 18-FDG flux in tumors. Two tumor groups are identified with distinct metabolic responses, an OXPHOS transcriptional response (OTR) group for which there is an increase in OXPHOS gene transcription and an FDG response group with increased 18-FDG uptake. Increase in proliferation, as measured by a validated proliferation signature, suggested that patients in the OTR group were resistant to metformin treatment. We conclude that mitochondrial response to metformin in primary breast cancer may define anti-tumor effect., (Crown Copyright © 2018. Published by Elsevier Inc. All rights reserved.)

Published
2018
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2. ADAM10 mediates trastuzumab resistance and is correlated with survival in HER2 positive breast cancer.

Author

Feldinger K, Generali D, Kramer-Marek G, Gijsen M, Ng TB, Wong JH, Strina C, Cappelletti M, Andreis D, Li JL, Bridges E, Turley H, Leek R, Roxanis I, Capala J, Murphy G, Harris AL, and Kong A

Subjects
ADAM Proteins biosynthesis, ADAM Proteins genetics, ADAM10 Protein, Amyloid Precursor Protein Secretases biosynthesis, Amyloid Precursor Protein Secretases genetics, Animals, Cell Line, Tumor, Cell Proliferation drug effects, Cell Proliferation physiology, Drug Resistance, Neoplasm, Female, Gene Knockdown Techniques, Humans, Membrane Proteins biosynthesis, Membrane Proteins genetics, Mice, Trastuzumab, Xenograft Model Antitumor Assays, ADAM Proteins metabolism, Amyloid Precursor Protein Secretases metabolism, Antibodies, Monoclonal, Humanized pharmacology, Antineoplastic Agents pharmacology, Breast Neoplasms drug therapy, Breast Neoplasms enzymology, Membrane Proteins metabolism, Receptor, ErbB-2 metabolism
Abstract

Trastuzumab prolongs survival in HER2 positive breast cancer patients. However, resistance remains a challenge. We have previously shown that ADAM17 plays a key role in maintaining HER2 phosphorylation during trastuzumab treatment. Beside ADAM17, ADAM10 is the other well characterized ADAM protease responsible for HER ligand shedding. Therefore, we studied the role of ADAM10 in relation to trastuzumab treatment and resistance in HER2 positive breast cancer. ADAM10 expression was assessed in HER2 positive breast cancer cell lines and xenograft mice treated with trastuzumab. Trastuzumab treatment increased ADAM10 levels in HER2 positive breast cancer cells (p ≤ 0.001 in BT474; p ≤ 0.01 in SKBR3) and in vivo (p ≤ 0.0001) compared to control, correlating with a decrease in PKB phosphorylation. ADAM10 inhibition or knockdown enhanced trastuzumab response in naïve and trastuzumab resistant breast cancer cells. Trastuzumab monotherapy upregulated ADAM10 (p ≤ 0.05); and higher pre-treatment ADAM10 levels correlated with decreased clinical response (p ≤ 0.05) at day 21 in HER2 positive breast cancer patients undergoing a trastuzumab treatment window study. Higher ADAM10 levels correlated with poorer relapse-free survival (p ≤ 0.01) in a cohort of HER2 positive breast cancer patients. Our studies implicate a role of ADAM10 in acquired resistance to trastuzumab and establish ADAM10 as a therapeutic target and a potential biomarker for HER2 positive breast cancer patients.

Published
2014
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3. Potential of PET to predict the response to trastuzumab treatment in an ErbB2-positive human xenograft tumor model.

Author

Kramer-Marek G, Gijsen M, Kiesewetter DO, Bennett R, Roxanis I, Zielinski R, Kong A, and Capala J

Subjects
Animals, Antibodies, Monoclonal, Humanized therapeutic use, Antineoplastic Agents therapeutic use, Biological Transport drug effects, Blood Vessels drug effects, Blood Vessels physiopathology, Breast Neoplasms metabolism, Breast Neoplasms pathology, Cell Line, Tumor, Dose-Response Relationship, Drug, Female, Gene Expression Regulation, Neoplastic drug effects, Humans, Mice, Neovascularization, Pathologic drug therapy, Protein Structure, Tertiary, Receptor, ErbB-2 chemistry, Trastuzumab, Treatment Outcome, Antibodies, Monoclonal, Humanized pharmacology, Antineoplastic Agents pharmacology, Breast Neoplasms diagnostic imaging, Breast Neoplasms drug therapy, Positron-Emission Tomography, Receptor, ErbB-2 metabolism, Xenograft Model Antitumor Assays
Abstract

Unlabelled: Currently, an alteration in the gross volume of a tumor is used to assess its response to trastuzumab; however, this approach provides only a late indication of response. Tissue-sample ex vivo assays are potentially valuable, but their procurement through biopsies is invasive and might be biased by tumor heterogeneity. We studied the feasibility of using PET to quantify changes in ErbB2 (HER2/neu) expression and to predict the response to trastuzumab in BT474 breast cancer xenografts with N-[2-(4-(18)F-fluorobenzamido)ethyl]maleimide ((18)F-FBEM)-HER(2:342) Affibody., Methods: Mice bearing BT474 tumors were given trastuzumab (50 mg/kg loading dose, 25 mg/kg maintenance dose, administered intraperitoneally twice a week) or saline (control) for a total of 5 doses. Tumor size was monitored twice a week. Animals were scanned before the treatment, at 48 h, and 2 wk after the beginning of therapy. After the final scan, PET results were correlated with tumor response and immunohistochemical assessment of ErbB2 level, as well as with vasculature in the treated tumors., Results: Analysis of PET images indicated that tracer uptake was significantly reduced after 1 dose of trastuzumab, compared with baseline, suggesting applicability as an early indicator of changes in ErbB2 expression. After 5 doses of trastuzumab, the overall decrease in (18)F-FBEM-HER(2:342) Affibody uptake also correlated with tumor response and downregulation of ErbB2 expression by immunohistochemical assessment. However, individual animals had different responses. There was a correlation between bigger PET changes and a higher vessel count in the tumors, suggesting that an increased number of vessels could lead to better trastuzumab delivery. We confirmed that the difference in average vessel count in the tumors was not related to the size of the tumors and therefore was not due to the selection of more vascular tumors. This finding is consistent with previous findings demonstrating that the number of vessels in a tumor could be a useful prognostic marker for treatment response., Conclusion: Our data suggest that Affibody-based PET can noninvasively provide specific information on changes in receptor expression and could be a valuable strategy for predicting tumor response to trastuzumab.

Published
2012
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4. Nuclear HER4 mediates acquired resistance to trastuzumab and is associated with poor outcome in HER2 positive breast cancer

Author

Ji-Liang Li, Carla Strina, Gabriela Kramer-Marek, Syed Haider, Merel Gijsen, Esther Bridges, Daniele Generali, Jacek Capala, Anthony Kong, Daniele Andreis, Adrian L. Harris, Mariarosa Cappelletti, Siti Norasikin Mohd Nafi, Roxanis Ioannis, Nafi, Siti Norasikin Mohd, Generali, Daniele, Kramer Marek, Gabriela, Gijsen, Merel, Strina, Carla, Cappelletti, Mariarosa, Andreis, Daniele, Haider, Syed, Li, Ji Liang, Bridges, Esther, Capala, Jacek, Ioannis, Roxani, Harris, Adrian L., and Kong, Anthony

Subjects
animal structures, Receptor, ErbB-4, Receptor, ErbB-2, Resistance, Antineoplastic Agents, Breast Neoplasms, Drug resistance, Mice, Breast cancer, Downregulation and upregulation, Trastuzumab, Cell Line, Tumor, HER2, Medicine, Neoplasm, Animals, Humans, HER4, skin and connective tissue diseases, neoplasms, Cell Nucleus, Oncology, Medicine (all), Gene knockdown, business.industry, medicine.disease, Prognosis, 3. Good health, Drug Resistance, Neoplasm, Immunology, Neratinib, Cancer research, MCF-7 Cells, Heterografts, Female, business, Tyrosine kinase, medicine.drug, Research Paper
Abstract

The role of HER4 in breast cancer is controversial and its role in relation to trastuzumab resistance remains unclear. We showed that trastuzumab treatment and its acquired resistance induced HER4 upregulation, cleavage and nuclear translocation. However, knockdown of HER4 by specific siRNAs increased trastuzumab sensitivity and reversed its resistance in HER2 positive breast cancer cells. Preventing HER4 cleavage by a γ-secretase inhibitor and inhibiting HER4 tyrosine kinase activity by neratinib decreased trastuzumab-induced HER4 nuclear translocation and enhanced trastuzumab response. There was also increased nuclear HER4 staining in the tumours from BT474 xenograft mice and human patients treated with trastuzumab. Furthermore, nuclear HER4 predicted poor clinical response to trastuzumab monotherapy in patients undergoing a window study and was shown to be an independent poor prognostic factor in HER2 positive breast cancer. Our data suggest that HER4 plays a key role in relation to trastuzumab resistance in HER2 positive breast cancer. Therefore, our study provides novel findings that HER4 activation, cleavage and nuclear translocation influence trastuzumab sensitivity and resistance in HER2 positive breast cancer. Nuclear HER4 could be a potential prognostic and predictive biomarker and understanding the role of HER4 may provide strategies to overcome trastuzumab resistance in HER2 positive breast cancer.

Published
2014

5. Integrated Pharmacodynamic Analysis Identifies Two Metabolic Adaption Pathways to Metformin in Breast Cancer

Author

Lord, Simon R, Cheng, Wei-Chen, Liu, Dan, Gaude, Edoardo, Haider, Syed, Metcalf, Tom, Patel, Neel, Teoh, Eugene J, Gleeson, Fergus, Bradley, Kevin, Wigfield, Simon, Zois, Christos, McGowan, Daniel R, Ah-See, Mei-Lin, Thompson, Alastair M, Sharma, Anand, Bidaut, Luc, Pollak, Michael, Roy, Pankaj G, Karpe, Fredrik, James, Tim, English, Ruth, Adams, Rosie F, Campo, Leticia, Ayers, Lisa, Snell, Cameron, Roxanis, Ioannis, Frezza, Christian, Fenwick, John D, Buffa, Francesca M, and Harris, Adrian L

Subjects
Adult, positron emission tomography, endocrine system diseases, cancer metabolism, Antineoplastic Agents, Breast Neoplasms, clinical study, Middle Aged, metabolomics, Metformin, 3. Good health, Mitochondria, Gene Expression Regulation, Neoplastic, Glucose, Positron Emission Tomography Computed Tomography, gene expression profiling, Humans, Hypoglycemic Agents, Female, Transcriptome, Metabolic Networks and Pathways, Aged
Abstract

Late-phase clinical trials investigating metformin as a cancer therapy are underway. However, there remains controversy as to the mode of action of metformin in tumors at clinical doses. We conducted a clinical study integrating measurement of markers of systemic metabolism, dynamic FDG-PET-CT, transcriptomics, and metabolomics at paired time points to profile the bioactivity of metformin in primary breast cancer. We show metformin reduces the levels of mitochondrial metabolites, activates multiple mitochondrial metabolic pathways, and increases 18-FDG flux in tumors. Two tumor groups are identified with distinct metabolic responses, an OXPHOS transcriptional response (OTR) group for which there is an increase in OXPHOS gene transcription and an FDG response group with increased 18-FDG uptake. Increase in proliferation, as measured by a validated proliferation signature, suggested that patients in the OTR group were resistant to metformin treatment. We conclude that mitochondrial response to metformin in primary breast cancer may define anti-tumor effect.

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