22 results on '"Nina Raulf"'
Search Results
2. MicroRNA‐9 inhibits growth and invasion of head and neck cancer cells and is a predictive biomarker of response to plerixafor, an inhibitor of its target CXCR4
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Hersi Mohamed Hersi, Nina Raulf, Joop Gaken, Najeem'deen Folarin, and Mahvash Tavassoli
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CXCL12 ,CXCR4 ,head and neck cancer ,MiR‐9 ,plerixafor ,tumour invasion ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Head and neck squamous cell carcinomas (HNSCC) are associated with poor morbidity and mortality. Current treatment strategies are highly toxic and do not benefit over 50% of patients. There is therefore a crucial need for predictive and/or prognostic biomarkers to allow treatment stratification for individual patients. One class of biomarkers that has recently gained importance are microRNA (miRNA). MiRNA are small, noncoding molecules which regulate gene expression post‐transcriptionally. We performed miRNA expression profiling of a cohort of head and neck tumours with known clinical outcomes. The results showed miR‐9 to be significantly downregulated in patients with poor treatment outcome, indicating its role as a potential biomarker in HNSCC. Overexpression of miR‐9 in HNSCC cell lines significantly decreased cellular proliferation and inhibited colony formation in soft agar. Conversely, miR‐9 knockdown significantly increased both these features. Importantly, endogenous CXCR4 expression levels, a known target of miR‐9, inversely correlated with miR‐9 expression in a panel of HNSCC cell lines tested. Induced overexpression of CXCR4 in low expressing cells increased proliferation, colony formation and cell cycle progression. Moreover, CXCR4‐specific ligand, CXCL12, enhanced cellular proliferation, migration, colony formation and invasion in CXCR4‐overexpressing and similarly in miR‐9 knockdown cells. CXCR4‐specific inhibitor plerixafor abrogated the oncogenic phenotype of CXCR4 overexpression as well as miR‐9 knockdown. Our data demonstrate a clear role for miR‐9 as a tumour suppressor microRNA in HNSCC, and its role seems to be mediated through CXCR4 suppression. MiR‐9 knockdown, similar to CXCR4 overexpression, significantly promoted aggressive HNSCC tumour cell characteristics. Our results suggest CXCR4‐specific inhibitor plerixafor as a potential therapeutic agent, and miR‐9 as a possible predictive biomarker of treatment response in HNSCC.
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- 2018
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3. 850 Interim results for phase 1b dose expansion of MTL-CEBPA in combination with pembrolizumab in patients with advanced solid tumour malignancies
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Ruth Plummer, Mikael Sodergren, Brid Ryan, Ilian Tachkov, Vikash Reebye, Tim Meyer, David Pinato, Debashis Sarker, Bristi Basu, Sarah Blagden, Natalie Cook, Jeff Evans, Jeffrey Yachnin, Cheng-Ean Chee, Daneng Li, Anthony El-Khoueiry, Maria Diab, Kai-Wen Huang, Antonio D'Alessio, Claudia Fulgenzi, Marcus Noel, Bridget Keenan, Devalingam Mahalingam, Nina Raulf, Rose Hogson, Choon Ping Tan, Joanna Nicholls, Alison Adderkin, Julia Vassiliadou, Robert Habib, John Rossi, and Nagy Habib
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- 2022
4. Abstract LB192: MTL-CEBPA in combination with pembrolizumab converts an immune desert to an inflamed TME in solid tumors resistant to checkpoint blockade
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Ruth Plummer, Mikael Sodergren, Brid Ryan, Ilian Tchakov, Nina Raulf, Rose Hodgson, CP Tan, Joanna P. Nicholls, Alison Adderkin, N Vasileiadou, Vikash Reebye, Tim Meyer, David J. Pinato, Debashis Sarker, Bristi Basu, Sarah Blagden, Natalie Cook, Jeff Evans, Jeffrey Yachnin, Cheng Ean Chee, Dan Li, Anthony El-Khoueiry, Maria Diab, Kai-Wen Huang, Marcus S. Noel, Bridget Keenan, Devalingam Mahalingam, Melanie Grosso, Denis Arnaud, Aurelie Auguste, Jan Storkholm, Iain McNeish, Robert Habib, John J. Rossi, and Nagy Habib
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Cancer Research ,Oncology - Abstract
Despite significant advances in outcomes with immunotherapy, most cancer patients do not benefit from currently approved immune checkpoint inhibitors (ICI). The reasons for ICI resistance are multi-faceted and suggest that additional immunomodulation is required to improve outcomes. MTL-CEBPA is a novel immunotherapy based on RNA activation that upregulates expression of a master myeloid transcription factor, CEBPA. The small activating RNA for CEBPA is encapsulated within a NOV340 liposome that targets the myeloid cell lineage. MTL-CEBPA has shown favorable safety and promising clinical activity in combination with tyrosine kinase inhibitors (Sorafenib) in hepatocellular carcinoma (NCT-02716012) [Hashimoto et al, CCR 2021; Sarker et al, CCR 2020]. We recently reported preliminary clinical data from the ongoing multi-center phase 1 TIMEPOINT study (NCT-04105335) evaluating the safety, pharmacokinetics, immunomodulation, and clinical activity of MTL-CEBPA in combination with pembrolizumab in patients with solid tumors who have exhausted standard therapy. This demonstrated a favorable safety profile and initial clinical activity [Plummer et al, JITC 2021]. Here we report the findings from a biomarker pharmacodynamic analysis of paired baseline and cycle 2 tumor sample biopsies in 23 patients from the TIMEPOINT trial. Brightplex® IHC and digital pathology analyses of the samples for myeloid and T cell panels were undertaken, alongside gene expression (Nanostring I/O 360). Prior to study treatment, nine patients out of 23 had an immune cold tumor microenvironment (TME) at baseline as measured by the Immunosign®21 score. Following the combination of MTL-CEBPA with pembrolizumab, seven of these patients converted to an inflamed TME by Immunosign®21 (P=0.008). This change in the TME was associated with infiltration of CD8 and cytotoxic T cells (CD8+, GrzB+, Ki-67+) (P=0.1). GSEA analysis indicated that a Tstem-like signature was enriched post-treatment. A Brightplex® IHC analysis of myeloid cells in these patients indicated that, post treatment, there was a significant influx of HLA-DR+ myeloid cells into the TME (P=0.04). We also observed a significant increase in the expression of CXCL9, 10, and 11. The remaining 14 patients had an inflamed TME at baseline. Here, we also observed an increase in HLA-DR+ cells, T cells, and chemokines, though to a lesser extent. Further, however, in these inflamed tumors—which have significantly greater infiltration of myeloid-derived suppressor cells (MDSCs) than desert tumors—we observed a reduction in 8/10 patients with detectable PMN-MDSCs (P=0.1) post treatment, consistent with the mechanism of action of CEBPA. An expression signature based on 18 genes significantly enriched for clinical response across all patients. Collectively, these data suggest a positive immunomodulatory TME effect of the combination of MTL-CEBPA with pembrolizumab. In both hot and cold TME tumors, the combination drives directed differentiation of progenitor monocytes into HLA-DR+ myeloid cells secreting chemokines that stimulate the ingress of T cells into the TME. We observe a significant positive correlation between the change in cytotoxic T cells and HLA-DR+ myeloid cells post treatment (P=0.004). These effects are most pronounced in cold tumors. Citation Format: Ruth Plummer, Mikael Sodergren, Brid Ryan, Ilian Tchakov, Nina Raulf, Rose Hodgson, CP Tan, Joanna P. Nicholls, Alison Adderkin, N Vasileiadou, Vikash Reebye, Tim Meyer, David J. Pinato, Debashis Sarker, Bristi Basu, Sarah Blagden, Natalie Cook, Jeff Evans, Jeffrey Yachnin, Cheng Ean Chee, Dan Li, Anthony El-Khoueiry, Maria Diab, Kai-Wen Huang, Marcus S. Noel, Bridget Keenan, Devalingam Mahalingam, Melanie Grosso, Denis Arnaud, Aurelie Auguste, Jan Storkholm, Iain McNeish, Robert Habib, John J. Rossi, Nagy Habib. MTL-CEBPA in combination with pembrolizumab converts an immune desert to an inflamed TME in solid tumors resistant to checkpoint blockade [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB192.
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- 2023
5. Upregulation of C/EBPα Inhibits Suppressive Activity of Myeloid Cells and Potentiates Antitumor Response in Mice and Patients with Cancer
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Nagy A. Habib, Emilio Sanseviero, Madhava Pai, Debashis Sarker, Ayumi Hashimoto, Daniel H. Palmer, Mikael H. Sodergren, Vikash Reebye, Jeff Evans, Shahid A. Khan, Nina Raulf, Y.T. Ma, Andrew V. Kossenkov, Robert Habib, David J. Pinato, Ruth Plummer, Cheng E. Chee, John J. Rossi, Kai-Wen Huang, Naouel Elasri, Sheba Jarvis, Duncan Spalding, Jenni Vasara, Dmitry I. Gabrilovich, Bristi Basu, Adeline Reynaud, Mark Cobbold, Anna Martirosyan, Tim Meyer, Rohini Sharma, Pinelopi Andrikakou, Hashimoto, Ayumi [0000-0002-6655-4896], Andrikakou, Pinelopi [0000-0002-3955-7995], Meyer, Tim [0000-0003-0782-8647], Huang, Kai-Wen [0000-0001-6375-8714], Plummer, Ruth [0000-0003-0107-1444], Chee, Cheng E [0000-0003-2385-7712], Spalding, Duncan [0000-0001-5066-054X], Sharma, Rohini [0000-0003-2441-549X], Basu, Bristi [0000-0002-3562-2868], and Apollo - University of Cambridge Repository
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Sorafenib ,Cancer Research ,Carcinoma, Hepatocellular ,Antineoplastic Agents ,Pembrolizumab ,Article ,Mice ,Immune system ,Downregulation and upregulation ,CEBPA ,medicine ,CCAAT-Enhancer-Binding Protein-alpha ,Tumor Cells, Cultured ,Animals ,Humans ,Myeloid Cells ,business.industry ,Liver Neoplasms ,Cancer ,medicine.disease ,Up-Regulation ,Treatment Outcome ,Oncology ,Tumor progression ,Hepatocellular carcinoma ,Cancer research ,business ,psychological phenomena and processes ,medicine.drug - Abstract
Purpose: To evaluate the mechanisms of how therapeutic upregulation of the transcription factor, CCAAT/enhancer-binding protein alpha (C/EBPα), prevents tumor progression in patients with advanced hepatocellular carcinoma (HCC) and in different mouse tumor models. Experimental Design: We conducted a phase I trial in 36 patients with HCC (NCT02716012) who received sorafenib as part of their standard care, and were given therapeutic C/EBPα small activating RNA (saRNA; MTL-CEBPA) as either neoadjuvant or adjuvant treatment. In the preclinical setting, the effects of MTL-CEBPA were assessed in several mouse models, including BNL-1ME liver cancer, Lewis lung carcinoma (LLC), and colon adenocarcinoma (MC38). Results: MTL-CEBPA treatment caused radiologic regression of tumors in 26.7% of HCC patients with an underlying viral etiology with 3 complete responders. MTL-CEBPA treatment in those patients caused a marked decrease in peripheral blood monocytic myeloid-derived suppressor cell (M-MDSC) numbers and an overall reduction in the numbers of protumoral M2 tumor-associated macrophages (TAM). Gene and protein analysis of patient leukocytes following treatment showed CEBPA activation affected regulation of factors involved in immune-suppressive activity. To corroborate this observation, treatment of all the mouse tumor models with MTL-CEBPA led to a reversal in the suppressive activity of M-MDSCs and TAMs, but not polymorphonuclear MDSCs (PMN-MDSC). The antitumor effects of MTL-CEBPA in these tumor models showed dependency on T cells. This was accentuated when MTL-CEBPA was combined with checkpoint inhibitors or with PMN-MDSC–targeted immunotherapy. Conclusions: This report demonstrates that therapeutic upregulation of the transcription factor C/EBPα causes inactivation of immune-suppressive myeloid cells with potent antitumor responses across different tumor models and in cancer patients. MTL-CEBPA is currently being investigated in combination with pembrolizumab in a phase I/Ib multicenter clinical study (NCT04105335).
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- 2021
6. 515 A phase 1 study of myeloid modulating agent MTL-CEBPA in combination with pembrolizumab in adult patients with advanced solid tumours
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Nagy A. Habib, Nina Raulf, Ilian Tchakov, Ruth Plummer, Debashis Sarker, Laura Sinigaglia, Robert Habib, Mikael H. Sodergren, Alessio Cortellini, Thomas Talbot, Vikash Reebye, Antonio D'Alessio, John J. Rossi, David J. Pinato, and Duncan Spalding
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Pharmacology ,Oncology ,Cancer Research ,medicine.medical_specialty ,Myeloid ,Combination therapy ,business.industry ,Immunology ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Pembrolizumab ,Neutropenia ,medicine.disease ,Discontinuation ,medicine.anatomical_structure ,Tolerability ,Internal medicine ,Hepatocellular carcinoma ,medicine ,Clinical endpoint ,Molecular Medicine ,Immunology and Allergy ,business ,RC254-282 - Abstract
BackgroundMTL-CEBPA is a novel immunotherapy targeting the myeloid cell lineage which has shown promising clinical activity as monotherapy and combination therapy with tyrosine kinase inhibitors in hepatocellular carcinoma (HCC). Immunosuppressive myeloid cells are associated with worse outcomes to checkpoint inhibitors. Pre-clinical data have shown that MTL-CEBPA potentiates the oncological effect of PD-1 inhibitors.MethodsThis phase 1A/B, first-in-human, open-label, multicenter study evaluates the safety, tolerability, PK, and efficacy of MTL-CEBPA in combination with a pembrolizumab in adult patients with advanced solid tumours across 3 dose cohorts (70mg/98mg/130mg/m2 MTL-CEBPA once weekly for 3 consecutive weeks with final week break per cycle, with 200mg pembrolizumab every 3 weeks). The primary endpoint is safety and ORR; key secondary endpoints include PK, CR rate & DCR. Key inclusion criteria: Patients with advanced solid tumours who have progressed on standard of care therapy or for whom no standard therapy is available, measurable disease, ECOG PS 3 months. A dose exploration will determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D).Results10 pts (3 men, 7 women; median age 50.5yrs), all with different tumor types (1 each of triple negative breast, methothelioma, squamous thymic, cholangiocarcinoma, eccrine, fibrolamellar hepatocellular, colorectal, pancreatic and 2 platinum resistant high-grade serous ovarian). 4 pts had ≥4 prior lines of treatment. All pts reported treatment-related AEs, 7 pts reported AEs considered related to MTL-CEBPA only and all were grade 1 or 2. The most common was nausea (n=3) followed by anaemia, headache, insomnia, neutropenia, pyrexia, transaminase increase and ventricular extrasystole (all n=1). Five pts reported AEs considered related to pembrolizumab only, 2AEs in 1 pt only were grade 3 (ALT and AST increases) There were no DLTs, SAEs or AEs leading to discontinuation or to death in the study. Tumor response was evaluated in 9 pts. 2 pts had a PR (epithelioid mesothelioma at 2 months with 83% tumour reduction, pt ongoing at 9 months & serous ovarian cancer at 2 months with 69% reduction in tumour, pt progressed at 6 months). Three pts had SD, 4 pts had PD as BOR, and 4 pts are continuing to receive treatment.ConclusionsMTL-CEBPA in combination with pembrolizumab demonstrated manageable toxicity at the dose levels tested and has shown antitumor activity. MTD was not reached and RP2D was determined at 130mg/m2 on day 1, 8 and 15 of a 28 day cycle. Enrolment into the dose expansion is ongoing.Trial RegistrationThis study was registered with ClinicalTrials.gov, number NCT04105335.Ethics ApprovalThe study was approved by the North East - Newcastle & North Tyneside 2 Research Ethics Committee, approval number 19/NE/0312.
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- 2021
7. Developing small activating RNA as a therapeutic: current challenges and promises
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Nagy A. Habib, Albert Kwok, and Nina Raulf
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Dendrimers ,RNA, Untranslated ,RNA Stability ,Pharmaceutical Science ,RNA activation ,02 engineering and technology ,030226 pharmacology & pharmacy ,03 medical and health sciences ,0302 clinical medicine ,Downregulation and upregulation ,Humans ,Clustered Regularly Interspaced Short Palindromic Repeats ,Gene Silencing ,Gene ,Drug Carriers ,Oligonucleotide ,Chemistry ,Liver Neoplasms ,RNA ,Aptamers, Nucleotide ,021001 nanoscience & nanotechnology ,Cancer treatment ,Muscular Atrophy ,Cancer research ,0210 nano-technology ,saRNA - Abstract
RNA activation (RNAa) allows specific gene upregulation mediated by a small activating RNA (saRNA). Harnessing this process would help in developing novel therapeutics for undruggable diseases. Since its discovery in mid 2000s, improvements of saRNA design, synthetic chemistry and understanding of the biology have matured the way to apply RNAa. Indeed, MiNA therapeutics Ltd has conducted the first RNAa clinical trial for advanced hepatocellular carcinoma patients with promising outcomes. However, to fully realize the RNAa potential better saRNA delivery strategies are needed to target other diseases. Currently, saRNA can be delivered in vivo by lipid nanoparticles, dendrimers, lipid and polymer hybrids and aptamers. Further developing these delivery technologies and novel application of RNAa will prove to be invaluable for new treatment development.
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- 2019
8. MicroRNA‐9 inhibits growth and invasion of head and neck cancer cells and is a predictive biomarker of response to plerixafor, an inhibitor of its target CXCR4
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Nina Raulf, Joop Gaken, Mahvash Tavassoli, Najeem’deen Folarin, and Hersi Mohamed Hersi
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0301 basic medicine ,Cancer Research ,Benzylamines ,Receptors, CXCR4 ,Cell ,Antineoplastic Agents ,Cyclams ,lcsh:RC254-282 ,CXCR4 ,03 medical and health sciences ,0302 clinical medicine ,Heterocyclic Compounds ,Cell Line, Tumor ,microRNA ,Gene expression ,Genetics ,Medicine ,Humans ,Neoplasm Invasiveness ,Research Articles ,Cell Proliferation ,Gene knockdown ,business.industry ,Plerixafor ,Cell Cycle ,plerixafor ,General Medicine ,CXCL12 ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Prognosis ,Phenotype ,Gene Expression Regulation, Neoplastic ,MicroRNAs ,030104 developmental biology ,medicine.anatomical_structure ,Treatment Outcome ,Oncology ,Cell culture ,Head and Neck Neoplasms ,030220 oncology & carcinogenesis ,MiR‐9 ,Cancer research ,Molecular Medicine ,head and neck cancer ,business ,medicine.drug ,Research Article ,tumour invasion - Abstract
Head and neck squamous cell carcinomas (HNSCC) are associated with poor morbidity and mortality. Current treatment strategies are highly toxic and do not benefit over 50% of patients. There is therefore a crucial need for predictive and/or prognostic biomarkers to allow treatment stratification for individual patients. One class of biomarkers that has recently gained importance are microRNA (miRNA). MiRNA are small, noncoding molecules which regulate gene expression post‐transcriptionally. We performed miRNA expression profiling of a cohort of head and neck tumours with known clinical outcomes. The results showed miR‐9 to be significantly downregulated in patients with poor treatment outcome, indicating its role as a potential biomarker in HNSCC. Overexpression of miR‐9 in HNSCC cell lines significantly decreased cellular proliferation and inhibited colony formation in soft agar. Conversely, miR‐9 knockdown significantly increased both these features. Importantly, endogenous CXCR4 expression levels, a known target of miR‐9, inversely correlated with miR‐9 expression in a panel of HNSCC cell lines tested. Induced overexpression of CXCR4 in low expressing cells increased proliferation, colony formation and cell cycle progression. Moreover, CXCR4‐specific ligand, CXCL12, enhanced cellular proliferation, migration, colony formation and invasion in CXCR4‐overexpressing and similarly in miR‐9 knockdown cells. CXCR4‐specific inhibitor plerixafor abrogated the oncogenic phenotype of CXCR4 overexpression as well as miR‐9 knockdown. Our data demonstrate a clear role for miR‐9 as a tumour suppressor microRNA in HNSCC, and its role seems to be mediated through CXCR4 suppression. MiR‐9 knockdown, similar to CXCR4 overexpression, significantly promoted aggressive HNSCC tumour cell characteristics. Our results suggest CXCR4‐specific inhibitor plerixafor as a potential therapeutic agent, and miR‐9 as a possible predictive biomarker of treatment response in HNSCC.
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- 2018
9. Abstract 1730: Up-regulation of C/EBPα inhibits suppressive activity of myeloid cells and potentiates antitumor response in mice and cancer patients
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Kai-Wen Huang, Nagy A. Habib, Mark Cobbold, Debashis Sarker, Vikash Reebye, Madhava Pai, John J. Rossi, Nina Raulf, Dmitry I. Gabrilovich, Mikael H. Sodergren, Daniel H. Palmer, Jenni Vasara, Y.T. Ma, Robert Habib, David J. Pinato, Cheng Ean Chee, Sheba Jarvis, Duncan Spalding, Pinelopi Andrikakou, Andrew V. Kossenkov, Bristi Basu, Adeline Reynaud, Anna Martirosyan, Tim Meyer, Rohini Sharma, Ayumi Hashimoto, Ruth Plummer, and Naouel Elasri
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Sorafenib ,Cancer Research ,biology ,business.industry ,medicine.medical_treatment ,Cancer ,Pembrolizumab ,medicine.disease ,Targeted therapy ,Immune system ,Oncology ,Downregulation and upregulation ,Hepatocellular carcinoma ,Cancer research ,medicine ,biology.protein ,Antibody ,business ,medicine.drug - Abstract
Tumor associated macrophages (TAM) and myeloid-derived suppressor cells (MDSC) are widely implicated in the suppression of immune responses in cancer and are associated with negative clinical outcomes. We report that in mouse tumor models, therapeutic up-regulation of the transcriptional factor C/EBPα with small activating RNA (MTL-CEBPA) blocks the suppressive activity of monocytic (M) MDSC and TAM without affecting polymorphonuclear (PMN) MDSC. MTL-CEBPA treatment demonstrated antitumor activity that was dependent on T cells. Combination of MTL-CEBPA and anti-PD1 antibody or with PMN-MDSC targeted therapy resulted in marked antitumor effect. A phase I trial was conducted in 36 patients with advanced hepatocellular carcinoma (HCC). Marked decrease in M-MDSC and the expression of genes and proteins involved in immune suppressive activity of these cells were observed. Combined treatment with MTL-CEBPA and sorafenib resulted in a 27% objective radiological response and three complete responses in patients with virally associated HCC. Tissue biopsies from these patients demonstrated decrease in M2 polarized macrophages within the tumors. Thus, therapeutic up-regulation of C/EBPα inhibited suppressive myeloid cells that resulted in potent antitumor effect in mice and with encouraging clinical response in cancer patients. We are currently recruiting to a multi-centre study of MTL-CEBPA in combination with a PD-1 inhibitor (pembrolizumab) in adult patients with advanced solid tumors (TIMEPOINT - ClinicalTrials.gov Identifier: NCT04105335). Citation Format: Ayumi Hashimoto, Debashis Sarker, Vikash Reebye, Sheba Jarvis, Mikael H. Sodergren, Andrew Kossenkov, Nina Raulf, Jenni Vasara, Pinelopi Andrikakou, Tim Meyer, Kai-Wen Huang, Ruth Plummer, Cheng Ean Chee, Duncan Spalding, Madhava Pai, David J. Pinato, Rohini Sharma, Bristi Basu, Daniel Palmer, Yuk-Ting Ma, Robert Habib, Anna Martirosyan, Naouel Elasri, Adeline Reynaud, John Rossi, Mark Cobbold, Nagy Habib, Dmitry Gabrilovich. Up-regulation of C/EBPα inhibits suppressive activity of myeloid cells and potentiates antitumor response in mice and cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1730.
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- 2021
10. Clinical update on head and neck cancer: molecular biology and ongoing challenges
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Ivano Amelio, E. Alsahafi, Philippe Lucarelli, Katheryn Begg, Thomas Sauter, Mahvash Tavassoli, Nina Raulf, Amelio, Ivano [0000-0002-9126-5391], Lucarelli, Philippe [0000-0001-6079-1623], and Apollo - University of Cambridge Repository
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0301 basic medicine ,Cancer Research ,Response to therapy ,Subsequent Relapse ,Molecular biology ,medicine.medical_treatment ,Immunology ,Review Article ,Multidisciplinary, general & others [F99] [Life sciences] ,Immunotherapy, Adoptive ,Targeted therapy ,Prognostic markers ,Multidisciplinaire, généralités & autres [F99] [Sciences du vivant] ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,0302 clinical medicine ,ddc:570 ,medicine ,Biomarkers, Tumor ,Tumor Microenvironment ,Humans ,Microbiome ,Molecular Targeted Therapy ,lcsh:QH573-671 ,Head and neck ,Papillomaviridae ,lcsh:Cytology ,business.industry ,Squamous Cell Carcinoma of Head and Neck ,Head and neck cancer ,Papillomavirus Infections ,Cell Biology ,Immunotherapy ,medicine.disease ,Radiation therapy ,030104 developmental biology ,Head and Neck Neoplasms ,030220 oncology & carcinogenesis ,business ,Transcriptome ,Signal Transduction - Abstract
Head and neck squamous cell carcinomas (HNSCCs) are an aggressive, genetically complex and difficult to treat group of cancers. In lieu of truly effective targeted therapies, surgery and radiotherapy represent the primary treatment options for most patients. But these treatments are associated with significant morbidity and a reduction in quality of life. Resistance to both radiotherapy and the only available targeted therapy, and subsequent relapse are common. Research has therefore focussed on identifying biomarkers to stratify patients into clinically meaningful groups and to develop more effective targeted therapies. However, as we are now discovering, the poor response to therapy and aggressive nature of HNSCCs is not only affected by the complex alterations in intracellular signalling pathways but is also heavily influenced by the behaviour of the extracellular microenvironment. The HNSCC tumour landscape is an environment permissive of these tumours’ aggressive nature, fostered by the actions of the immune system, the response to tumour hypoxia and the influence of the microbiome. Solving these challenges now rests on expanding our knowledge of these areas, in parallel with a greater understanding of the molecular biology of HNSCC subtypes. This update aims to build on our earlier 2014 review by bringing up to date our understanding of the molecular biology of HNSCCs and provide insights into areas of ongoing research and perspectives for the future.
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- 2019
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11. Phase Ib dose escalation and cohort expansion study of the novel myeloid differentiating agent MTL-CEBPA in combination with sorafenib in patients with advanced hepatocellular carcinoma (HCC)
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Debashis Sarker, Jenni Vasara, Vikash Reebye, Nina Raulf, David C. Blakey, Mikael H. Sodergren, Nagy A. Habib, David J. Pinato, Daniel H. Palmer, Duncan Spalding, Robert Habib, Elizabeth Ruth Plummer, Bristi Basu, Cheng Ean Chee, Daniel McVeigh, Kai-Wen Huang, Yuk Ting Ma, Tim Meyer, T.R. Jeffry Evans, and Pinelopi Andrikakou
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Sorafenib ,Cancer Research ,Myeloid ,business.industry ,RNA ,medicine.disease ,Clinical trial ,medicine.anatomical_structure ,Oncology ,Myeloid Cell Differentiation ,Hepatocellular carcinoma ,CEBPA ,Cohort ,medicine ,Cancer research ,business ,medicine.drug - Abstract
4601 Background: MTL-CEBPA is the first small activating RNA to enter clinical trials and upregulates C/EBPα, a master regulator of myeloid cell differentiation. We previously reported a favourable safety profile of MTL-CEBPA as a single agent in HCC (Sarker D et al, ASCO 2018). After discontinuation of MTL-CEBPA, 3 out of 5 patients (pts) treated with sorafenib off study had a complete response (CR) of 7-18 months duration; 2 pts of which demonstrated resolution of lung metastases for > 1 year. Here we provide new data on pts prospectively treated with MTL-CEBPA + sorafenib. Methods: Primary objective was to assess safety and tolerability of MTL-CEBPA 90-130mg/m2 QW or BIW in combination with sorafenib 400mg BD administered to HCC patients either concomitantly or sequentially, in cohorts either tyrosine kinase inhibitor (TKI) naive or resistant. Secondary objectives included preliminary assessment of activity by response rate (RECIST v1.1) and immune landscape analysis. Results: As at the cut off date of 1 Feb 2020, 12 pts have been treated with MTL-CEBPA co-administered with sorafenib and 14 pts with MTL-CEBPA followed by sorafenib (23M/3F, median age 65.5years, range 44-83, ECOG PS 0/1: 18/8). The most common treatment-related AEs (all grades/grade 3-4) in these groups include facial flushing (4/0), raised AST (4/2) raised ALT (2/1), fatigue (5/0), raised ALP (2/0), and anaemia (2/2), diarrhoea (3/0), rash (2/0) and anorexia (1/0). Of 14 evaluable pts in the TKI naive cohorts, 2 pts had CR, 3 pts had partial response and 7 had stable disease. 9/10 pts in the TKI resistant cohorts evaluable for efficacy had stable disease. Flow cytometry demonstrated statistically significant decreases in frequency of immature CD66+CD10− neutrophils and myeloid derived suppressor cells. IHC demonstrated significant reduction in M2 macrophages in tumour biopsies. Conclusions: MTL-CEBPA + sorafenib is well tolerated with an acceptable safety profile. This study has confirmed signals of objective response to the combination treatment in TKI naïve HCC patients with viral aetiology, warranting expanded development in these patients. Updated efficacy and safety data will be presented. Clinical trial information: NCT02716012. [Table: see text]
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- 2020
12. First-in-human phase I trial of small activating RNA (saRNA) oligonucleotide MTL-CEBPA in combination with sorafenib in patients with advanced hepatocellular carcinoma (HCC)
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Cheng Ean Chee, Daniel McVeigh, T.R. Jeffry Evans, Daniel H. Palmer, David J. Pinato, Jenni Vasara, Pinelopi Andrikakou, Duncan Spalding, Tim Meyer, Mikael H. Sodergren, Nagy A. Habib, Yuk Ting Ma, Vikash Reebye, David C. Blakey, Bristi Basu, Nina Raulf, Kai-Wen Huang, Debashis Sarker, Robert Habib, and Elizabeth Ruth Plummer
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Sorafenib ,Cancer Research ,business.industry ,RNA ,medicine.disease ,Clinical trial ,03 medical and health sciences ,0302 clinical medicine ,Oncology ,Myeloid Cell Differentiation ,030220 oncology & carcinogenesis ,Hepatocellular carcinoma ,CEBPA ,medicine ,Cancer research ,business ,Transcription factor ,saRNA ,030215 immunology ,medicine.drug - Abstract
554 Background: MTL-CEBPA is the first saRNA to enter clinical trials and targets the transcription factor C/EBPα, a master regulator of myeloid cell differentiation. We have previously reported a favourable safety profile of MTL-CEBPA given as a single agent QWx3 every 28 days, in patients with HCC (Sarker D et al, ASCO 2018). After discontinuation of MTL-CEBPA, three out of five patients treated with sorafenib off study have had maintained complete radiological response (CR) of 7-18 months duration; 2 patients demonstrated resolution of lung metastases > 1 year. Here we provide updated data on phase 1 patients treated with sorafenib off study as well as subsequent combination cohorts. Methods: MTL-CEBPA 130mg/m2 QWx3 or BIW and sorafenib 400mg bd were administered to patients with HCC using combination or sequential dosing regimens, in cohorts either tyrosine kinase inhibitor naive or resistant. On treatment liver biopsies evaluated changes in M2 macrophages (CD163). Flow cytometry of peripheral blood determined changes in myeloid cell populations. Results: 12 patients have been treated with MTL-CEBPA co-administered with sorafenib and 14 patients treated with MTL-CEBPA followed by sorafenib (23M/3F, median age 65.5years, range 44-83, ECOG PS 0/1: 18/8). The most common treatment-related AEs (all grades/grade 3) in this group include facial flushing (4/0), raised AST (3/1) raised ALT (2/1), fatigue (5/0), raised ALP (2/0), and anaemia (2/2), diarrhoea (3/0), rash (2/0) and anorexia (1/0). 1 TKI naïve patient in the co-administration cohort has maintained CR at 7 months and two patients have SD (ongoing at 3 & 4 months both in sequential cohort). IHC in the patient with CR has demonstrated 95% reduction in M2 macrophages with significant decrease in frequency of immature CD10- neutrophils (-85.7%; p = 0.0078), PMN-MDSCs (-49.3%; p = 0.00145) and M-MDSCs (-18.4%; P = 0.0072). All responding patients have underlying HBV or HCV. Conclusions: MTL-CEBPA is a novel saRNA targeting myeloid cells which may result in a significantly enhanced oncological response in HCC of viral aetiology. Updated safety and efficacy data will be presented. Clinical trial information: NCT02716012.
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- 2020
13. Annexin A1 regulates EGFR activity and alters EGFR-containing tumour-derived exosomes in head and neck cancers
- Author
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S. Brown, Nina Raulf, Mahvash Tavassoli, Selvam Thavaraj, J. M. Vicencio, Philippe Lucarelli, and Thomas Sauter
- Subjects
0301 basic medicine ,Cancer Research ,endocrine system ,Cetuximab ,Biochemistry, biophysics & molecular biology [F05] [Life sciences] ,Exosomes ,EGFR signalling ,03 medical and health sciences ,0302 clinical medicine ,Downregulation and upregulation ,Formyl peptide receptor ,microRNA ,medicine ,Humans ,Phosphorylation ,Head and neck cancer ,Biochimie, biophysique & biologie moléculaire [F05] [Sciences du vivant] ,Annexin A1 ,Cell Proliferation ,Messenger RNA ,Squamous Cell Carcinoma of Head and Neck ,Cell growth ,business.industry ,Tumor Suppressor Proteins ,Cancer ,Annexin A1 (ANXA1) ,medicine.disease ,Head and neck squamous-cell carcinoma ,miR-196a ,ErbB Receptors ,Gene Expression Regulation, Neoplastic ,HEK293 Cells ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Mutation ,Cancer research ,EGFR phosphorylation ,Phosphatidylinositol 3-Kinase ,business ,Proto-Oncogene Proteins c-akt ,Signal Transduction ,medicine.drug - Abstract
Background Head and neck squamous cell carcinoma (HNSCC) is the 6th most common cancer with approximately half a million cases diagnosed each year worldwide. HNSCC has a poor survival rate which has not improved for over 30 years. The molecular pathogenesis of HNSCCs remains largely unresolved; there is high prevalence of p53 mutations and EGFR overexpression; however, the contribution of these molecular changes to disease development and/or progression remains unknown. We have recently identified microRNA miR-196a to be highly overexpressed in HNSCC with poor prognosis. Oncogenic miR-196a directly targets Annexin A1 (ANXA1). Although increased ANXA1 expression levels have been associated with breast cancer development, its role in HNSCC is debatable and its functional contribution to HNSCC development remains unclear. Methods ANXA1 mRNA and protein expression levels were determined by RNA Seq analysis and immunohistochemistry, respectively. Gain- and loss-of-function studies were performed to analyse the effects of ANXA1 modulation on cell proliferation, mechanism of activation of EGFR signalling as well as on exosome production and exosomal phospho-EGFR. Results ANXA1 was found to be downregulated in head and neck cancer tissues, both at mRNA and protein level. Its anti-proliferative effects were mediated through the intracellular form of the protein. Importantly, ANXA1 downregulation resulted in increased phosphorylation and activity of EGFR and its downstream PI3K-AKT signalling. Additionally, ANXA1 modulation affected exosome production and influenced the release of exosomal phospho-EGFR. Conclusions ANXA1 acts as a tumour suppressor in HNSCC. It is involved in the regulation of EGFR activity and exosomal phospho-EGFR release and could be an important prognostic biomarker.
- Published
- 2018
14. MicroRNA-196a promotes an oncogenic effect in head and neck cancer cells by suppressing annexin A1 and enhancing radioresistance
- Author
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Mahvash Tavassoli, Teresa Guerrero Urbano, Jessica Bullenkamp, Jacques Huot, Eddy Odell, Y. Suh, Joop Gaken, Nina Raulf, Katherine Lawler, and Stéphane Gobeil
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,Gene knockdown ,Cell growth ,Biology ,medicine.disease ,Head and neck squamous-cell carcinoma ,Gentamicin protection assay ,Internal medicine ,Radioresistance ,microRNA ,medicine ,Epithelial–mesenchymal transition ,Annexin A1 - Abstract
Radiotherapy is a major treatment modality for head and neck squamous cell carcinoma (HNSCC). Up to 50% of patients with locally advanced disease relapse after radical treatment and there is therefore a need to develop predictive bomarkers for clinical use that allow the selection of patients who are likely to respond. MicroRNA (miRNA) expression profiling of a panel of HNSCC tumours with and without recurrent disease after surgery and radiotherapy detected miR-196a as one of the highest upregulated miRNAs in the poor prognostic group. To further study the role of miR-196a, its expression was determined in eight head and neck cancer cell lines. Overexpression of miR-196a in HNSCC cells, with low endogenous miR-196a expression, significantly increased cell proliferation, migration and invasion, and induced epithelial to mesenchymal transition. Conversely, miR-196a knockdown in cells with high endogenous expression levels significantly reduced oncogenic behaviour. Importantly, overexpression of miR-196a increased radioresistance of cells as measured by gamma H2AX staining and MTT survival assay. Annexin A1 (ANXA1), a known target of miR-196a, was found to be directly modulated by miR-196a as measured by luciferase assay and confirmed by Western blot analysis. ANXA1 knockdown in HNSCC exhibited similar phenotypic effects to miR-196a overexpression, suggesting the oncogenic effect of miR-196a may at least be partly regulated through suppression of ANXA1. In conclusion, this study identifies miR-196a as a potential important biomarker of prognosis and response of HNSCC to radiotherapy. Furthermore, our data suggest that miR-196a and/or its target gene ANXA1 could represent important therapeutic targets in HNSCC.
- Published
- 2015
15. Differential response of head and neck cancer cell lines to TRAIL or Smac mimetics is associated with the cellular levels and activity of caspase-8 and caspase-10
- Author
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Henning Walczak, Domenico Delia, Daniele Lecis, Radien El-Attar, Edward Odell, Nina Raulf, Kerstin Papenfuss, Mahvash Tavassoli, and Dagmar Kulms
- Subjects
Cancer Research ,medicine.medical_specialty ,Blotting, Western ,caspase-10 ,TRAIL ,Apoptosis ,Enzyme-Linked Immunosorbent Assay ,Biology ,Caspase 8 ,HNSCC ,caspase-8 ,TNF-Related Apoptosis-Inducing Ligand ,Biomimetics ,Internal medicine ,medicine ,Tumor Cells, Cultured ,Humans ,Caspase 10 ,Cell Proliferation ,Oncogene ,Cell growth ,Tumor Necrosis Factor-alpha ,Triazoles ,Bridged Bicyclo Compounds, Heterocyclic ,Endocrinology ,Oncology ,Cell culture ,Head and Neck Neoplasms ,TNF-α ,Cancer cell ,Cancer research ,Carcinoma, Squamous Cell ,Tumor necrosis factor alpha ,Smac mimetics ,biological phenomena, cell phenomena, and immunity ,Translational Therapeutics ,BH3 Interacting Domain Death Agonist Protein - Abstract
Background: Current treatment strategies for head and neck cancer are associated with significant morbidity and up to 50% of patients relapse, highlighting the need for more specific and effective therapeutics. Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) and Smac mimetics (SMs) are promising anticancer agents, but their effect on head and neck squamous cell carcinoma (HNSCC) remains unknown. Methods: We examined the response of a panel of nine HNSCC cell lines to TRAIL and SMs and investigated the mechanism of cell type-specific response by functional analysis. Results: Head and neck cancer cell lines revealed a converse response pattern with three cell lines being highly sensitive to Smac-164 (SM) but resistant to TRAIL, whereas the other six were sensitive to TRAIL but resistant to SM. Distinct protein expression and activation patterns were found to be associated with susceptibility of HNSCC cell lines to TRAIL and SM. Tumour necrosis factor-related apoptosis-inducing ligand sensitivity was associated with high caspase-8 and Bid protein levels, and TRAIL-sensitive cell lines were killed via the type II extrinsic apoptotic pathway. Smac mimetic-sensitive cells expressed low levels of caspase-8 and Bid but had high TNF-α expression. Smac mimetic-induced cell death was associated with caspase-10 activation, suggesting that in the absence of caspase-8, caspase-10 mediates response to SM. Cotreatment with TNF-α sensitised the resistant cells to SM, demonstrating a decisive role for TNF-α-driven feedback loop in SM sensitivity. Conclusions: Tumour necrosis factor-related apoptosis-inducing ligand and SMs effectively kill HNSCC cell lines and therefore represent potential targeted therapeutics for head and neck cancer. Distinct molecular mechanisms determine the sensitivity to each agent, with levels of TNF-α, caspase-8, Bid and caspase-10 providing important predictive biomarkers of response to these agents.
- Published
- 2014
16. Cytosolic Bax
- Author
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Nina Raulf, Stephanie Bregenhorn, Sandra Vogel, Ulrich Maurer, Peter E. Czabotar, Martin L. Biniossek, and Christoph Borner
- Subjects
biology ,Immunoprecipitation ,Bcl-2 family ,Context (language use) ,Cell Biology ,Plasma protein binding ,Biochemistry ,Hsp90 ,Cell biology ,Cytosol ,Transmembrane domain ,Bcl-2-associated X protein ,biology.protein ,Molecular Biology - Abstract
Bax is kept inactive in the cytosol by refolding its C-terminal transmembrane domain into the hydrophobic binding pocket. Although energetic calculations predicted this conformation to be stable, numerous Bax binding proteins were reported and suggested to further stabilize inactive Bax. Unfortunately, most of them have not been validated in a physiological context on the endogenous level. Here we use gel filtration analysis of the cytosol of primary and established cells to show that endogenous, inactive Bax runs 20–30 kDa higher than recombinant Bax, suggesting Bax dimerization or the binding of a small protein. Dimerization was excluded by a lack of interaction of differentially tagged Bax proteins and by comparing the sizes of dimerized recombinant Bax with cytosolic Bax on blue native gels. Surprisingly, when analyzing cytosolic Bax complexes by high sensitivity mass spectrometry after anti-Bax immunoprecipitation or consecutive purification by gel filtration and blue native gel electrophoresis, we detected only one protein, called p23 hsp90 co-chaperone, which consistently and specifically co-purified with Bax. However, this protein could not be validated as a crucial inhibitory Bax binding partner as its over- or underexpression did not show any apoptosis defects. By contrast, cytosolic Bax exhibits a slight molecular mass shift on SDS-PAGE as compared with recombinant Bax, which suggests a posttranslational modification and/or a structural difference between the two proteins. We propose that in most healthy cells, cytosolic endogenous Bax is a monomeric protein that does not necessarily need a binding partner to keep its pro-apoptotic activity in check.
- Published
- 2012
17. PO-199 Lysyl oxidase in head and neck cancer: metastasis and therapy response
- Author
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E. Alsahafi, H.M. Hersi, J. Wyatt, Nina Raulf, Teresa Guerrero-Urbano, Y. Suh, Katheryn Begg, and Mahvash Tavassoli
- Subjects
Cancer Research ,integumentary system ,biology ,business.industry ,food and beverages ,Vimentin ,Lysyl oxidase ,medicine.disease ,Head and neck squamous-cell carcinoma ,Metastasis ,Oncology ,Downregulation and upregulation ,Radioresistance ,biology.protein ,Cancer research ,Medicine ,business ,Clonogenic assay ,Transcription factor - Abstract
Introduction Hypoxia occurs when tumours out-grow the vasculature. It can induce therapy resistance, contribute to metastasis and is a potential biomarker of radioresistance (RR) in Head and Neck Squamous Cell Carcinoma (HNSCC). However, neither identification of patients who might benefit from hypoxia-modification, nor a full understanding of the molecular changes that contribute to metastasis/RR, has been achieved. A recent study by our lab was able to link hypoxic volume in patients with a genetic signature correlating to poor progression-free survival. Lysyl oxidase (LOX) was chosen for further investigation as it has been previously implicated in poor prognosis and hypoxia-induced metastasis. LOX has not however been extensively studied in the context of RR. Additionally, factors other than hypoxia have been shown to contribute to LOX’s regulation, but, their relative contributions to metastasis and RR have not been defined. Material and methods LOX was found to be differentially expressed in a metastatic pair of HNSCC cell lines: HSC3 (primary tumour, low expression) and HSC3-M3 (metastatic daughter line, high expression). Using this model, the role of LOX in hypoxia-induced metastasis was studied using invasion, migration and anoikis-resistance assays. LOX was also overexpressed and inhibited (using active site inhibitor BAPN) to determine LOX-specificity. Currently, we are investigating LOX as an inducer of RR by clonogenic assays, comet assay and γH2AX staining. Pathways including epithelial-to-mesenchymal transition (EMT) have so far been investigated as mechanisms. Next we will use bioinformatics to correlate follow up data from our original study and existing datasets, to LOX’s involvement in treatment failure and survival. Results and discussions Our results have shown that high expression of LOX, endogenously in metastatic HSC3-M3 cells or by overexpression, can induce a metastatic phenotype resulting in increased invasion, migration and anoikis resistance. Inhibition of LOX reverses these effects, exaggerated in hypoxia where LOX is upregulated. LOX upregulation has also been linked to a change in expression/localisation of EMT regulators such as E-Cadherin and Vimentin. Early results show a potential link to RR. Ongoing studies aim to determine if this effect is a result of LOX’s enzymatic activity, or potential transcription factor functioning. Conclusion This work will be the first to highlight LOX as an important biomarker not only in hypoxia-induced metastasis of HNSCC, but also in therapy resistance.
- Published
- 2018
18. PO-164 Modulation of EGFR to overcome tumour resistance and improve radiotherapy response in HPV positive and negative head and neck cancer cells
- Author
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Nina Raulf, E. Alsahafi, H.M. Hersi, J. Naglik, Mahvash Tavassoli, and Katheryn Begg
- Subjects
Cancer Research ,biology ,business.industry ,medicine.medical_treatment ,Head and neck cancer ,Disease ,medicine.disease ,Metastasis ,Targeted therapy ,Radiation therapy ,Oncology ,Cancer cell ,medicine ,Cancer research ,biology.protein ,Epidermal growth factor receptor ,business ,EGFR inhibitors - Abstract
Introduction Squamous cell carcinoma of the head and neck (HNSCC) is a significant cause of morbidity and mortality, with over 6 00 000 new cases diagnosed annually. Development of targeted agents to improve survival and preserve organs is vital. This could be achieved through better understanding of the molecular status of HNSCC and availability of specific biomarkers to enable better detection, prognosis and prediction of treatment response. Epidermal growth factor receptor (EGFR) has a central role in HNSCC, causing excessive growth, survival and progression of cancer cells thus representing a promising molecular target for this disease. Over-expression of EGFR is detected in 80%–90% of HNSCC and correlates with worse disease outcome. More importantly, EGFR expression is lower in HPV positive HNSCC than HPV negative ones with the former demonstrating favourable prognosis. Moreover, hypoxia is a strong factor in solid tumours and is linked to more aggressive phenotype. Despite the development of anti-EGFR agents, limited clinical efficacy has been reported for EGFR inhibitors in HNSCC. In this study we assessed the effects of EGFR over-expression in relation to HPV status and further investigated the role of EGFR response to standard and targeted therapies. Additionally, we aim to understand the link between tumour hypoxia and EGFR signalling as well as the other ErbB family members in HNSCC cell lines. Material and methods HNSCC cell line SCC072 (HPV negative) and SCC154 (HPV positive) with low endogenous EGFR level were infected with EGFR-retroviral vector. The over-expression of EGFR was confirmed. Functional characterisation of both modulated cell lines was performed by assessment of cellular proliferation, migration, invasion and response to radiation/EGFR inhibitors. Additionally, EGFR activation and other ErbB family members were studied in both modulated cell lines. Results and discussions Modulation of EGFR in both cell lines showed variance in sub-cellular localisation. EGFR over-expression demonstrated oncogenic phynotype in both modulated cells. HPV- cells were resistance to targeted therapy, which suggest that EGFR over-expression may not be the only mechanism of response to targeted therapy. The presence of other EGFR family members may influence the response. Conclusion Studies are in progress to investigate EGFR pathways involved in invasion, metastasis and response to therapies. More importantly, is to consider the effect of tumour hypoxia on EGFR response to anti-cancer agents.
- Published
- 2018
19. NIR an inhibitor of histone acetyltransferases regulates transcription factor TAp63 and is controlled by the cell cycle
- Author
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Kristina Heyne, Roland Schüle, Marcel P. Conrad, Klaus Roemer, Julia Schneider, Nina Raulf, and Vivienne Willnecker
- Subjects
Cyclin-Dependent Kinase Inhibitor p21 ,Transcriptional Activation ,Repressor ,Gene Regulation, Chromatin and Epigenetics ,03 medical and health sciences ,Transactivation ,0302 clinical medicine ,Transcription (biology) ,Genetics ,Humans ,Mitosis ,Transcription factor ,neoplasms ,Cells, Cultured ,030304 developmental biology ,Histone Acetyltransferases ,0303 health sciences ,Nucleoplasm ,biology ,Cell Cycle ,technology, industry, and agriculture ,Promoter ,Histone acetyltransferase ,equipment and supplies ,Molecular biology ,Repressor Proteins ,surgical procedures, operative ,Gene Expression Regulation ,030220 oncology & carcinogenesis ,Gene Knockdown Techniques ,biology.protein ,Trans-Activators ,Cell Nucleolus - Abstract
p63 is a sequence-specific transcription factor that regulates epithelial stem cell maintenance and epithelial differentiation. In addition, the TAp63 isoform with an N-terminal transactivation domain functions as an inducer of apoptosis during the development of sympathetic neurons. Previous work has indicated that the co-activator and histone acetyltransferase (HAT), p300, can bind to TAp63 and stimulate TAp63-dependent transcription of the p21Cip1 gene. Novel INHAT Repressor (NIR) is an inhibitor of HAT. Here, we report that the central portion of NIR binds to the transactivation domain and the C-terminal oligomerization domain of TAp63. NIR is highly expressed in G2/M phase of the cell cycle and only weakly expressed in G1/S. Furthermore, except during mitosis, NIR is predominantly localized in the nucleolus; only a small portion co-localizes with TAp63 in the nucleoplasm and at the p21 gene promoter. Consistent with NIR acting as a repressor, the induced translocation of NIR from the nucleolus into the nucleoplasm resulted in the inhibition of TAp63-dependent transactivation of p21. Conversely, knockdown of NIR by RNAi stimulated p21 transcription in the presence of TAp63. Thus, NIR is a cell-cycle-controlled, novel negative regulator of TAp63. The low levels of nucleoplasmic NIR might act as a buffer toward potentially toxic TAp63.
- Published
- 2010
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20. Bortezomib sensitises TRAIL-resistant HPV-positive head and neck cancer cells to TRAIL through a caspase-dependent, E6-independent mechanism
- Author
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Edward Odell, Bushra Ayaz, Nina Raulf, Jessica Bullenkamp, Selvam Thavaraj, Henning Walczak, Mahvash Tavassoli, and Dagmar Kulms
- Subjects
Cancer Research ,Programmed cell death ,Immunology ,Cell ,TRAIL, tumour necrosis factor-related apoptosis-inducing ligand ,HNSCC, head and neck squamous cell carcinoma ,HPV+/−, human papillomavirus positive/negative ,RT/CT, radio-chemotherapy ,TRAIL-R, TRAIL receptor ,DISC, death-inducing signalling complex ,nec-1, necrostatin-1 ,Apoptosis ,X-Linked Inhibitor of Apoptosis Protein ,Biology ,Bortezomib ,TNF-Related Apoptosis-Inducing Ligand ,Cellular and Molecular Neuroscience ,Cell Line, Tumor ,medicine ,Humans ,Papillomaviridae ,Caspase 8 ,Protein Stability ,Head and neck cancer ,Cancer ,Drug Synergism ,Oncogene Proteins, Viral ,Cell Biology ,medicine.disease ,Boronic Acids ,Up-Regulation ,XIAP ,Receptors, TNF-Related Apoptosis-Inducing Ligand ,HEK293 Cells ,medicine.anatomical_structure ,Drug Resistance, Neoplasm ,Head and Neck Neoplasms ,Pyrazines ,Proteasome inhibitor ,Cancer research ,Original Article ,Tumor Suppressor Protein p53 ,BH3 Interacting Domain Death Agonist Protein ,medicine.drug - Abstract
Human papillomavirus (HPV) is causative for a new and increasing form of head and neck squamous cell carcinomas (HNSCCs). Although localised HPV-positive cancers have a favourable response to radio-chemotherapy (RT/CT), the impact of HPV in advanced or metastatic HNSCC remains to be defined and targeted therapeutics need to be tested for cancers resistant to RT/CT. To this end, we investigated the sensitivity of HPV-positive and -negative HNSCC cell lines to TRAIL (tumour necrosis factor-related apoptosis-inducing ligand), which induces tumour cell-specific apoptosis in various cancer types. A clear correlation was observed between HPV positivity and resistance to TRAIL compared with HPV-negative head and neck cancer cell lines. All TRAIL-resistant HPV-positive cell lines tested were sensitised to TRAIL-induced cell death by treatment with bortezomib, a clinically approved proteasome inhibitor. Bortezomib-mediated sensitisation to TRAIL was associated with enhanced activation of caspase-8, -9 and -3, elevated membrane expression levels of TRAIL-R2, cytochrome c release and G2/M arrest. Knockdown of caspase-8 significantly blocked cell death induced by the combination therapy, whereas the BH3-only protein Bid was not required for induction of apoptosis. XIAP depletion increased the sensitivity of both HPV-positive and -negative cells to TRAIL alone or in combination with bortezomib. In contrast, restoration of p53 following E6 knockdown in HPV-positive cells had no effect on their sensitivity to either single or combination therapy, suggesting a p53-independent pathway for the observed response. In summary, bortezomib-mediated proteasome inhibition sensitises previously resistant HPV-positive HNSCC cells to TRAIL-induced cell death through a mechanism involving both the extrinsic and intrinsic pathways of apoptosis. The cooperative effect of these two targeted anticancer agents therefore represents a promising treatment strategy for RT/CT-resistant HPV-associated head and neck cancers.
- Published
- 2014
21. MicroRNA-196a promotes an oncogenic effect in head and neck cancer cells by suppressing annexin A1 and enhancing radioresistance
- Author
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Yae-Eun, Suh, Nina, Raulf, Joop, Gäken, Katherine, Lawler, Teresa Guerrero, Urbano, Jessica, Bullenkamp, Stéphane, Gobeil, Jacques, Huot, Eddy, Odell, and Mahvash, Tavassoli
- Subjects
MicroRNAs ,Epithelial-Mesenchymal Transition ,HEK293 Cells ,Cell Movement ,Head and Neck Neoplasms ,Cell Line, Tumor ,Carcinoma, Squamous Cell ,Humans ,Prognosis ,Radiation Tolerance ,Annexin A1 ,Cell Proliferation - Abstract
Radiotherapy is a major treatment modality for head and neck squamous cell carcinoma (HNSCC). Up to 50% of patients with locally advanced disease relapse after radical treatment and there is therefore a need to develop predictive bomarkers for clinical use that allow the selection of patients who are likely to respond. MicroRNA (miRNA) expression profiling of a panel of HNSCC tumours with and without recurrent disease after surgery and radiotherapy detected miR-196a as one of the highest upregulated miRNAs in the poor prognostic group. To further study the role of miR-196a, its expression was determined in eight head and neck cancer cell lines. Overexpression of miR-196a in HNSCC cells, with low endogenous miR-196a expression, significantly increased cell proliferation, migration and invasion, and induced epithelial to mesenchymal transition. Conversely, miR-196a knockdown in cells with high endogenous expression levels significantly reduced oncogenic behaviour. Importantly, overexpression of miR-196a increased radioresistance of cells as measured by gamma H2AX staining and MTT survival assay. Annexin A1 (ANXA1), a known target of miR-196a, was found to be directly modulated by miR-196a as measured by luciferase assay and confirmed by Western blot analysis. ANXA1 knockdown in HNSCC exhibited similar phenotypic effects to miR-196a overexpression, suggesting the oncogenic effect of miR-196a may at least be partly regulated through suppression of ANXA1. In conclusion, this study identifies miR-196a as a potential important biomarker of prognosis and response of HNSCC to radiotherapy. Furthermore, our data suggest that miR-196a and/or its target gene ANXA1 could represent important therapeutic targets in HNSCC.
- Published
- 2014
22. Cytosolic Bax: does it require binding proteins to keep its pro-apoptotic activity in check?
- Author
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Sandra, Vogel, Nina, Raulf, Stephanie, Bregenhorn, Martin L, Biniossek, Ulrich, Maurer, Peter, Czabotar, and Christoph, Borner
- Subjects
Apoptosis ,Cell Line ,Intramolecular Oxidoreductases ,Mice ,Cytosol ,Protein Structure and Folding ,Hepatocytes ,Animals ,Humans ,Carrier Proteins ,Cells, Cultured ,Prostaglandin-E Synthases ,Protein Binding ,bcl-2-Associated X Protein - Abstract
Bax is kept inactive in the cytosol by refolding its C-terminal transmembrane domain into the hydrophobic binding pocket. Although energetic calculations predicted this conformation to be stable, numerous Bax binding proteins were reported and suggested to further stabilize inactive Bax. Unfortunately, most of them have not been validated in a physiological context on the endogenous level. Here we use gel filtration analysis of the cytosol of primary and established cells to show that endogenous, inactive Bax runs 20–30 kDa higher than recombinant Bax, suggesting Bax dimerization or the binding of a small protein. Dimerization was excluded by a lack of interaction of differentially tagged Bax proteins and by comparing the sizes of dimerized recombinant Bax with cytosolic Bax on blue native gels. Surprisingly, when analyzing cytosolic Bax complexes by high sensitivity mass spectrometry after anti-Bax immunoprecipitation or consecutive purification by gel filtration and blue native gel electrophoresis, we detected only one protein, called p23 hsp90 co-chaperone, which consistently and specifically co-purified with Bax. However, this protein could not be validated as a crucial inhibitory Bax binding partner as its over- or underexpression did not show any apoptosis defects. By contrast, cytosolic Bax exhibits a slight molecular mass shift on SDS-PAGE as compared with recombinant Bax, which suggests a posttranslational modification and/or a structural difference between the two proteins. We propose that in most healthy cells, cytosolic endogenous Bax is a monomeric protein that does not necessarily need a binding partner to keep its pro-apoptotic activity in check.
- Published
- 2012
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