Leuven Cancer Institute LKI

Leuven, Belgium

Leuven Cancer Institute LKI

Leuven, Belgium
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Dekervel J.,Catholic University of Leuven | Bulle A.,Catholic University of Leuven | Bulle A.,University Hospitals g Leuven | Windmolders P.,Catholic University of Leuven | And 11 more authors.
Translational Oncology | Year: 2017

Epithelial-to-mesenchymal transition (EMT) is linked to tumor invasion, drug resistance and aggressive disease and this is largely dependent on the cell's microenvironment. Acriflavine (ACF) is an old antibacterial drug recently also suggested as anticancer agent and HIF inhibitor. We wanted to study the effect of acriflavine on EMT in different human cancer models. Pancreatic cancer cells (Panc-1) were exposed to TGF-β1 or cobalt chloride (to mimick severe hypoxia) to induce EMT. For our third model we exposed HepG2 liver cancer cells to sorafenib which resulted in development of acquired drug resistance with strong features of EMT and aggressive behavior. These models were morphologically and functionally (invasion assay) characterized. Markers of EMT were determined using qRT-PCR and Western blotting. Transcriptome analysis was performed following gene expression determination and combining the iRegulon tool and Gene Set Enrichment Analysis (GSEA). We made the following observations: (1) acriflavine inhibited EMT based on changes in cell morphology, invasive capacities and markers of EMT (at protein and gene expression level). (2) Transcriptome analysis revealed potent inhibition of ATF4 target genes and of the unfolded protein response. We showed that acriflavine blocked eIF2a phosphorylation and reduced ATF4 translation thereby inhibiting the PERK/eIF2a/ATF4 UPR pathway. (3) ACF restored drug sensitivity of cells that obtained acquired resistance. Conclusions: We identified acriflavine as a potent inhibitor of EMT and the UPR, thereby re-sensitizing the cancer cells to antineoplastic drugs. © 2016 The Authors. Published by Elsevier Inc.


Egelmeer A.G.T.M.,Maastricht University | Velazquez E.R.,Maastricht University | De Jong J.M.A.,Maastricht University | Oberije C.,Maastricht University | And 13 more authors.
Radiotherapy and Oncology | Year: 2011

Introduction: To advise laryngeal carcinoma patients on the most appropriate form of treatment, a tool to predict survival and local control is needed. Materials and methods: We performed a population-based cohort study on 994 laryngeal carcinoma patients, treated with RT from 1977 until 2008. Two nomograms were developed and validated. Performance of the models is expressed as the Area Under the Curve (AUC). Results: Unfavorable prognostic factors for overall survival were low hemoglobin level, male sex, high T-status, nodal involvement, older age, lower EQD 2T (total radiation dose corrected for fraction dose and overall treatment time), and non-glottic tumor. All factors except tumor location were prognostic for local control. The AUCs were 0.73 for overall survival and 0.67 for local control. External validation of the survival model yielded AUCs of 0.68, 0.74, 0.76 and 0.71 for the Leuven (n = 109), the VU Amsterdam (n = 178), the Manchester (n = 403) and the NKI cohort (n = 205), respectively, while the validation procedure for the local control model resulted in AUCs of 0.70, 0.71, 0.72 and 0.62. The resulting nomograms were made available on the website www.predictcancer.org. Conclusions: For patients with a laryngeal carcinoma treated with RT alone, we have developed visual, easy-to-use nomograms for the prediction of overall survival and primary local control. These models have been successfully validated in four external centers. © 2011 Elsevier Ltd. All rights reserved.


PubMed | Leuven Cancer Institute LKI, Catholic University of Leuven and Center for the Biology of Disease
Type: | Journal: Blood | Year: 2017

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy caused by the accumulation of genomic lesions that affect the development of T-cells. Since many years, it has been established that deregulated expression of transcription factors, impairment of the CDKN2A/2B cell cycle regulators and hyperactive NOTCH1 signaling play prominent roles in the pathogenesis of this leukemia. In the past decade, systematic screening of T-ALL genomes by high resolution copy number arrays and next- generation sequencing technologies has revealed that T-cell progenitors accumulate additional mutations affecting JAK/STAT signaling, protein translation and epigenetic control, providing novel attractive targets for therapy. In this review, we provide an update on our knowledge on T-ALL pathogenesis, on the opportunities for the introduction of targeted therapy and on the challenges that are still ahead.


Dirix P.,Leuven Cancer Institute LKI | Nuyts S.,Leuven Cancer Institute LKI
The Lancet Oncology | Year: 2010

Intensification of radiotherapy treatment for locally advanced head and neck cancer by use of altered fractionation schedules or concomitant chemotherapy has resulted in substantially improved locoregional control and survival. However, these improvements have come at the cost of increased acute, and late, toxic effects. The application of technological advances, such as intensity-modulated radiotherapy, is expected to further improve the therapeutic index of radiotherapy for head and neck cancer, by limiting toxicity and possibly by increasing locoregional control. However, the organ-sparing potential of such highly conformal radiotherapy techniques relies heavily on the appropriate selection and accurate delineation of the crucial organs at risk, with the application of rigorous dose constraints during planning. Because xerostomia and dysphagia are the main causes of decreased quality of life after radiotherapy for head and neck cancer, the prevention of these two complications will form the focus of this review. © 2010 Elsevier Ltd. All rights reserved.


PubMed | Leuven Cancer Institute LKI
Type: Journal Article | Journal: The Lancet. Oncology | Year: 2010

Intensification of radiotherapy treatment for locally advanced head and neck cancer by use of altered fractionation schedules or concomitant chemotherapy has resulted in substantially improved locoregional control and survival. However, these improvements have come at the cost of increased acute, and late, toxic effects. The application of technological advances, such as intensity-modulated radiotherapy, is expected to further improve the therapeutic index of radiotherapy for head and neck cancer, by limiting toxicity and possibly by increasing locoregional control. However, the organ-sparing potential of such highly conformal radiotherapy techniques relies heavily on the appropriate selection and accurate delineation of the crucial organs at risk, with the application of rigorous dose constraints during planning. Because xerostomia and dysphagia are the main causes of decreased quality of life after radiotherapy for head and neck cancer, the prevention of these two complications will form the focus of this review.

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