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Dive into the research topics where Christophe Deben is active.

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Featured researches published by Christophe Deben.


Critical Reviews in Oncology Hematology | 2016

TP53 and MDM2 genetic alterations in non-small cell lung cancer: Evaluating their prognostic and predictive value.

Christophe Deben; Filip Lardon; Christian Rolfo; Patrick Pauwels

The p53 pathway has been extensively studied for its role in carcinogenesis. Disruption of the pathway occurs in more than half of all cancers, often leading to a worse prognosis for the patient. In recent years several compounds have been successfully developed to target and restore the p53 pathway, either by blocking the MDM2-p53 interaction, restoring wild type conformation of mutant p53, or exploiting the presence of mutant p53 by blocking DNA damage repair pathways. In this review the known data on the role of p53 on prognosis and response to commonly used chemotherapeutics in non-small cell lung cancer is summarized. The focus is on the presence of genetic alterations in the TP53 or MDM2 gene, p53s main negative regulator. In addition, promising therapeutic options will be discussed in relation to specific alterations in the p53 pathway.


Cancer Letters | 2016

APR-246 (PRIMA-1(MET)) strongly synergizes with AZD2281 (olaparib) induced PARP inhibition to induce apoptosis in non-small cell lung cancer cell lines.

Christophe Deben; Filip Lardon; An Wouters; Ken Op de Beeck; Jolien Van den Bossche; Julie Jacobs; Nele Van Der Steen; Marc Peeters; Christian Rolfo; Patrick Pauwels

APR-246 (PRIMA-1(Met)) is able to bind mutant p53 and restore its normal conformation and function. The compound has also been shown to increase intracellular ROS levels. Importantly, the poly-[ADP-ribose] polymerase-1 (PARP-1) enzyme plays an important role in the repair of ROS-induced DNA damage. We hypothesize that by blocking this repair with the PARP-inhibitor AZD2281 (olaparib), DNA damage would accumulate in the cell leading to massive apoptosis. We observed that APR-246 synergistically enhanced the cytotoxic response of olaparib in TP53 mutant non-small cell lung cancer cell lines, resulting in a strong apoptotic response. In the presence of wild type p53 a G2/M cell cycle block was predominantly observed. NOXA expression levels were significantly increased in a TP53 mutant background, and remained unchanged in the wild type cell line. The combined treatment of APR-246 and olaparib induced cell death that was associated with increased ROS production, accumulation of DNA damage and translocation of p53 to the mitochondria. Out data suggest a promising targeted combination strategy in which the response to olaparib is synergistically enhanced by the addition of APR-246, especially in a TP53 mutant background.


Diagnostic Molecular Pathology | 2013

Expression analysis on archival material revisited : isolation and quantification of RNA extracted from FFPE samples

Christophe Deben; Karen Zwaenepoel; Carolien Boeckx; An Wouters; Patrick Pauwels; Marc Peeters; Filip Lardon; Marc Baay

Background:Formalin-fixed paraffin-embedded (FFPE) tissue is the most readily available source of RNA for the gene expression studies. The main disadvantage is the poor quality of isolated RNA. Our group recently compared 5 commercially available RNA isolation kits and concluded that the RNeasy FFPE kit from Qiagen was the most appropriate one. However, this kit has been discontinued and replaced by a new version. In this study both kits were compared, and spectrophotometric and fluorometric analyses for quantification of RNA samples extracted from FFPE tissue. Methods:Both RNeasy FFPE kits were compared for the total RNA and DNA yields, purity, and raw cycle threshold. Quantity and quality of the isolated RNA was measured using the NanoDrop ND-1000 spectrophotometer and Qubit 2.0 fluorometer. Results:The average concentration of RNA extracted from FFPE tissue measured using the NanoDrop was 32.0%±9.5% higher than the concentration measured using the Qubit. When measuring an RNA sample extracted from a cell line, the concentration measured using both methods was similar. When comparing both RNeasy FFPE kits, marginal differences were observed for total RNA yield, purity, and raw cycle threshold. However, the residual DNA in the samples isolated using the old kit was higher than in the samples isolated using the new kit. Conclusions:A fluorometric analysis is more suitable for quantification of RNA samples extracted from FFPE tissue compared with spectrophotometric analysis. For RNA isolation from FFPE tissue, both old and new RNeasy FFPE kits were adequate. The new kit resulted in more efficient DNA removal.


Tumor Biology | 2017

Deep sequencing of the TP53 gene reveals a potential risk allele for non–small cell lung cancer and supports the negative prognostic value of TP53 variants

Christophe Deben; Jolien Van den Bossche; Nele Van Der Steen; Filip Lardon; An Wouters; Ken Op de Beeck; Christophe Hermans; Julie Jacobs; Marc Peeters; Guy Van Camp; Christian Rolfo; Patrick Pauwels

The TP53 gene remains the most frequently altered gene in human cancer, of which variants are associated with cancer risk, therapy resistance, and poor prognosis in several tumor types. To determine the true prognostic value of TP53 variants in non–small cell lung cancer, this study conducted further research, particularly focusing on subtype and tumor stage. Therefore, we determined the TP53 status of 97 non–small cell lung cancer adenocarcinoma patients using next generation deep sequencing technology and defined the prognostic value of frequently occurring single nucleotide polymorphisms and mutations in the TP53 gene. Inactivating TP53 mutations acted as a predictor for both worse overall and progression-free survival in stage II–IV patients and patients treated with DNA-damaging (neo)adjuvant therapy. In stage I tumors, the Pro-allele of the TP53 R72P polymorphism acted as a predictor for worse overall survival. In addition, we detected the rare R213R (rs1800372, minor allele frequency: 0.0054) polymorphism in 7.2% of the patients and are the first to show the significant association with TP53 mutations in non–small cell lung cancer adenocarcinoma patients (p = 0.003). In conclusion, Our findings show an important role for TP53 variants as negative predictors for the outcome of non–small cell lung cancer adenocarcinoma patients, especially for TP53 inactivating mutations in advanced stage tumors treated with DNA-damaging agents, and provide the first evidence of the R213R G-allele as possible risk factor for non–small cell lung cancer.


Journal of Cancer | 2017

Towards Prognostic Profiling of Non-Small Cell Lung Cancer: New Perspectives on the Relevance of Polo-Like Kinase 1 Expression, the TP53 Mutation Status and Hypoxia

Jolien Van den Bossche; Christophe Deben; Ken Op de Beeck; Christophe Hermans; Ines De Pauw; Julie Jacobs; Paul Van Schil; Jan B. Vermorken; Patrick Pauwels; Marc Peeters; Filip Lardon; An Wouters

Background: Currently, prognosis of non-small cell lung cancer (NSCLC) patients is based on clinicopathological factors, including TNM stage. However, there are considerable differences in patient outcome within a similar staging group, even when patients received identical treatments. In order to improve prognostic predictions and to guide treatment options, additional parameters influencing outcome are required. Polo-like kinase 1 (Plk1), a master regulator of mitotic cell division and the DNA damage response, is considered as a new potential biomarker in this research area. While several studies reported Plk1 overexpression in a broad range of human malignancies, inconsistent results were published regarding the clinical significance hereof. A prognostic panel, consisting of Plk1 and additional biomarkers that are related to the Plk1 pathway, might further improve prediction of patient prognosis. Methods: In this study, we evaluated for the first time the prognostic value of Plk1 mRNA and protein expression in combination with the TP53 mutation status (next generation sequencing), induction of apoptotic cell death (immunohistochemistry for cleaved caspase 3) and hypoxia (immunohistochemistry for carbonic anhydrase IX (CA IX)) in 98 NSCLC adenocarcinoma patients. Results: Both Plk1 mRNA and protein expression and CA IX protein levels were upregulated in the majority of tumor samples. Plk1 mRNA and protein expression levels were higher in TP53 mutant samples, suggesting that Plk1 overexpression is, at least partially, the result of loss of functional p53 (<0.05). Interestingly, the outcome of patients with both Plk1 mRNA and CA IX protein overexpression, who also harbored a TP53 mutation, was much worse than that of patients with aberrant expression of only one of the three markers (p=0.001). Conclusion: The combined evaluation of Plk1 mRNA expression, CA IX protein expression and TP53 mutations shows promise as a prognostic panel in NSCLC patients. Moreover, these results pave the way for new combination strategies with Plk1 inhibitors.


Oncogenes and Tumour Suppressor Genes | 2018

PO-087 Oxidative stress as a selective anticancer agent: preclinical evaluation of a targeted combination strategy for mutant P53 non-small cell lung cancer

Christophe Deben; C Rolfo; M Peeters; Filip Lardon; P Pauwels

Introduction Increased oxidative stress is a hallmark of cancer cells, which makes them more vulnerable to induction of reactive oxygen species (ROS). P53 plays a crucial role in sensing and removing oxidative damage to DNA, and inactivating mutations in the TP53 gene attenuate this function. In addition, it was shown that mutant p53 is able to suppress the function of major antioxidant factors. Therefore, mutant p53 renders cancer cells even more susceptible to the induction of oxidative stress. Besides p53, the poly (ADP-ribose) polymerase 1 (PARP-1) protein plays an important role in the repair of ROS-induced DNA-damage. This led us to explore the potential of combining oxidative stress induction with the targeted inhibition of the PARP-1 protein to selectively target mutant p53 NSCLC cancer cells. Material and methods APR-246 and Auranofin (inhibition glutathione (GSH) and/or thioredoxin reductase 1 (TrxR1)) and Olaparib (PARP-1 inhibitor) were used. The cytotoxicity (SRB-assay) of these compounds was determined in a panel of NSCLC cell lines with different p53 status, including isogenic cell lines (p53 shRNA-knockdown, p53 knock-in). Total GSH content (GSH/GSSG-GloTM) and ROS content (CellROX) were determined. N-acetyl-l-cysteine (NAC) was used as a potent ROS-scavenger. Induction of apoptosis/cell death was determined by the AnnV/PI assay (FC) or the Cytotox Reagent (IncuCyte). DNA-damage was assessed by g-H2AX foci (IF) and the Comet Assay. Synergism was determined using the Additive model. Results and discussions P53Mut knock-down reduces the cytotoxic effect of APR-246, Auranofin and Olaparib, while p53Mut knock-in sensitised cells for all three compounds. APR-246/Olaparib treatment reduced GSH levels and increased ROS content, resulting in a strong accumulation of DNA-damage and synergistic induction of cell death. Co-treatment with NAC or p53-knockdown significantly reduced this cytotoxic response. Similar synergistic effects were observed for Auranofin/Olaparib treatment in several cell lines with clinically relevant p53 mutations. Conclusion Mutant p53 protein expression renders NSCLC cells more susceptible to APR-246, Auranofin and Olaparib treatment. In addition, the combination of oxidative stress induction (APR-246, Auranofin) with PARP-1 inhibition (Olaparib) results in remarkable synergistic effects in the presence of mutant p53. Therefore, this combination strategy could be a promising and selective treatment option for mutant p53 NSCLC patients in which resistance to standard therapies often occurs.


OncoImmunology | 2018

Poly(I:C) primes primary human glioblastoma cells for an immune response invigorated by PD-L1 blockade

Jorrit De Waele; Elly Marcq; Jonas Van Audenaerde; Jinthe Van Loenhout; Christophe Deben; Karen Zwaenepoel; Erik Van de Kelft; David Van der Planken; Tomas Menovsky; Johan Van den Bergh; Yannick Willemen; Patrick Pauwels; Zwi N. Berneman; Filip Lardon; Marc Peeters; An Wouters; Evelien Lj Smits

ABSTRACT Prognosis of glioblastoma remains dismal, underscoring the need for novel therapies. Immunotherapy is generating promising results, but requires combination strategies to unlock its full potential. We investigated the immunomodulatory capacities of poly(I:C) on primary human glioblastoma cells and its combinatorial potential with programmed death ligand (PD-L) blockade. In our experiments, poly(I:C) stimulated expression of both PD-L1 and PD-L2 on glioblastoma cells, and a pro-inflammatory secretome, including type I interferons (IFN) and chemokines CXCL9, CXCL10, CCL4 and CCL5. IFN-β was partially responsible for the elevated PD-1 ligand expression on these cells. Moreover, real-time PCR and chloroquine-mediated blocking experiments indicated that poly(I:C) triggered Toll-like receptor 3 to elicit its effect. Cocultures of poly(I:C)-treated glioblastoma cells with peripheral blood mononuclear cells enhanced lymphocytic activation (CD69, IFN-γ) and cytotoxic capacity (CD107a, granzyme B). Additional PD-L1 blockade further propagated immune activation. Besides activating immunity, poly(I:C)-treated glioblastoma cells also doubled the attraction of CD8+ T cells, and to a lesser extent CD4+ T cells, via a mechanism which included CXCR3 and CCR5 ligands. Our results indicate that by triggering glioblastoma cells, poly(I:C) primes the tumor microenvironment for an immune response. Secreted cytokines allow for immune activation while chemokines attract CD8+ T cells to the front, which are postulated as a prerequisite for effective PD-1/PD-L1 blockade. Accordingly, additional blockade of the concurrently elevated tumoral PD-L1 further reinforces the immune activation. In conclusion, our data proposes poly(I:C) treatment combined with PD-L1 blockade to invigorate the immune checkpoint inhibition response in glioblastoma.


Monday Poster Presentation | 2018

PO-018 Immunogenic potential of cold atmospheric plasma for the treatment of pancreatic cancer

J Van Loenhout; Christophe Deben; Julie Jacobs; J. K. De Waele; J Van Audenaerde; Elly Marcq; Sylvia Dewilde; Annemie Bogaerts; Evelien Smits

Introduction Pancreatic ductal adenocarcinoma (PDAC) is a tumour with a fibroblastic stroma compartment that consists of pancreatic stellate cells (PSC) which play a complex role in supporting carcinogenesis, immunosuppression and therapy resistance. Therefore, the 5 year survival rate for PDAC patients remains below a disappointing 8%, stressing the need for new and more effective treatments. Recently, cold atmospheric plasma (CAP) has emerged as a potent treatment option for cancer. Although, CAP is being investigated for several years, the involvement of the immune system after CAP treatment remains poorly understood. The immunogenic cell death (ICD) concept describes that the killing of cancer cells leads to direct activation of the immune system through release of so-called ‘danger-associated molecular patterns’. ICD can be elicited by several physical means such as irradiation and photodynamic therapy, providing a rationale for the induction of ICD after CAP treatment. The aim of this study is to investigate the induction of a specific antitumoral immune response after CAP treatment in PDAC, in vitro. Material and methods Phosphate-buffered saline (PBS) was treated with CAP, generated by the kINPenIND, and subsequently added to monocultures of both pancreatic cancer cell (PCC) lines and PSC lines. To evaluate the four most important hallmarks of ICD, being membrane exposure of calreticulin, secretion of ATP and release of HMGB1 and type I interferon, the treatment parameters were optimised (i.e. treatment time, gas flow and gap distance) to obtain 50% cell death. The cellular difference in sensitivity for CAP treatment was assessed through cytotoxic analysis. After attaining the optimal treatment parameters, we investigated the translocation of calreticulin onto the cell surface with flow cytometry. ATP secretion was investigated with a bioluminescence assay, while ELISA was used to monitor the release of HMGB1 and interferon type I in the supernatants. Results and discussions Our data report a cytotoxic effect of CAP treatment in vitro on both PCC and PSC. In both PCC and PSC our results show a significant expression of calreticulin after CAP treatment, together with a significant release of ATP in PCC, but not in PSC. The evaluation of other ICD hallmarks after CAP treatment is currently ongoing. Conclusion We strongly believe that CAP therapy can be a good alternative for the treatment of PDAC. However, the results warrant further in vivo validation to refine the involvement of the immune system after CAP treatment.


Cancers | 2018

Hypoxia-Induced Cisplatin Resistance in Non-Small Cell Lung Cancer Cells Is Mediated by HIF-1α and Mutant p53 and Can Be Overcome by Induction of Oxidative Stress

Christophe Deben; Jorrit De Waele; Julie Jacobs; Jolien Van den Bossche; An Wouters; Marc Peeters; Christian Rolfo; Evelien Smits; Filip Lardon; Patrick Pauwels

The compound APR-246 (PRIMA-1MET) is a known reactivator of (mutant) p53 and inducer of oxidative stress which can sensitize cancer cells to platinum-based chemotherapeutics. However, the effect of a hypoxic tumor environment has been largely overlooked in this interaction. This study focusses on the role of hypoxia-inducible factor-1α (HIF-1α) and the p53 tumor suppressor protein in hypoxia-induced cisplatin resistance in non-small cell lung cancer (NSCLC) cells and the potential of APR-246 to overcome this resistance. We observed that hypoxia-induced cisplatin resistance only occurred in the p53 mutant NCI-H2228Q331* cell line, and not in the wild type A549 and mutant NCI-H1975R273H cell lines. Cisplatin reduced HIF-1α protein levels in NCI-H2228Q331* cells, leading to a shift in expression from HIF-1α-dependent to p53-dependent transcription targets under hypoxia. APR-246 was able to overcome hypoxia-induced cisplatin resistance in NCI-H2228Q331* cells in a synergistic manner without affecting mutant p53Q331* transcriptional activity, but significantly depleting total glutathione levels more efficiently under hypoxic conditions. Synergism was dependent on the presence of mutant p53Q331* and the induction of reactive oxygen species, with depletion of one or the other leading to loss of synergism. Our data further support the rationale of combining APR-246 with cisplatin in NSCLC, since their synergistic interaction is retained or enforced under hypoxic conditions in the presence of mutant p53.


Oncotarget | 2017

Preclinical data on the combination of cisplatin and anti-CD70 therapy in non-small cell lung cancer as an excellent match in the era of combination therapy

Julie Jacobs; Christian Rolfo; Karen Zwaenepoel; Jolien Van den Bossche; Christophe Deben; Karen Silence; Hans de Haard; Christophe Hermans; Sylvie Rottey; Christel Vangestel; Filip Lardon; Evelien Smits; Patrick Pauwels

In contrast to the negligible expression of the immunomodulating protein CD70 in normal tissue, we have demonstrated constitutive overexpression of CD70 on tumor cells in a subset of primary non-small cell lung cancer (NSCLC) biopsies. This can be exploited by CD70-targeting antibody-dependent cellular cytotoxicity (ADCC)-inducing antibodies. Early clinical trials of these antibodies have already shown promising results in CD70-positive malignancies.In this study, we explored the potential of cisplatin to induce CD70 expression in NSCLC. Using real-time measurement tools, we also assessed the efficacy of a combination regimen with cisplatin and anti-CD70 therapy under normoxia and hypoxia. We identified an induction of CD70 expression on lung cancer cells upon low doses of cisplatin, independent of oxygen levels. More importantly, the use of cisplatin resulted in an enhanced ADCC-effect of anti-CD70 therapy. As such, this combination regimen led to a significant decrease in lung cancer cell survival cell survival, broadening the applicability the applicability of CD70-targeting therapy.This is the first study that proves the potential of a combination therapy with cisplatin and CD70-targeting drugs in NSCLC. Based on our data, we postulate that this combination strategy is an interesting approach to increase tumor-specific cytotoxicity and reduce drug-related side effects.In contrast to the negligible expression of the immunomodulating protein CD70 in normal tissue, we have demonstrated constitutive overexpression of CD70 on tumor cells in a subset of primary non-small cell lung cancer (NSCLC) biopsies. This can be exploited by CD70-targeting antibody-dependent cellular cytotoxicity (ADCC)-inducing antibodies. Early clinical trials of these antibodies have already shown promising results in CD70-positive malignancies. In this study, we explored the potential of cisplatin to induce CD70 expression in NSCLC. Using real-time measurement tools, we also assessed the efficacy of a combination regimen with cisplatin and anti-CD70 therapy under normoxia and hypoxia. We identified an induction of CD70 expression on lung cancer cells upon low doses of cisplatin, independent of oxygen levels. More importantly, the use of cisplatin resulted in an enhanced ADCC-effect of anti-CD70 therapy. As such, this combination regimen led to a significant decrease in lung cancer cell survival cell survival, broadening the applicability the applicability of CD70-targeting therapy. This is the first study that proves the potential of a combination therapy with cisplatin and CD70-targeting drugs in NSCLC. Based on our data, we postulate that this combination strategy is an interesting approach to increase tumor-specific cytotoxicity and reduce drug-related side effects.

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