Research team
Expertise
1) CORE The Center for Oncological Research (CORE) has research expertise in personalized cancer medicine, with emphasis on 1) developing novel and more effective therapeutic strategies; 2) an improved detection and understanding of mechanisms driving therapeutic resistance; and 3) identifying and validating biomarkers for personalized therapy, in different cancers in need for improved therapeutic outcomes. Novel and emerging anticancer strategies that we investigate are targeted therapy, immunotherapy, radiotherapy, cold atmospheric plasma therapy as well as novel combination therapies. In CORE, there is a strong interdisciplinary collaboration between basic, translational and clinical researchers. The members of our consortium bring together unrivaled access to biobank patient samples and to a dedicated oncological clinical phase I/II unit with a unique and complementary set of methods and skills covering the entire spectrum of molecular techniques, 2D and 3D cellular assays (in vitro and ex vivo), animal studies and clinical studies. CORE gathers experts with an excellent research track record in targeted therapy, immunotherapy, radiotherapy, combination therapies, genomics, transcriptomics, proteomics, bioinformatics, liquid biopsies, pathology and clinical studies. 2) Personal expertise: - Fundamental and translational cancer research - Cell death mechanism (apoptosis, ferroptosis and immunogenic cell death) - The p53 protein and the biological implications of mutant p53 - Oxidative stress as a therapeutic target for the treatment cancer - Focus on lung cancer and pancreatic cancer - Targeted therapies with the focus on drug repurposing - Immunotherapy - Combination strategies: conventional/targeted; conventional/immunotherapy; targeted/immunotherapy - Primary cancer organoids (lung and pancreas) - Prognostic and predictive biomarker studies - The role of a hypoxic tumor microenvironment on therapy respons - Cold-atmospheric plasma for the treatment of cancer - In vivo syngeneic mouse models for lung cancer
Exploring the potential and underlying mechanisms of therapeutic activation of p53 in combination with immunotherapy to stimulate an innate immune response against non-small cell lung cancer.
Abstract
Cancer treatment is advancing to personalized precision medicine following the continuous development of new targeted therapies and immunotherapies. Despite several recent breakthroughs, lung cancer remains the leading cause of cancer-related death worldwide. Non-small cell lung cancer is characterized by a 5-year survival rate of less than 20%, which is often the result of resistance mechanisms against current therapies. At the Center for Oncological Research we focused on targeting the tumor suppressor p53 protein to overcome resistance to conventionally used DNA-damaging agents. We showed that therapeutic reactivation of either wild type or mutant p53 greatly increased the cytotoxic response to cisplatin in a synergistic manner. Now we want to further improve these results by involving the immune system in the antitumor effect. Therefore, this study will explore the potential of p53 targeting therapies, as monotherapy or in combination with the DNA-damaging agent cisplatin, to eliminate tumor cells by recruitment and activation of natural killer (NK) cells. The outcome of this study could result in an innovate therapeutic strategy which combines a DNA-damaging agent with state-of-the-art targeted- and immunotherapy. As such, tumor cells can be targeted more directly and eliminated using the patient's own defense systems.Researcher(s)
- Promoter: Smits Evelien
- Co-promoter: Deben Christophe
- Fellow: Freire Boullosa Laurie
Research team(s)
Funding
- FWO
Project type(s)
- Research Project
Oxidative stress as a selective anticancer agent: investigation of a targeted combination strategy for mutant p53 non-small cell lung cancer and other solid tumors.
Abstract
Despite many efforts, non-small cell lung cancer (NSCLC) has a dismal 5-year survival rate of less than 20% due to frequently occurring therapy resistance. In addition, currently available targeted therapies are only applicable to limited subgroups of patients. The presence of TP53 mutations is associated with resistance to a wide array of therapeutics that are currently used as first-line treatment in NSCLC, including platinum-based therapies and EGFR tyrosine kinase inhibitors. Since TP53 mutations occur in over 50% of all NSCLC patients, there is a pressing medical need for more effective treatment strategies to improve survival of these patients. In this project, we propose an innovative combination strategy which exploits the presence of mutant p53 by targeting the cellular redox balance. 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 and important role in the repair of ROS-induced DNA-damage. This led us to explore the potential of combining oxidative stress induction, using the compound APR-246, with the targeted inhibition of the PARP-1 protein, using olaparib. In our lab, this combination strategy showed promising in vitro results in NSCLC cell lines, resulting in strong synergistic interactions in the presence of mutant p53. Following our promising data, this project aims to translate this novel and selective combination strategy to the clinic. In this preclinical study we will explore the combination of two oxidative stress-inducing compounds, APR-246 and auranofin, in combination with the PARP-1 inhibitor olaparib. We will study the predictive value of mutant p53 and the role of ROS in the synergistic cytotoxic effects in NSCLC cell lines. Since oxidative stress and mutant p53 are characteristics that are also frequently observed in other tumor types, we will expand our study to pancreatic ductal adenocarcinoma in vitro.Researcher(s)
- Promoter: Deben Christophe
Research team(s)
Funding
- BOF
Project type(s)
- Research Project
Involving the innate immune system in p53-targeted combination therapies.
Abstract
Cancer treatment is advancing to personalized precision medicine following the continuous development of new targeted therapies and immunotherapies. Despite several recent breakthroughs, lung cancer remains the leading cause of cancer-related death worldwide. Non-small cell lung cancer is characterized by a 5-year survival rate of less than 20%, which is often the result of resistance mechanisms against current therapies. At the Center for Oncological Research we focused on targeting the tumor suppressor p53 protein to overcome resistance to conventionally used DNA-damaging agents. We showed that therapeutic reactivation of either wild type or mutant p53 greatly increased the cytotoxic response to cisplatin in a synergistic manner. Now we want to further improve these results by involving the immune system in the antitumor effect. Therefore, this study will explore the potential of p53 targeting therapies, as monotherapy or in combination with the DNA-damaging agent cisplatin, to eliminate tumor cells by recruitment and activation of natural killer (NK) cells via the receptor NKG2D. For this, we will study (I) the p53 dependent induction of NKG2D ligand expression and NK cell targeting chemo- and cytokine secretion in a panel of NSCLC cell lines; (II) NK cell-mediated NSCLC tumor cell killing in co-culture experiments; and (III) the potential additional antitumor effect of interleukin 15 as potent NK cell activator. The outcome of this study could result in an innovate therapeutic strategy which combines a DNA-damaging agent with state-of-the-art targeted- and immunotherapy. As such, tumor cells can be targeted more directly and eliminated using the patient's own defense systems.Researcher(s)
- Promoter: Smits Evelien
- Co-promoter: Deben Christophe
- Fellow: Freire Boullosa Laurie
Funding
- BOF
Project type(s)
- Research Project
Preclinical research on the role and mechanism of MDM2 "small molecule" inhibitors combined with conventional chemo- and/or radiotherapy under normoxic and hypoxic conditions.
Abstract
This project represents a research agreement between the UA and on the onther hand IWT. UA provides IWT research results mentioned in the title of the project under the conditions as stipulated in this contract.Researcher(s)
- Promoter: Pauwels Patrick
- Fellow: Deben Christophe
Funding
- IWT
Project type(s)
- Research Project