Research team

Center for Oncological Research (CORE)

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

OrBITS Platform: A Cloud-Based Image Analysis and Drug Screening Service. 01/09/2021 - 31/08/2022

Abstract

Advances in artificial intelligence (AI) have facilitated the development of solutions for numerous industrial, academic, and research challenges. We have developed a software, named Organoid Brightfield Identification-based Therapy Screening (OrBITS), for image-based analysis of 2D and 3D cancer cell cultures using computer vision technology combined with a convolutional network, machine learning approach (priority patents filed). As such, our OrBITS software can provide 2 major services: 1) software as a service for image-based research analysis and 2) high-throughput screening of therapeutic compounds. The technology and services are already of high interest to both industrial and academic partners, and we have begun performing image analysis and drug screening services for both internal and external groups. However, in order to facilitate and expand our service capacity, some technological and operational gaps must be met. Notably, we require dedicated personnel to perform drug screening of compounds provided by the clients, conduct routine maintenance of biological cultures, and integrate our current workflow with recently acquired state-of-the-art equipment (e.g. Tecan Spark Cyto live imager, Tecan D300e drug printer, Opentron OT-2 pipetting robot). The documentation and standardization of this workflow will streamline future expansion and increase service capacity. Furthermore, we aim to migrate our software to a cloud-based system to centralize data storage and training of the software AI network. Setting up this cloud system will resolve many issues associated with image-based analysis (e.g. inadequate data storage and traffic, inefficient and incremental software updates, absent data sets), which are described by our industrial and academic collaborators. Setting up this cloud-based system will further allow our AI software training unit to stay up-to-date and relevant with the fast past of scientific and translational research, thus keeping our image-based analysis and drug screening services at the cutting edge. Lastly, we aim to work with a dedicated business developer to perform market analysis, optimize pricing and advertisement strategies, and develop a business plan for our service platform, as currently we are working on a collaborative (case-by-case) modality. The technology and business development aims proposed here will enable the establishment of the OrBITS Platform to become a self-sustaining service provider with the ability to scale as the clients and needs increase.

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Rationally designed drug combination screen in more physiologically relevant in vitro organoid models: can we improve personalized therapy for pancreatic cancer? 01/11/2020 - 31/10/2022

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a rapidly progressing and usually fatal disease with a 5-year overall survival rate of less than 8%. Despite significant advances in understanding the molecular disease pathways and treatment of cancer, predicting individual responses to both standard of care and targeted therapies remains a stumbling block. The recent introduction of patient-derived tumor organoids as more physiological relevant models has revolutionized both basic and translational cancer research. However, current readouts to study these multicellular constructs only provide limited information. Considering the limitations described above, I aim to develop an innovative and more physiological relevant predictive co-culture platform that implements the effects of cancer associated fibroblast (CAFs) and hypoxia on treatment response. By using these state-of-the-art high-throughput multiplex endpoint and real-time live-cell imaging assays, I will screen a broad range of rationally designed combination strategies. Through this approach, I aim to unravel more effective and personalized combination strategies for pancreatic cancer. Eventually, I will also associate treatment sensitivity of the most promising combinations with gene mutation and expression signatures to identify novel predictive biomarkers for our innovative combination strategies.

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Rationally designed drug combination screen in more physiologically relevant in vitro organoid models: can we improve personalised therapy for pancreatic cancer? 01/10/2020 - 30/09/2024

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a rapidly progressing and usually fatal disease with a 5-year overall survival rate of less than 8%. Despite significant advances in understanding the molecular disease pathways and treatment of cancer, predicting individual responses to both standard of care and targeted therapies remains a stumbling block. This limited response rate is a result of the heterogeneity combined with an inadequate understanding of the complexity of the tumor microenvironment of PDAC. Therefore, tremendous efforts have been made in developing more physiologically relevant in vitro models that can accurately predict clinical outcome. Even though two-dimensional (2D) in vitro cancer cell lines have been widely used to unravel the molecular mechanism of tumor growth, these models are not able to mimic the in vivo complexity of PDAC. Patient-derived organoids on the other hand represent a more physiologically relevant model because they preserve the cellular heterogeneity and morphology of the primary tumor tissue. However, current readouts to study these multicellular constructs only provide limited information. Considering the major hurdles described above, we aim to develop an innovative and more physiological relevant predictive platform that implements the effects of cancer associated fibroblast (CAFs) and hypoxia on treatment response. By using these state-of-the-art high-throughput multiplex endpoint and real-time live-cell imaging assays we will screen a broad range of rationally designed combination strategies. Through this approach, we aim to unravel more effective and personalized combination strategies for pancreatic cancer. Eventually, we will also associate treatment sensitivity of the most promising combinations with gene mutation and expression signatures to identify novel predictive biomarkers for our innovative combination strategies.

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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. 01/10/2020 - 26/10/2022

Abstract

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. In our search for new anticancer therapies, we discovered that Auranofin, an old drug currently used for rheumatoid arthritis, is highly effective against mutant p53 expressing cancer cells. P53 is the most frequently mutated gene in lung cancer and is often associated with an unfavorable therapeutic outcome. Auranofin is a selective inhibitor of the antioxidant thioredoxin reductase. Previous studies have shown that Auranofin dependent inhibition of this antioxidant blocks several pro-tumorigenic pathways. Recent findings have shown that these pathways are also involved in attracting immunosuppressive cells to the tumor microenvironment and in hiding cancer cells from immune cells. To date, little is known about the underlying mechanisms by which AF induces cancer cell death and if Auranofin can modulate the immune suppressive tumor microenvironment. In this strategic basic research project, we recently discovered that Auranofin induces different types of immunogenic cell death pathways, including the type of cellular 'rust' ferroptosis, which can stimulate the patient's immune cells to efficiently eliminate lung cancer cells. In addition, we will study the in vivo effect of Auranofin on different types of immune cells inside the tumor and peripheral blood to determine if Auranofin is a potential candidate for combination strategies with immunotherapy.

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Versterking van de anti-kanker immuunrespons door modulatie van longkankercellen en de tumor micro-omgeving met behulp van Auranofin. 01/04/2020 - 31/03/2021

Abstract

Despite the discovery of new therapeutic strategies, lung cancer still accounted for more than 18% of the cancer-related deaths in 2018. P53 is the most frequently mutated gene in lung cancer and is often associated with an unfavorable therapeutic outcome. In our search for new anticancer therapies, we discovered that Auranofin (AF), an old drug currently used for rheumatoid arthritis, is highly effective against mutant p53 expressing cancer cells. The drug is a selective inhibitor of the antioxidant thioredoxin reductase. Previous studies have shown that AF dependent inhibition of this antioxidant blocks several pro-tumorigenic pathways. Recent findings have shown that these pathways are also involved in attracting immunosuppressive cells to the tumor microenvironment and in hiding cancer cells from immune cells. To date, little is known about the underlying mechanisms by which AF induces cancer cell death and if AF can modulate the immune suppressive tumor microenvironment. We hypothesize that AF can induce immunogenic cell death, a type of cell death that alerts the patient's immune system leading to an antitumor immune response. In addition, we will study the in vivo effect of AF on different types of immune cells inside the tumor to determine if AF is a potential candidate for combination strategies with immunotherapy.

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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. 01/10/2018 - 30/09/2020

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.

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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. 01/04/2018 - 31/03/2019

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.

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Involving the innate immune system in p53-targeted combination therapies. 01/10/2017 - 30/09/2018

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.

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    Preclinical research on the role and mechanism of MDM2 "small molecule" inhibitors combined with conventional chemo- and/or radiotherapy under normoxic and hypoxic conditions. 01/01/2012 - 31/12/2015

    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.

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