Research Peter Van Dam

Abstract

Breast cancer (BC) and cervical cancer (BHK) patients, especially those with advanced disease, are in urgent need of new agents that improve survival and quality of life. One promising strategy is immunotherapy, but the cancer has developed mechanisms that circumvent its effects and benefit only a minority of patients. Recently, the RANK(L) signaling pathway is considered a significant mechanism, as it allows many cancers - including BK and BHK - to disrupt the communication of the immune cells and thus undermine the immune response. Supported by our initial results, we strongly believe that blocking this signal can override the immune system and improve susceptibility to immunotherapy. We therefore seek to reveal the most appropriate anti-RANK(L) immunotherapy to elicit an optimal anti-tumor immune response. Building on the results of our clinical studies, additional laboratory testing will allow us to identify that one, superior combination strategy, which we will further optimize in mouse models. Finally, this project will validate a novel imaging technique to select patients who will benefit from this therapy in order to minimize treatment and financial burden.

Researcher(s)

• Promoter: Van Dam Peter
• Co-promoter: De Waele Jorrit
• Co-promoter: Lardon Filip
• Co-promoter: Prenen Hans
• Co-promoter: Smits Evelien
• Co-promoter: Van den Wyngaert Tim

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

The research activities of the consortium IPPON (Integrated Personalized & Precision Oncology Network) are at the forefront of integrated 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 early detection and personalized therapy, in different cancers in need for improved therapeutic outcomes. In this way, we aim to deliver the right treatment to the right cancer patient at the right time. Novel and emerging anticancer strategies that we investigate include - but are not limited to - locoregional perfusion, targeted therapy, immunotherapy, cold atmospheric plasma therapy as well as novel combination therapies. We are convinced that the interdisciplinary collaboration between basic, translational and clinical researchers, catalyzed through this consortium, will enable us to tackle burning research questions and clinical unmet needs to advance the field of personalized cancer medicine. The members of our consortium bring together unrivaled access to biobank patient samples and to a dedicated clinical phase I/II oncological 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), small- and large animal studies and clinical studies. IPPON gathers experts with an excellent research track record in fundamental, translational and clinical oncology; surgical techniques; targeted therapy; immunotherapy; (epi)genomics; (epi)transcriptomics; proteomics; imaging; liquid biopsies; pathology and clinical studies.

Researcher(s)

• Promoter: Peeters Marc
• Co-promoter: Dewilde Sylvia
• Co-promoter: Hendriks Jeroen
• Co-promoter: Lardon Filip
• Co-promoter: Pauwels Patrick
• Co-promoter: Smits Evelien
• Co-promoter: Van Dam Peter
• Co-promoter: Vanden Berghe Wim
• Co-promoter: Van den Wyngaert Tim

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Inflammatory breast cancer (IBC) is a rare yet aggressive subtype of breast cancer, with a high mortality amongst others due to the lack of a specific treatment. The primary goal of this project is to strive towards a more comprehensive characterization of the tissue architecture and molecular complexity in IBC. This goal translates in two work packages. Firstly, we aim to investigate the communication between monocytes and B-lymphocytes, two cell types that are relevant to IBC biology based on available literature and our preliminary data. Secondly, using state-of-the-art technologies, we will Investigate the global composition of the tumor microenvironment in IBC beyond the cell types mentioned in the first aim. Then, the acquired knowledge of the composition of the tumor micro-environment and the molecular pathways of intercellular communication in IBC will be used to develop new strategies for targeted therapy. For this purpose, the use of preclinical models that optimally recapitulate tumor biology is quintessential. Therefore, this project will secondarily focus on the development of patient-derived tumor organoids (PDOs) that represent a significant advance for testing new treatment modalities. For this goal, again two work packages can be discerned. First, we aim to establish IBC PDOs that recapitulate the tissue architecture and molecular traits of primary IBC tissue samples as closely as possible. Secondly, we will use these organoid lines to test the efficacy of selected drugs in inducing cancer cell death and identifying predictive biomarkers of treatment response.

Researcher(s)

• Promoter: Van Dam Peter
• Fellow: Vermeulen Chloé

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Cervical cancer (CC) patients, especially those with advanced disease, are urgently in need of new treatment options that can increase their survival rate and quality of life. A promising strategy is immunotherapy, however, only a minority of patients responds to it because the cancer has developed mechanisms that evade its effects. In recent years, the RANKL/RANK signaling pathway has been implicated as one such mechanism, as it allows many cancer types - including CC - to circumvent the immune response by disrupting the communication of the immune cells. Supported by our first results, we strongly believe that blocking the RANKL/RANK signal can release the brakes on the immune system and reinvigorate the tumor's susceptibility to immunotherapy. We therefore aim to expose the best possible immunotherapeutic partner(s) for anti-RANK(L) therapy in order to achieve the most optimal anti-tumor immune effects. For this, we have unique access to CC samples retrieved from patients before and after anti-RANKL monotherapy, which we will thoroughly investigate to reveal immune related changes. Thereafter, we will perform additional laboratory tests that will allow us to pinpoint one best-in-class anti-RANKL combination strategy, which we will further optimize in CC mouse models. Finally, this project will validate a novel imaging technique to stratify patients and monitor treatment response for this therapy, thereby minimizing treatment - and economic burden.

Researcher(s)

• Promoter: Van Dam Peter
• Co-promoter: De Waele Jorrit
• Co-promoter: Van den Wyngaert Tim
• Fellow: Verhoeven Yannick

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

COVID-19 is a disease caused by an infectious outbreak of the SARS-CoV-2 virus. Today, the virus is widely spread throughout the world and declared by the World Health Organisation (WHO) as a pandemic. There are a broad range of clinical presentations of a SARS-CoV-2 viral infection varying from asymptomatic, sensation of a mild cold or flu to severe bilateral pneumonia and death. The mortality is the highest in the elderly and in people with a pre-existing condition such as cancer. In addition, it has already been shown that in patients with a severe COVID-19 infection the cytokine levels in the blood are very high, which can lead to organ failure. Since in cancer patients cytokine production is already increased by their disease and by treatment, this implies a higher susceptibility to develop severe COVID-19 when an exaggerated immune response to this virus produces even more cytokines ("cytokine storm"). The aim of this project is to be able to detect preventively when there is a risk of developing a "cytokine storm" so that potential therapy such as cytokine inhibitors can be used. To accomplish this, the response of the immune system to SARS-Cov2 infection will be mapped in this project. This will be done by performing immunological tests on blood samples from cancer patients and a healthcare workers the same oncology units who seropositive for the SARS-CoV-2 infection. Both blood samples from symptomatic and asymptomatic COVID-19 subjects will be examined immunologically. The immunological tests include immunoassays, flow cytometry and immunomethylomics. The collection of blood samples has already started at the end of March 2020 and the inclusion period is 3 months, so that the early phase, the peak phase and the foreseen decline of the pandemic are included. Cancer patients are asked to take additional blood samples during routine blood samples. A monthly blood sample is requested from the group of healthcare workers (4 samples per participant). First of all, the seropositive samples will be detected on the basis of a serological test. These results also provide insight into the proportion of infected high-risk patients in a hospital environment. On the basis of the immunological tests, the immune response will be compared between the symptomatic cancer patients and asymptomatic cancer patients and matched controlled healthcare workers. In this way, immunological risk factors for the development of severe COVID-19 can be identified and a new outbreak can be controlled in a scientifically responsible manner.

Researcher(s)

• Promoter: Van Dam Peter
• Co-promoter: Huizing Manon
• Co-promoter: Peeters Marc
• Co-promoter: Vanden Berghe Wim
• Co-promoter: Vulsteke Christof

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Cancer patients are at higher risk of developing COVID-19 and suffer a higher likelihood of poor disease outcome due to their underlying illness and/or therapy. Therefore, effective vaccination of cancer patients is of utmost importance. However, it is unclear if the immune system of cancer patients under active oncological treatment is able to mount an effective immune response. We aim to assess the development of protective immunity against COVID-19 upon vaccination in cancer patients.

Researcher(s)

• Promoter: Van Dam Peter

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Cervical cancer (CC) remains a leading cause of cancer related deaths in women worldwide. Over the last decades, little progress has been made in the systemic treatment of patients with advanced or recurrent forms. To successfully battle this cancer and improve long-term benefits for the patient, anti-cancer responses need to be stimulated whereby the immune system eradicates all residual cancer cells and prevents disease outbreak by anti-tumor immunity. Since CC has shown to be immunogenic, a promising hot field of research in oncology that opens new perspectives for its treatments is immunotherapy. However, tumor cells seem to have multiple mechanisms for evading immune surveillance, which is believed to be a major confounding factor involved in failure of currently used immunotherapies, like immune checkpoint inhibitors (ICI). In recent years, the RANKL/RANK signaling pathway has been implicated as a key player in this tumor-induced immunosuppression, making it a very attractive target to reinvigorate the tumor susceptibility to checkpoint inhibition. Signaling between receptor activator of nuclear factor-kappa B (RANK) and its ligand (RANKL) is best described for its obligate role in the differentiation of bone-resorbing osteoclasts and consequential bone-derived diseases, such as postmenopausal osteoporosis and cancer-related bone destruction. This has led to the development of denosumab, a fully human monoclonal antibody that binds RANKL, thereby blocking the interaction with its receptor, RANK. Recently however, it has been shown that RANK and RANKL are commonly highly co- expressed on tumor cells and immune cells in their tumor microenvironment (TME). Accumulating evidence highlights the pivotal role that RANK/L signaling has in allowing tumor cells to evade immune surveillance by modulating the tumor immune environment, and in participating in every step of cancer progression, given its pleiotropic effects on tumor cells and its microenvironment. The primary objective of the proposed research project is to expose the functional mechanisms of the RANK/L signaling pathway in CC. The second objective is to exploit the effects of denosumab on the migratory and invasive features of cervical cancer cells. We hypothesize that RANK/L signaling plays a key role in both the metastatic as immune modulating features of CC, and therefore we see great potential in investigating the drug repurposing of denosumab in the battle against this type of cancer.

Researcher(s)

• Promoter: Van Dam Peter

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

IBC is characterized by a rapid onset, redness and swelling of the breast. Despite an aggressive therapy with chemotherapeutics, radiation and surgery the survival rate is the worst among all breast cancers with less than 40 % survival after 5 years. Therefore, further research is necessary. Although IBC and non-IBC (nIBC) tumours are different diseases in many ways, our lab showed that genetically an IBC tumour and a nIBC tumour are not so different after all. Based on these findings we think that the non-cancerous cells that are part of the tumour or the patient's response to the tumour can explain the difference. Thus we are interested in how the surrounding tissue and especially the immune cells respond to IBC and how this is different from nIBC. To examine this we will start our research by determining what types of cells are present in both tumour types and whether they are functioning as they should be. By correlating the presence of certain cell types or functional markers with response to treatment, survival information and properties of the tumour we can see what type of cells or functional markers could predict prognosis or response to therapy and can be called biomarkers. Furthermore, the combination of this information with data about which genes in a tumour sample are over- or underexpressed could lead to a better understanding of the genetic pathways that are important in IBC growth. If we can alter these pathways, we might find new targets for therapy.

Researcher(s)

• Promoter: Van Dam Peter
• Co-promoter: Colpaert Cecile
• Co-promoter: Trinh Xuan Bich
• Co-promoter: Van Laere Steven
• Fellow: Van Berckelaer Christophe

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

To study in a retrospective series of archival paraffin embedded cervical, CIN I, CIN III and invasive cervical cancer samples the relationship between RANK signaling, the immune infiltrate and targets for checkpoint inhibition. This should be the preliminary work for FWO or KotK grant application

Researcher(s)

• Promoter: Van Dam Peter

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

IBC is characterized by a rapid onset, redness and swelling of the breast. Despite an aggressive therapy with chemotherapeutics, radiation and surgery the survival rate is the worst among all breast cancers with less than 40 % survival after 5 years. Therefore, further research is necessary. Although IBC and non-IBC (nIBC) tumours are different diseases in many ways, our lab showed that genetically an IBC tumour and a nIBC tumour are not so different after all. Based on these findings we think that the non-cancerous cells that are part of the tumour or the patient's response to the tumour can explain the difference. Thus we are interested in how the surrounding tissue and especially the immune cells respond to IBC and how this is different from nIBC. To examine this we will start our research by determining what types of cells are present in both tumour types and whether they are functioning as they should be. By correlating the presence of certain cell types or functional markers with response to treatment, survival information and properties of the tumour we can see what type of cells or functional markers could predict prognosis or response to therapy and can be called biomarkers. Furthermore, the combination of this information with data about which genes in a tumour sample are over- or underexpressed could lead to a better understanding of the genetic pathways that are important in IBC growth. If we can alter these pathways, we might find new targets for therapy.

Researcher(s)

• Promoter: Van Dam Peter
• Co-promoter: Van Laere Steven
• Fellow: Van Berckelaer Christophe

Research team(s)

Project type(s)

• Research Project

Abstract

This project will be centred on a large, considering the rare nature of IBC, database of more than 200 IBC patients diagnosed in GZA Sint-Augustinus, Antwerp; Antwerp University Hospital, Antwerp and Institut Paoli Calmettes, Marseile since 1997. We have access to detailed clinical data, up to date survival information and affymetrix gene expression profiles. Besides we also have large numbers of nIBC patients in these centra and due to the large IBC database subtype specific- and matched research will be possible. Although there is only an international consensus on IBC diagnosis since 2011, these 3 research institutions have always used the same clinical and pathological criteria to diagnose IBC. Because this is an innovative study, many of the immune parameters have never been looked at in IBC. Therefore it is impossible to do a power-analysis for the whole study. However, if we look at the proportions of different types of immune cells in nIBC  and at our preliminary analysis that showed an enrichment for TAM and activated B-cells we should be able to show proportional changes since the absolute number of TILs in IBC and nIBC are probably the same. We calculated that with a sample size of +/- 200 patients in each group we will have 80% power to detect a difference between proportions of at least 10% for TAM (e.g. IBC: 15% vs nIBC: 5%), and 12% for B-cells (e.g. IBC: 32% vs nIBC: 20%), using a two group chi-square test with a 0.05 two-sided significance level.

Researcher(s)

• Promoter: Van Dam Peter
• Fellow: Van Berckelaer Christophe

Research team(s)

Project type(s)

• Research Project