Title Promoter Affiliations Abstract "Exploring the consequences of nuclear envolope stress in cancer cells." "Winnok De Vos" "Laboratory of cell biology and histology" "Altered nuclear shape is a defining feature of cancer cells, but the relationship with pathology development remains elusive. Recent observations indicate that nuclear dysmorphy correlates with an enhanced propensity of nuclei to rupture. Such ruptures transiently perturb nuclear compartmentalization but also provoke DNA damage. Thus, nuclear dysmorphy and fragility – jointly referred to as nuclear envelope (NE) stress – may contribute to genome instability and thereby represent a novel emerging hallmark of cancer. To better understand the contribution of NE stress to the carcinogenic process, I propose to systematically investigate the short- and long-term molecular consequences. To this end, I intend to analyze the population-level changes in the transcriptome as well as in the genome upon targeted, temporary disruption of nuclear compartmentalisation. This way, I expect to generate a comprehensive view on the impact of NE stress on cell fate. In extensu, this work may also lead to the identification of novel synthetic lethal targets that could be exploited in clinical applications." "Metabolic editing of the tumor microenvironment as a novel strategy to abate immunosuppression" "Max Mazzone" "Laboratory of Tumor Inflammation and Angiogenesis (VIB-KU Leuven)" "Cancer immunotherapy has provided patients with a promising treatment approach but also revealed that several tumors rarely exhibit objective responses to these therapies. The harsh tumor microenvironment (TME) along with all his cellular and metabolic crosstalk between cancer and stromal cells is certainly a key player in orchestrating alternative immunosuppressive mechanisms. The next challenge is therefore to identify novel mechanisms and therapeutic targets able to promote a potent anti-tumor immune response in all those cases where immune intervention does not offer a durable response, or in the worst case, the tumor is completely refractory to this treatment. Here we now propose to study how our candidate metabolic alteration in cancer cells is able to promote the influx and fitness of the cytotoxic T cells in the tumor microenvironment. The outcome of our research will offer proof-of-principle that genetic and pharmacological inhibition of our metabolic target can promote anti-tumor immune response in preclinical relevant murine models. This represents a novel frontier of cancer immunotherapy and the insights obtained will therefore have important implications for therapeutic purposes, to the benefit of future patient care and cure." "Targeting CD70-positive cancer-associated fibroblasts to improve chemotherapy and alleviate the immuno-suppressive tumor microenvironment in advanced colorectal cancer." "Patrick Pauwels" "Faculty of Medicine and Health Sciences - other, Ghent University, Center for Oncological Research (CORE)" "Colorectal cancer (CRC) retains its position as one of the most prevalent types of cancer with around 700,000 deaths per year worldwide. Treatments focused on altering the immune system have recently paved their way into oncology with clinical achievements seen in a broad spectrum of solid tumors. However, signals of activity in CRC are largely involving microsatellite instable tumors, leaving a great need for effective immunotherapy in the majority of patients. The biologica! complexity of the tumor microenvironment seems to be an obstacle for cancer immunotherapy, suggesting that a strategy to solely targeting tumor cells is inadequate to overwhelm the aggressively growing tumor in CRC. Cancer-associated fibroblasts (CAFs) represent the dominant constituents of the tumor stroma and play a critica! role in the proliferative and invasive behavior of CRC. Additionally, CAFs provide a physical barrier for the efficient delivery of systemic therapy to the tumor making it an attractive target to combine with conventional treatment. Clinically addressing CAFs has been challenging due to its heterogeneous nature with both cancer-promoting and cancer-restraining features. We have recently identified a phenotypically distinct subset of CAFs in invasive CRC specimens, marked by the expression of CD70, and associated with poor prognosis of the patient. Moreover, CD70-positive CAFs proved to stimulate tumor invasion and to promote immune escape by the accumulation of immune suppressive regulatory T-cells. lnterestingly, CD70 is totally absent from normal epithelial tissue making it a safe target to eradicate the tumor-promoting CAFs. Based on our preliminary data, we hypothesize that targeting CD70-positive CAFs in CRC has a potential triple mode of action by enhancing anti-tumor immunity, eradicating a permissive niche for tumor invasion and increasing the efficacy of first-line chemotherapeutics. The primary objective of the proposed project is to find the ideal approach to deplete CD70-positive CAFs. The second objective is to design a combination strategy of CD70-targeted therapy with a first-line chemotherapeutic agent that elicits a potent anti-tumor immune response. The third objective is to identify potential bloodbased biomarkers for diagnosis and to monitor treatment response. Experiments will be performed in vitro under normoxic and hypoxic conditions and in vivo in an orthotopic syngeneic mouse model to identify the ideal timing and dosing of our combination strategy. This translational research project wil! lead to the launch of a phase 1/11 clinical trial in patients with advanced CRC with a grim prognosis of only 12 to 14 months. Since we have also found CD70 expression in the desmoplastic stroma of pancreatic cancer, this study will also pave the way to application in one of the most therapeutically resistant maliçinancies." "Investigation of combined immune checkpoint blockade in malignant pleural mesothelioma." "Evelien Smits" "Center for Oncological Research (CORE)" "Malignant pleural mesothelioma (MPM) is an aggressive cancer that is causally associated with previous, mostly professional, asbestos exposure in most afflicted patients. Although preventive measures to limit asbestos use and exposure have been around for several decades, the incidence of MPM is still expected to increase over the next decade due to the long latency between asbestos exposure and MPM development. The prognosis of patients diagnosed with MPM remains dismal with a median overall survival of only 9-12 months and a 5-year survival rate of less than 5%, due to its aggressive nature and the limited effectiveness of any conventional anti-cancer treatment (i.e. chemotherapy, surgery and radiotherapy). The new chemotherapy regimens consisting of a combination of a platinum compound and the folate antimetabolites pemetrexed or raltitrexed have a significant but limited impact on overall survival in MPM. Therefore, new therapeutic strategies are needed to complement the limited armamentarium against MPM. The observation that the immune system can recognize and eliminate tumors is the impetus of the fast-growing research domain of cancer immunotherapy. With the discovery of immune checkpoints, immunotherapy of cancer has entered a new and exciting phase. Clinical studies in a.o. melanoma, renal cell cancer and lung cancer have shown that anti-PD-1 immunotherapy has durable clinical activity, even after treatment cessation, resulting in approval. Also anti-PD-L1 immunotherapy has been approved for treatment of different cancers. PD-1 and PD-L1 expression data in MPM of us and others laid the basis to evaluate their suitability as immunotherapeutic targets also in MPM. Two clinical trials, investigating PD-1 or PD-L1 inhibition in mesothelioma (KEYNOTE-28 and JAVELIN trial, respectively), have already shown promising results with room for improvement. Two other immune checkpoints, being lymphocyte activation gene-3 (LAG-3) and T-cell mucin immunoglobulin-3 (TIM-3), recently gained more interest since they have been described to be associated with T-cell tolerance and exhausted T cells that are infiltrating the tumor micro-environment. Our data on TIM-3 and LAG-3 expression in MPM effusions and on TIM-3 in MPM tissue samples identify both as promising new targets in MPM. Combined targeting of PD-1/PD-L1 with TIM-3 or LAG-3 was highly effective in controlling tumor growth in vivo in different other solid tumor models, providing a rationale to investigate combined blockade also in MPM. Smart combination strategies might improve the antitumor response by interfering with multiple immune escape mechanisms." "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." "Evelien Smits" "Center for Oncological Research (CORE)" "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." "Unlocking the TCR repertoire for personalized cancer immunotherapies." "Center for Oncological Research (CORE), Laboratory for Experimental Hematology (LEH), ADReM Data Lab (ADReM)" "Cancer is one of the leading causes of death worldwide. Over the past decades, new therapies have been developed that target the patients' immune system to mount an antitumor response. The efficacy of these immunotherapies has already been demonstrated in various clinical trials. Nevertheless, these therapies show a large variation in their individual responses as some patients respond well to the therapy, while others do not. In this project, we will investigate the differences between the T cell receptor (TCR) repertoires of responders and non-responders as a possible marker for immunotherapy responsiveness. We will apply state-of-the-art data mining methods and newly developed immunoinformatics tools to uncover those features that make a patient a clinical responder or non-responder. This will reveal the underlying mechanism of DC-based vaccine responsiveness. This can potentially accelerate general health care in terms of personalized medicine and will save costs." "The future of TRACE: a Belgian PDX platform boosting cutting edge cancer research" "Eleonora Leucci" "Laboratory for RNA Cancer Biology" "In the near future, TRACE had the ambition to reinforce its position as the leading Belgian platform for preclinical research by expanding the collection models and engineer them to better mimic human cancers." "Understanding intra-tumor heterogeneity in glioblastoma in space and in time." "Gabriele Bergers" "Laboratory for Tumor Microenvironment and Therapeutic Resistance (VIB-KU Leuven)" "Intra-tumor heterogeneity is the main obstacle to effective cancer treatment and personalized medicine. The mechanistic underpinnings of intra-tumor heterogeneity in progression and therapeutic resistance are however largely unknown. Single-cell RNA-sequencing (scRNA-seq) has revealed significant inter- and intra-tumoral molecular heterogeneity in Glioblastoma (GBM), an aggressive brain tumor that is obstinate to most therapies. However, this technology lacks spatial information resulting from tissue dissociation. This is important as GBMs are also phenotypically heterogeneous and are comprised of specific niches that regulate metabolic needs, immunesurveillance, survival, and invasion, as well as stem cell maintenance. Intra-tumor heterogeneity is therefore likely to be promoted by interactions between tumor cells and their environment. To unravel cell-cell communication in the tissue context, this proposal is aimed at investigating intratumor heterogeneity in a genetically engineered mouse model of GBM using scRNA-seq and spatial transcriptomics, an emerging state-of-the-art technology that allows visualization and quantitative analysis of the transcriptome of single cells with spatial resolution. It provides invaluable information about tumor organisation and the interactions between tumor cells and the local environment. I will zoom into different GBM niches to determine the presence of tumor subclones and how they interact with the tumor vasculature and immune cells. " "High-dose locoregional chemotherapy in the lung: towards a less invasive percutaneous technique." "Antwerp Surgical Training, Anatomy and Research Centre (ASTARC)" "Surgical resection of lung metastases is a widely accepted procedure but due to local and distant recurrences reported 5-year survival rates are only 30 to 40%. Reoperations are feasible but often patients become inoperable due to insufficient pulmonary reserve and for this reason new treatment modalities are being investigated. The maximal dose of intravenous chemotherapy is limited due to systemic side-effects, mainly haematological. As is the case with isolated limb and liver perfusion, isolated lung perfusion has the advantage of selectively delivering an agent into the lung while diverting the venous effluent. Phase I and phase II studies have shown that isolated lung perfusion is feasible and may decrease local recurrence rate. However, it remains an invasive technique and less invasive alternative methods are being investigated. Pulmonary artery infusion is such a technique by injecting a cytostatic drug directly in the pulmonary artery without control of the venous effluent. This offers the advantage of high drug exposure in lung parenchyma with some controlled systemic exposure. In this way, isolated lung perfusion is combined with classical intravenous chemotherapy, which may offer an additional advantage to control distant systemic spread. Pulmonary artery infusion is mostly performed with a balloon catheter inflated in the pulmonary artery, so-called blood flow occlusion. The pulmonary circulation is temporarily arrested to allow a better uptake of the injected drug in the lung parenchyma. This represents a minimally invasive, endovascular technique, which can be repeated several times and which can also be applied in patients who cannot tolerate one-lung ventilation or initially, have inoperable lung metastases or even primary lung cancer. In the present research proposal, a minimally invasive and percutaneous method and device of use will be developed and tested in vitro to occlude and infuse/perfuse a lung locoregionally in large animals and patients. Devices and method are tested in vitro. Results are discussed in a design review whereby the parties concerned will jointly decide whether or not the objectives have been met which will conclude the investigation under this application. Regarding subsequent investigations, pulmonary infusion will be evaluated in a pig model of blood flow occlusion with injection of gemcitabine as this drug was found to be most promising in the experimental rodent setting. Pharmacokinetics will be determined specifically looking at lung and systemic concentrations. Afterwards, a phase I trial will be performed in patients with inoperable lung metastases or primary lung cancer. When the dose-limiting toxicity and maximum tolerated dose have been determined, a phase II trial may be designed similar to what as has been performed for isolated lung perfusion. By combining both worlds of high locoregional and distant exposure of chemotherapeutic drugs, we hope to improve the overall and disease-free survival rate of our patients with lung metastases or primary lung cancer." "Imaging of receptor activator of the nuclear factor κ B ligand (RANKL) tumor microenvironment using immuno-positron emission tomography (PET) in models of head-and-neck and breast cancer." "Tim Van den Wyngaert" "Molecular Imaging and Radiology (MIRA), Molecular Imaging, Pathology, Radiotherapy & Oncology (MIPRO)" "The receptor activator of the nuclear factor κ B ligand (RANKL) is an important component in carcinogenesis, specifically in the maintenance of self-renewal of cancer stem cells and up-regulation of anti-apoptotic pathways. In the tumor microenvironment, RANKL expression by tumor cells is associated with poor prognosis and more aggressive disease, of amongst others head-and-neck and breast cancer; two malignancies with poor outcome and in urgent need of better prognostic biomarkers and treatment options. However, current research on RANKL is hampered by the lack of a non-invasive biomarker of RANKL expression and dynamics in the tumor microenvironment. We propose a novel use of immuno-positron emission tomography (PET) by radiolabeling the anti-RANKL monoclonal antibody denosumab as longitudinal non-invasive imaging biomarker. The current proposal of this innovative approach includes developing and validating the labeling procedure, establishing the preclinical mouse models, evaluating the biodistribution, and biomarker validation in xenograft and metastatic mice models of oral squamous cell cancer (OSCC) and triple-negative breast cancer (TNBC). To this end, tumor models will be created with high and low RANKL expression, as well as modulation of tumor-derived RANKL using pharmacological intervention. Both a long (zirconium-89) and a short (gallium-68) half-life PET emitter will be studied to facilitate translation to human applications. Novel techniques will have to be developed to optimize antibody labeling with specific application to RANKL imaging, to derive unique immuno-PET imaging signatures of RANKL expression, and to establish the predictive value of this new biomarker. This challenging project will contribute to the understanding of the heterogeneity of RANKL expression, the dynamics of RANKL binding, and impact of RANKL-directed treatment on the tumor microenvironment. This can ultimately impact and improve the selection of patients in trials of RANKL-directed cancer treatments in these two frequent and aggressive diseases (i.e. OSCC and TNBC)."