Research Hans Prenen

Abstract

Precision oncology has been shown to greatly improve outcomes of cancer patients, with tailored treatment approaches that consist of patient-directed therapies on the molecular characteristics of a patient. Despite this, chemo- and radiotherapy are still the basis of most standard treatment regimens, especially for gastrointestinal (GI) cancer patients. Importantly, there are significant differences in how GI cancer patients respond to standard-of-care (SOC) chemotherapy (CT) and chemoradiation (CRT), resulting in a majority of patients experiencing either over- or undertreatment and a delay in starting the optimal treatment. Tailored treatment approaches for SOC CT/CRT to enable precision oncology for these standard therapies is of high interest in order to improve quality-of-life and survival of GI cancer patients. With no existing predictive biomarkers for CT/CRT, and genomic profiling falling short on this front, there is therefore a clear unmet medical need for a novel model that can distinguish CT/CRT responders and non-responders in GI cancer patients. Patient-derived tumor organoids (PDOs), a functional precision oncology strategy, are 3D vivo models generated from individual patient tumor tissue and have recently emerged as a promising tool for predicting CT/CRT responses in cancer patients. PDO-guided treatment has not yet been implemented in the clinic, because some limitations need to be overcome first. With this study, we aim to overcome the most important limitations by developing a multiparametric, live-cell imaging-based drug response signature for ex vivo PDO screenings that enables monitoring of the true PDO drug response. We hypothesize that this will drastically improve the predictive value of PDOs and feasibility of using PDO drug screenings in routine clinical practice. To test this and as proof-of-concept we will also perform a multicentric prospective observational cohort study with our novel PDO screening platform for prediction of neoadjuvant CT/CRT response in rectal and esophageal cancer patients in regional hospitals. If successful, we aim to set up a prospective clinical phase-1 trial in the future, and on the long term implement our PDO drug response signature as a tool to help guide clinical decision-making of CT/CRT treatment choices for GI cancer patients.

Researcher(s)

• Promoter: Prenen Hans
• Co-promoter: Deben Christophe
• Co-promoter: Komen Niels
• Fellow: Peeters Sofía
• Fellow: Seghers Sofie

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

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

Both targeted and immunotherapies are the key to precision medicine for the treatment of cancer patients. Deregulated signalling of the epidermal growth factor receptor (EGFR) plays an integral role in the tumourigenesis of multiple cancer types. Furthermore, it is well established that immune checkpoints are crucial for the tumour cell's escape from the immune system. The presence of drug resistance and/or immune evasion is a major obstacle to progress in the field. In our project, we will concentrate specifically on head and neck squamous cell carcinoma (HNSCC), a highly relevant tumour type with poor prognosis that is intensively studied at the Centre for Oncological Research (CORE) Antwerp. To date, there is still an urgent need to enhance the response to cetuximab treatment in recurrent/metastatic (R/M) HNSCC. Over the last years, cetuximab-related resistance mechanisms have been extensively studied at CORE. Based on our results and reports in literature, we hypothesize that inhibiting oncogenic bypass pathways responsible for cetuximab resistance, by a novel treatment strategy can lead to elimination of HNSCC cells that are resistant to treatment with cetuximab alone. In the proposed project, we will investigate the potency of a novel triple combination strategy in order to enhance the response to cetuximab therapy in HNSCC patients. To achieve this, cetuximab will be combined with buparlisib, a selective PI3K inhibitor, and an immune checkpoint inhibitor. Importantly, we will investigate the role of human papilloma virus (HPV) in this response, as HPV positive HNSCC patients represent a biologically distinct group. Furthermore, the nature of our project is translational, as from the beginning, we will use patient-derived HNSCC tumour organoids to validate our results from cell line experiments. These patient-derived tumour organoids are a very innovative and reliable model to identify effective treatment strategies and can actually be considered as a 'patient in the lab'. We are convinced that precision medicine using combinations of targeted therapies with immunotherapy may achieve the much-needed progress in HNSCC treatment. As reported in literature, both cetuximab and buparlisib treatment are able to promote anti-tumour immune response. Therefore, in the first work package, we will characterize the anti-tumour activity and immunomodulating effects of cetuximab in combination with buparlisib in HNSCC cell lines and patient-derived HNSCC organoids. Secondly, we will investigate the immunomodulating effects of cetuximab in combination with buparlisib on immune cells. In parallel, the effect of this combination treatment on the immune checkpoint profile will be assessed. Finally, the novel triple combination therapy consisting of cetuximab, buparlisib and an immune checkpoint inhibitor will be investigated in a humanized, PBMC engrafted HNSCC mouse model. This preclinical work will ultimately guide the start-up of a clinical trial to demonstrate feasibility of the novel triple combination therapy to treat HNSCC patients. Given the extensive preclinical (both in vitro and in vivo) and translational work packages to optimise the novel triple combination strategy, we are confident that the data generated in this project will provide insight into how therapeutic response to cetuximab treatment can be optimized, thus favouring the setup of a successful clinical trial with the newly identified triple combination therapy.

Researcher(s)

• Promoter: Lardon Filip
• Co-promoter: Pauwels Patrick
• Co-promoter: Peeters Marc
• Co-promoter: Prenen Hans
• Co-promoter: Smits Evelien
• Co-promoter: Wouters An

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project