Development and validation of a novel rationally designed immunotherapeutic combination strategy built upon targeting RANK(L) for cervical cancer. 01/11/2020 - 31/10/2022

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.

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Integrated Personalized & Precision Oncology Network (IPPON). 01/01/2020 - 31/12/2025

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.

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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. 01/10/2018 - 30/09/2022

Abstract

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).

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