IPPON investigates both intrinsic and acquired drug resistance as these are major roadblocks in the field of cancer medicine. The underlying mechanisms are studied by identifying key signalling pathways that are responsible for resistance toward specific, highly relevant anti-cancer drugs, via (epi)genome, transcriptome, proteome and kinome data. IPPON currently investigates the following mechanisms:
- Cetuximab resistance in head and neck squamous cell carcinoma
- Glucocorticoid resistance in hematologic cancers
- Withaferin A as a chemosensitizing agent for glucocorticoid resistant multiple myeloma and T- and B-cell leukaemia’s
Secondly, hypoxia is investigated as a major contributor to therapy resistance.
As tumor hypoxia is associated with tumor aggressiveness, chemoradiotherapy resistance and a poor clinical outcome, IPPON investigates several strategies to overcome the negative influence of hypoxia.
For appropriate patient selection and follow-up, non-invasive imaging biomarkers such as positron emission tomography (PET) radiolabelled ligands are studied, in order to deliver insights into the complex dynamic and highly heterogeneous process of hypoxia.
Recently, hypoxia has been identified as a potential source of resistance to immune checkpoint blockade, driven by the establishment of a highly interdependent network of immunosuppressive stromal cells. Treatments that can overcome hypoxia, may succeed in overcoming this immunosuppressive environment resulting in enhanced infiltration of effector T cells. For this, PET imaging is an indispensable tool.
Importantly the tumor microenvironment and treatment also modulate a spectrum of cell death pathways, being necrosis-necroptosis-apoptosis-autophagy-ferroptosis, with strong variations in immunogenicity. Due to dynamic changes in the tumor microenvironment, tumor cells show huge epigenetic heterogeneity, which frequently triggers acquired drug resistance by clonal selection for survival of non-responder tumor cells upon cancer treatment. We are exploring epigenetic plasticity of cell death pathways, immunogenicity and therapy response in conditions of hypoxia and high oxidative stress (lipid peroxidation, perturbed mitochondria, hyperthermia).