BePrepared

Head and neck squamous cell carcinoma (HNSCC) ranks among the top ten most prevalent cancers globally. Despite aggressive multimodal treatments, patient survival has seen minimal improvement over recent decades, with recurrence rates of 40-60%. The repertoire of approved molecular drugs for HNSCC remains limited, and those available for recurrent disease are often used without biomarker guidance. This underscores the critical need to enhance the reproducibility and translatability of preclinical models to improve the development of novel more effective combination treatment regimens in HNSCC.
Current drug development predominantly relies on tumour cell lines, xenograft models, and, more recently, patient-derived organoids (PDOs). However, a significant limitation of these models is their lack of human tumour microenvironment (TME) components, including immune and stromal cells, which can substantially influence treatment efficacy. We propose that incorporating human TME components into PDOs could significantly enhance their utility in the development of novel, effective combination therapies and the identification of relevant biomarkers to guide treatment selection.
Our objectives are threefold: (1) To complexify PDOs with TME components; (2) To perform screens including standard treatments, novel drug combinations and radiotherapy-drug combinations in clinical development, aiming to specifically identify the impact of the TME on tumour cell killing; (3) To elucidate the molecular mechanisms of resistance and identify potential novel targets for combination therapies and biomarkers for patient selection.
This project leverages the consortium's extensive expertise in patient-derived xenograft (PDX) and organoid (PDO) models, multi-omics tumour profiling, biomarker development, and drug/radiosensitivity screens. We will utilise organoid models derived from fresh patient specimens and established PDO/PDX models. PDOs will be complexed with HLA-matched allogeneic or autologous TME components, employing either standard techniques or innovative bioprinting. Model refinement will involve adapting protocols to mimic in vivo conditions of treatment resistance, such as hypoxia and altered glucose metabolism. We will employ multiparametric fluorescence imaging for evaluating drug efficacy in tumour cell eradication and the role of TME therein. We will use single-cell RNA sequencing, spatial transcriptomics and proteomics to elucidate resistance mechanisms arising from tumour-TME interactions and biomarker identification.
Maximizing the potential of our findings, our collaborative partnership especially in EU projects, with its long-standing expertise in clinical trials for HNSCC, will ensure that promising results can lead to future studies investigating the clinical efficacy of candidate combination therapies. This holds significant medical and socioeconomic benefits for managing high-burden, recurrence-prone HNSCC.