Head and neck cancers account for >900,000 newly diagnosed cancers and >500,000 deaths per year worldwide. The mainstay of treatment for most entities remains surgery, which can be severely debilitating due to the proximity of vital structures. Currently there are no effective second line therapies available for nonresectable recurrent or metastatic disease.
To facilitate development of new personalised treatment approaches for these cancers, we have developed a significant pre-clinical pipeline of 44 patient-derived xenograft (PDX) models and 30 patient-derived cell lines (PDCLs). The majority of our head and neck cancer models represent mucosal squamous cell carcinoma. Beyond these common cases, we have also achieved the establishment of PDX models for rare cancers in the head and neck area.
A highlight of this suite of models is the establishment the world's first PDX from an Intraosseous Rhabdomyosarcoma (IORMS) to our knowledge. This highly uncommon and aggressive subtype was officially recognized as a separate cancer entity by the WHO in 2022. Due to the rarity of IORMS, no standard of care systemic treatment has been established yet.To address this therapeutic gap, we have performed whole-genome sequencing on both the patient surgical sample and matched cell line of IORMS. This analysis revealed a deletion on chromosome 9 including loss of the gene MTAP, which has been described in the literature as predicting sensitivity to PRMT-5-inhibitors. Furthermore, alterations of multiple genes linked to the PI3K-mTOR pathway were detected.
In line with these findings, we selected a panel of 21 drugs that were tested on the cell line in vitro as monotherapies and combinatorial therapies. These efforts have identified promising treatment candidates, including the ALK-inhibitor Crizotinib, the PI3K-inhibitor Dactolisib and the combination of Dactolisib with the PRMT-5-inhibitor LLY-283 that were further assessed on the PDX model. Excitingly, we could confirm in vivo that targeting the PI3K/mTOR pathway is a promising treatment approach in this rare cancer type and a combination with the PRMT5-inhibitor LLY-283 synergistically further improves the efficacy. These findings further the understanding of IORMS and will hopefully pave the way towards a more effective treatment in future patients.