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Assessment of targeted therapy opportunities in sinonasal cancers using patient-derived functional tumor models
Noora Lehtinen1, Janne Suhonen1, Kiesha Rice1
1Misvik Biology Oy, Turku, Finland.
Abstract:
Malignant tumors derived from the epithelium lining the nasal cavity region are termed sinonasal cancers, a highly heterogeneous group of rare tumors accounting for 3 - 5 % of all head and neck cancers. Progress with next-generation molecular profiling has improved our understanding of the complexity of sinonasal cancers and resulted in the identification of an increasing number of distinct tumor entities. Despite these significant developments, the treatment of sinonasal cancers has hardly evolved since the 1980s, and an advanced sinonasal cancer presents a poor prognosis as targeted therapies are usually not available. To gain insights into potential targeted therapeutic opportunities, we performed a multiomics profiling of patient-derived functional tumor models to identify molecular characteristics associated with pharmacological responses in the different subtypes of sinonasal cancer.
Methods:
Patient-derived ex vivo tumor models representing four distinct sinonasal cancer subtypes: sinonasal intestinal-type adenocarcinoma, sinonasal neuroendocrine carcinoma, sinonasal undifferentiated carcinoma and SMARCB1 deficient sinonasal carcinoma were included in the analyses. Results of functional drug screens of 160 anti-cancer therapies were integrated with gene panel sequencing and histological analyses of the tumor tissues and the ex vivo cell cultures to establish associations between drug sensitivity and molecular characteristics including driver mutations.
Results:
The different sinonasal cancer subtypes display considerable differential drug sensitivity. Underlying the drug sensitivity profiles, each subtype was associated with unique molecular features. The therapeutic vulnerabilities correlating with specific genomic background were extended and validated with in silico analyses of cancer cell lines representing different human cancers and with reported case studies of sinonasal cancers treated with targeted therapies.
Conclusion:
The results demonstrate the importance of understanding the differential biology and the molecular features associated with the different subtypes of sinonasal cancers. Patient-derived ex vivo tumor models can be a powerful tool for investigating these rare cancers and prioritizing targeted therapeutic strategies for future clinical development and personalized medicine.
Insights
This study reveals unique molecular features in sinonasal cancer subtypes, guiding personalized medicine. Patient-derived models help identify targeted therapies for these rare head and neck cancers.
Area of Science:
- Oncology
- Genomics
- Translational Medicine
Background:
- Sinonasal cancers are rare, heterogeneous head and neck malignancies with limited treatment options.
- Despite molecular profiling advances, targeted therapies for advanced sinonasal cancers remain scarce, leading to poor prognoses.
- Understanding subtype-specific molecular characteristics is crucial for developing effective treatments.
Purpose of the Study:
- To identify molecular features associated with drug responses in different sinonasal cancer subtypes.
- To explore potential targeted therapeutic opportunities through multiomics profiling of patient-derived tumor models.
Main Methods:
- Utilized patient-derived ex vivo tumor models of four distinct sinonasal cancer subtypes.
- Performed functional drug screens with 160 anti-cancer therapies.
- Integrated gene panel sequencing, histological analyses, and in silico validation.
Main Results:
- Demonstrated considerable differential drug sensitivity across sinonasal cancer subtypes.
- Associated unique molecular features and genomic backgrounds with specific drug sensitivity profiles.
- Validated therapeutic vulnerabilities using in silico analyses and clinical case studies.
Conclusions:
- Highlighting the importance of understanding the differential biology of sinonasal cancer subtypes.
- Established patient-derived ex vivo models as powerful tools for rare cancer research.
- Aimed to prioritize targeted therapeutic strategies for future clinical development and personalized medicine.
