Abstract 396P
Background
Pleural mesothelioma (PM) is a highly heterogeneous and aggressive cancer with limited therapeutic options. To advance personalized treatments, patient-derived tumoroid cultures that preserve their original morphological and molecular characteristics across the epithelioid-sarcomatoid spectrum were established. High-throughput screening of these tumoroids with 3,000 FDA-approved compounds identified both common and patient-specific targets. Here,we conducted in vivo studies to validate the efficacy of promising therapeutic candidates using optimized tumoroid xenograft models.
Methods
We developed orthotopic intrapleural and subcutaneous xenograft models using the PM050 PM tumoroid cell line—bearing biphasic characteristics—and engineered it to express fluorescent and bioluminescent markers for non-invasive disease monitoring. Injection parameters were optimized for reproducible tumor growth kinetics. Pilot studies evaluated the therapeutic effects of romidepsin, a histone deacetylase inhibitor, and sepantronium bromide (YM155), a survivin inhibitor, compared to cisplatin-pemetrexed, the current standard of care. Tumor growth was monitored through imaging and confirmed by histological analysis.
Results
Both orthotopic and subcutaneous models produced detectable tumor phenotypes with growth kinetics correlating to the number of cells injected. Subcutaneous grafts developed visible macroscopic tumors, while intrapleural grafts demonstrated diffuse growth patterns. Histological analysis confirmed that xenografts retained the expression of key PM markers including negative calretinin and positive vimentin, consistent with in vitro tumoroids and the original tumor tissue. No significant tumor size reduction was observed with cisplatin-pemetrexed or romidepsin, whereas YM155 exhibited a trend toward tumor growth attenuation.
Conclusions
We demonstrated the feasibility of tumoroid xenograft models for preclinical validation of PM therapies. The models accurately reflect disease heterogeneity and provide a robust platform for drug testing. Our initial data suggest survivin as a novel target, warranting further studies to confirm the therapeutic efficacy of YM155.
Funding
Sinergia Grant
Disclosure
All authors have declared no conflicts of interest.