Year: 2025
Type: conference-abstract
Abstract: BACKGROUND Chordomas are rare primary malignant tumors, faulty considered as benign, with a high relapse rate and an unfavorable outcome in case of suboptimal treatment. Today, recurrent chordomas constitute a real challenge in oncology. Due to the rarity of these tumors, clinical trials are scarce with disappointing results and in vitro studies are missing. Pi3k-AKT-mTOR and MAPkinase pathways are demonstrated to be involved in chordoma tumorigenesis. This study aims to develop new preclinical models and to test active targeted therapies and potential combinations in chordomas. MATERIAL AND METHODS In vitro 2D primary cell cultures were conducted on 15 fresh chordomas well characterized at a clinical and histological level. The cell viability, cell proliferation and apoptosis were analyzed under Pi3K-AKT-mTOR (Alpelisib and Everolimus) and MAPKinase (Trametinib) inhibitors. Drugs were tested alone and in combination. RESULTS Primary cell cultures were validated through expression of brachyury and inhibitors were validated by western blot analysis. Alpelisib induced a dose dependent decrease in cell viability (maximal effect -67%, IC50 10-6M) in all tested chordomas. This effect was stronger than those of Everolimus (maximal effect -22%, IC50 10-10M) and Trametinib (maximal effect -30%, IC50 10-8M). On the other hand, Trametinib had the stronger dose dependent effect on cell proliferation (maximal effect -73%, IC50 10-9M), compared to those of Alpelisib (maximal effect -61%, IC50 10-8M) and Everolimus (maximal effect -41%, IC50 10-10M). Combination of Alpelisib at 10-6M and Trametinib at 10-7M induced a stronger decrease in cell viability than each drug alone. Combination of Trametinib at 10-7M with either Everolimus or Alpelisib induced the same strong effect on cell proliferation as Trametinib at 10-7M alone. CONCLUSION 2D culture of fresh human chordoma seems to be a promising preclinical model to test the effects of targeted therapies alone or in combination. PI3K-Akt-mTOR and MAPkinase pathways constitute relevant targets in chordoma therapy. In our preclinical model, co-targeting Pi3k-Akt-mTOR and MAPkinase pathways improved cell viability inhibition in comparison to the target of each pathway alone. Effects of co-targeting on cell viability and proliferation is yet unclear with ongoing experiments.
Source: Neuro-Oncology
Authors: A Mansourt, G Mondielli, A Barlier, T Graillon
Language: English
Subfield: Rheumatology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W4414800044
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