Endocrine Abstracts

Introduction: Patients with unresectable NENs are offered a variety of non-curable therapeutic options, which eventually fail due to drug resistance. Increasing evidence suggest an anticancer trait of cannabinoids, via cellular pathways including mTOR, known to be associated with drug resistance development. Still, limited data exist on the anti-cancer effects of cannabinoids in NENs.

Aims: To understand the possible anti-tumor role of the cannabinoids and the endocannabinoid system in NENs, and their ability to overcome resistance to everolimus.

Materials and methods: The endocannabinoid receptors expression on NENs cell lines of lung (NCI-H727) and pancreatic (BON1) origin and on human samples was examined using FACS/immunofluorescence staining and RNA-Seq. Cells were treated with multiple cannabinoids extracts with different chemical profile. Viability and apoptosis were examined using WST-1 and Annexin/PI. Endocannabinoid receptors blocking with specific antagonists examined cannabis extracts -induced toxicity. The effect of everolimus ± cannabis extracts/ endocannabinoid receptors antagonists on cell viability was examined.

Results: The endocannabinoid receptor CB1, but not CB2, is highly expressed in NEN cell lines and tumor samples. The expression of other endocannabinoid receptors (TRPV1, TRPV2, PPARα and PPARγ) is heterogeneous. 50 cannabis extracts were initially tested, identifying 6 cannabis extracts that significantly reduced cell viability by ~40% via CB1. Also, CB1 blocking vigorously decreased cells viability and increased apoptosis. Cells viability decreased by 15% with everolimus alone; this effect was enhanced when cannabis extracts and mainly when CB1 antagonists were added (by 33% and 59%, respectively). Even more, combining everolimus with endocannabinoid receptor blocking in a NEN mouse model showed synergistic effect with impressive decrease in tumor size.

Conclusions: Our preliminary results suggest that modulation of endocannabinoid system seems promising in NENs models, mostly via the endocannabinoid receptor CB1. Addition of cannabis extracts /CB1 antagonist to everolimus may have synergistic effects that might lead to a novel and efficient modality to treat NEN and diminishes the development of drug resistance.