Endocrine Abstracts

Pheochromocytoma and Paraganglioma, collectively referred to as PPGLs, are rare, mostly benign neuroendocrine tumors arising from chromaffin cells of the adrenal gland or of extra-adrenal sites, respectively. Surgery is the first-line therapy for localized PPGLs. However, up to 17% of PPGLs show metastatic spread, and for these cases there is no curative treatment. Therefore, the identification of novel therapeutic approaches for advanced PPGLs is highly clinically relevant. We aimed to find a new targeted therapy option for PPGLs based on their molecular profile. We set out to target two of the most dysregulated pathways in PPGLs, i.e. the PI3K and the CDK4/6 pathways, using BKM120 (pan-PI3K inhibitor) and LEE011 (CDK4/6 inhibitor). We analyzed the effect of these two drugs, as single agents or in combination, on PPGL cell lines and on primary rat and human PPGL cells in vitro and in xenograft experiments in vivo. Our results showed a clear reduction in the viability of PPGL cell lines upon treatment with the two drugs used as single agents. More importantly, a beneficial effect of the drug combination was observed in both 2D and 3D culture conditions. Moreover, we saw reduced migration as well as inhibited clonogenic potential of PPGL cell lines treated with both BKM120 and LEE011 compared to the single treatments. Interestingly, also primary PPGL cells (from an endogenous rat model and from human patients) responded to the single treatments with BKM120 or LEE011, and showed a beneficial combinatorial effect of the two drugs. Based on these promising in vitro effects, we engrafted PC12 cells in immunodeficient mice and treated them for 21 days with BKM, LEE and their combination. We observed a clear reduction of tumor growth in the groups treated with the single drugs, and even tumor shrinkage in mice treated with the drug combination. Overall, our novel approach to combine a PI3K with a CDK4/6 inhibitor emerged as a new effective therapeutic option for PPGLs, especially interesting for inoperable and metastatic cases.