Endocrine Abstracts

For metastatic phaeochromocytomas (PCCs) and paragangliomas (PGLs), there are currently no highly effective therapies available. We therefore investigated multiple novel molecular-targeted drug combinations in murine PCC cell lines and, most importantly, in human PCC/PGL 2D and 3D primary cultures (n = 18). Additionally, we analysed signalling pathway alterations as well as somatic mutations in the patients’ tumours in order to correlate these data with drug responsivity of individual patient tumours. In a large cohort of 16 human PCC/PGL 2D primary cultures, we confirmed that the mTORC1 inhibitor everolimus in combination with the PI3K inhibitor BYL719 was highly effective at low clinically-relevant doses via strong inhibition of mTORC1/p70S6K signalling and significant attenuation of everolimus-induced AKT activation. Everolimus in combination with other targeted drugs such as the tyrosine kinase inhibitor sunitinib also additively decreased primary culture growth (n = 16), while combination therapy of BYL719 with the MEK inhibitor trametinib even synergistically decreased PCC/PGL primary culture viability (n = 3). Additionally, we discovered that the BRAF inhibitor dabrafenib promoted PCC/PGL primary culture survival through a paradoxical MAPK activation (n = 13). Combination therapy of the HDAC inhibitor entinostat with the PARP inhibitor niraparib showed antagonistic effects in PCC/PGL cultures (n = 15). In one patient primary culture, extraordinarily high SSTR2 expression was found by Western blot analyses. This patient is currently being treated with SSTR2-guided radionuclide therapy and responded very well to the first 2-cycles. We further verified drug efficacy in human PCC/PGL 3D tumour spheroids and murine PCC cell lines. Moreover, we have engrafted two different human PGL primary cultures into R2G2 immunodeficient mice to serve as relevant experimental models for in vivo drug screening of human PCCs/PGLs. Utilising patient-derived 2D/3D primary cultures we have established models to generate highly clinically relevant data, emphasizing combinatorial therapy, providing further insight and evidence for personalised therapy (precision medicine) of PCCs/PGLs.