Preclinical in vitro investigation to evaluate novel molecular targeted therapy options for neuroendocrine neoplasms

GEP-NETs are highly complex, rare and heterogeneous tumor entities [1]. Current treatment approaches are unsatisfying, due to their limited efficacy [2-4]. Ergo, novel therapeutic strategies, including molecularly targeted therapeutics, are urgently needed [9, 14]. The aim of this doctoral thesis was to evaluate different novel molecular targeted therapy options for neuroendocrine neoplasms in vitro. By targeting different signaling pathways, we obtained novel insights into NET tumor biology and assessed possible novel treatment strategies. Several dual-targeting approaches prevented feed-back loops within a signaling pathway, as well as cross-talk activation between signaling pathways and enhanced single substance treatment. This cumulative doctoral thesis is based on the following original publications: The novel cyclin-dependent kinase 4/6 inhibitor ribociclib (LEE011) alone and in dual -targeting approaches demonstrates antitumoral efficacy in neuroendocrine tumors in vitro; Neuroendocrinology. 2017 Feb; doi: 10.1159/000463386. PMID: 28226315. Aristizabal Prada ET, Nölting S, Spöttl G, Maurer J, Auernhammer CJ. The MTH1 inhibitor TH588 demonstrates anti-tumoral effects alone and in combination with everolimus, 5-FU and gamma-irradiation in neuroendocrine tumor cells. PLoS ONE. 2017 May; doi: 10.1371/journal.pone.0178375. PMID: 28542590. Aristizabal Prada ET, Orth M, Nölting S, Spöttl G, Maurer J, Auernhammer CJ