SFEBES2016 Poster Presentations Neuroendocrinology and pituitary (34 abstracts)
1Academic Endocrine Unit, OCDEM, University of Oxford, Oxford, UK; 2Structural Genomics Consortium, University of Oxford, Oxford, UK.
Epigenetic modifications and chromatin remodelling have been demonstrated to play a key role in the development, and progression of multiple cancers, and compounds regulating these mechanisms represent a novel class of anti-cancer drugs. Menin, which is encoded by the MEN1 gene, whose mutations result in a syndrome characterised by pituitary, parathyroid and pancreatic islet tumours, binds histone modifying enzymes, including the histone methyltransferase MLL1. Furthermore, menin, together with the acetyl-lysine recognising bromo and extra terminal (BET) family protein, BRD4, has been shown to be an important mediator of transformation, e.g. in MLL-fusion leukemia, and blocking of binding of the BRD4 bromodomain to acetylated histones using the chemical inhibitor (+)-JQ1 (JQ1+) has been shown to have efficacy in several cancers, including Men1-associated pancreatic neuroendocrine tumours. We therefore hypothesised that JQ1+ may be effective in treating pituitary tumours, and we examined the efficacy of JQ1+ in vitro and in vivo using the mouse pituitary cell line, AtT20, and pituitary tumours developing in Men1L/L/RIP2-Cre mice, respectively. JQ1+1 μM treatment at 96 h significantly reduced AtT20 cell proliferation (assessed by CellTitre Blue assay) by 95% (P<0.0001), and significantly increased apoptosis (assessed by CaspaseGlo assay) by 53-fold (P<0.0001), compared to cells treated with an inactive stereoisomer control, JQ1−. To examine the in vivo efficacy of JQ1+, female Men1L/L/RIP2-Cre mice were injected twice weekly (i.p.) with either 50 mg/kg JQ1+ or JQ1−, or vehicle (n=4 mice per group), for one month and proliferation and apoptosis analysed in pituitary tumours using bromodeoxyuridine staining and TUNEL assay, respectively. JQ1+ significantly increased apoptosis when compared to JQ1− (3.4-fold increase, P<0.005) and vehicle (3.5-fold increase, P<0.005) treatments, but had no significant effects on pituitary tumour cell proliferation. Thus, BET protein inhibitors may represent novel compounds for the treatment of pituitary tumours.