Endocrine Abstracts (2015) 38 OC2.6 | DOI: 10.1530/endoabs.38.OC2.6

Treatment with the epigenetic modifying compound JQ1+ can significantly reduce the proliferation of pancreatic neuroendocrine tumours in a mouse model of multiple endocrine neoplasia type 1

Kate E Lines1, Mark Stevenson1, Panagis Filippakopoulos2, Susanne Muller2, Stefan Knapp2, Chas Bountra2 & Rajesh V Thakker1

1Academic Endocrine Unit, OCDEM, University of Oxford, Oxford, UK; 2Structural Genomics Consortium, University of Oxford, Oxford, UK.

There are currently no curative treatments for metastatic pancreatic neuroendocrine tumours (PNETs), and the 5-year survival is <50%. Such tumours frequently have mutations in chromatin remodelling genes as well as the protein encoded by the multiple endocrine neoplasia type 1 (MEN1) gene, menin, which is mutated in up to 40% of sporadic PNETs, and binds the histone methyltransferase MLL1. Histone modifications, and specifically acetylated residues on histone tails, are recognised by members of the bromo and extra terminal (BET) protein family, via their bromodomains, causing alterations in the transcription of growth stimulating genes. We therefore examined the expression of the BET family genes, bromodomain-containing (Brd) 2, Brd3 and Brd4 in PNETs isolated from a conditional MEN1 knockout model, Men1L/L/RIP2-Cre, whereby menin expression is lost specifically in pancreatic beta cells. We show that Brd2, Brd3 and Brd4 are all expressed in PNETs from this model, in a relative ratio of 3:1:1, making Brd2 the most abundant. Activity of the BET family can be inhibited by the small molecular probe, JQ1+, through binding to, and inhibiting their bromodomains. We therefore treated female (n=4) and male (n=4) mice with 50 mg/kg JQ1+, vehicle only, or the JQ1+ negative stereoisomer (JQ1−), by intraperitoneal injection, weekly for 1 month. Bromodeoxyuridine (BrdU) was also administered for the final 3 weeks. At the end of the study, pancreases were harvested and proliferation rates calculated (number of BrdU incorporated cells/mm2 of tissue/days of BrdU administration×100), by immunostaining. We show that after one month, PNETs from JQ1+ treated mice have a significantly lower proliferation rate (3.7%), than both vehicle only (8.1%) and JQ1− treated mice (7.1%), P<0.005 and P<0.05, respectively; with JQ1+ having an equal effect in both male and female mice. Thus, BET protein inhibitors may represent potential compounds for the treatment of NETs.