Pancreatic neuroendocrine tumours (PNETs) are increasing in incidence, and have a 5-year survival rate of <50%. This is largely because, despite recent advances, current treatments are often ineffective, and therefore additional therapeutic agents are required. Epigenetic inhibitors may offer a novel class of anti-cancer drugs, as PNETs harbour mutations of chromatin remodelling genes including ATRX and DAXX, while menin, encoded by MEN1, interacts with chromatin remodelling proteins, including the histone methyltransferase MLL1. Furthermore, we have previously demonstrated that JQ1, a bromo and extra terminal domain inhibitor (BETi) that prevents binding of the BET family of proteins to acetylated histone residues, significantly decreased proliferation and increased apoptosis of a human PNET cell line (BON-1), and PNETs in a pancreatic cell specific Men1 knockout mouse model. However, JQ1 is effective against multiple tumours, indicating it may lack specificity. This may lead to significant off-target adverse effects, which could be overcome by targeting JQ1 specifically to PNET cells. Neuroendocrine tissues, including PNETs express somatostatin receptors (SSTRs), of which there are 5, SSTR1-5, that play a role in hormone synthesis and secretion. Analogues that bind these receptors, including the SSTR2-binding somatostatin analogue octreotide, have also been shown to control symptoms in NET patients. In our study, we have therefore synthesised a novel molecule that is a conjugate of an orally active derivative of JQ1, OTX-015, that is currently undergoing clinical trials for leukaemia and glioblastoma, to the somatostatin analogue octreotide, via a protease degradable linker. We have undertaken initial dose escalation studies in conditional Men1 knockout mice that develop SSTR 1, 2, 3 and 5 expressing PNETs from 6 months of age. These studies indicate that the conjugate molecule is well tolerated in concentrations up to 50 mg/kg, injected intraperitoneally, which is comparable to the concentration of JQ1 used in previous in vivo mouse studies. Thus, we have developed a novel NET-targeted BETi that is now available for preclinical in vitro and in vivo evaluation.
02 Dec 2019
UK and Ireland Neuroendocrine Tumour Society