2015 Young Investigator Award
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 (MEN1).
Kate Lines, Oxford
Cancer can develop in the cells in the pancreas that are responsible for making hormones. This type of cancer is called a PNET, and at the moment there are no good drugs for people who have one of these cancers. Our work therefore aims to find a drug that can shrink PNETs and stop them from spreading to other parts of the body. In 2010 a drug was made, called JQ1+. This drug stops a family of proteins, called the BET family, from working normally in cells. The BET family is important for activating genes that cause a cell to grow. We tested this drug in a mouse with PNETs. We found that if we treated the mice for one month then the cancers stopped growing as quickly, and the cancer cells began to die. This drug has also been tested in patients with other cancers. Our work is therefore the first to suggest that this drug may be useful for treating PNET patients in the future.
There are currently no curative treatments for metastatic pancreatic neuroendocrine tumours (PNETs), and the 5-year survival is less than 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 n=4 female and n=4 male mice with 50mg/kg (+)-JQ1, vehicle only, or the negative stereoisomer ((-)-JQ1), by intraperitoneal injection, weekly for one 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.