Digital Image Analysis in NETs

Michelle Kang Kim, MD, PhD

Year: 2020
Institution: Icahn School of Medicine at Mount Sinai
Country: United States
State: NY
Award Type: Pilot
NET Type: Multiple
Science Type: Clinical

General Description

The most common known mutation in human neuroendocrine tumors is in the MEN1 gene. Dr. Meyerson’s laboratory has uncovered a biochemical function for the menin protein produced by this gene. Menin modifies the structure of histone proteins that are bound to DNA. The goal of this project is to map the specific modifications made to the histone proteins and also to look for enzymes whose action counteracts the activity of menin. Since menin function is absent in carcinoid tumors, inhibiting enzymes with opposite activity may be useful for carcinoid treatment.  Researchers hope to elucidate the role of the MEN1 gene in carcinoid tumors and to determine a functional connection between the genes MEN1, Rbp2 and p27.


Meyerson found that MEN1 helps to add an important protein modification (called histone methylation) that controls gene expression, and that MEN1 mutations impair this addition. Based on this discovery, Meyerson hypothesized that it might be possible to partly offset the effects of MEN1 mutations by inhibiting another gene, called RBP2, which removes this same protein modification. In other words, inhibiting RBP2 might help restore the appropriate balance. Remarkably, he found that this approach works: mice carrying mutations in both MEN1 and RBP2 survive much longer than mice carrying only MEN1 mutations.

In July 2011, published results suggest a novel strategy for treating neuroendocrine tumors without menin function (as well as other cancer types) by inhibiting a specific class of enzymes, histone H3 trimethyl-lysine 4 demethylase enzymes. Dr. William Kaelin, a colleague of Dr. Meyerson, identified the first histone H3 trimethyl-lysine 4 demethylase; RBP2. Dr. Meyerson’s team has shown that Rbp2 inhibition can slow tumorigenesis caused by loss of menin function in mice with neuroendocrine tumors. This work suggests that RBP2 inhibitors should be developed and might have anti-cancer effects in patients with neuroendocrine cancers. 


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Lin W, Cao J, Liu J, Beshiri ML, Fujiwara Y, Francis J, Cherniack AD, Geisen C, Blair LP, Zou MR, Shen X, Kawamori D, Liu Z, Grisanzio C, Watanabe H, Minamishima YA, Zhang Q, Kulkarni RN, Signoretti S, Rodig SJ, Bronson RT, Orkin SH, Tuck DP, Benevolenskaya, EV, Meyerson M, Kaelin WG, Yan Q. Loss of the retinoblastoma binding protein 2 (RBP2) histone demethylase suppresses tumorigenesis in mice lacking Rb1 or Men1. Proceedings of the National Academy of Sciences Aug 2011, 108 (33) 13379-13386; DOI:10.1073/pnas.1110104108.


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