Elucidate the Role of the MEN1 Gene in Carcinoid Tumors and Determine a Functional Connection between the Genes MEN1, Rbp2 and p27
Researcher: Matthew Meyerson, MD, PhD Location: Dana-Farber Cancer Institute State: Massachusetts Year: 2006 Status: Finished
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To elucidate the role of the MEN1 gene in carcinoid tumors and to determine a functional connection between the genes MEN1, Rbp2 and p27.
To define the changes in histone H3 lysine 4 methylation that are dependent on menin function, first in model cellular systems and subsequently in carcinoid tumors.
To identify histone demethylase enzymes involved in the demethylation of histone H3 lysine 4.
The most common known mutation in human carcinoid 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.
Research Progress and Results:
Made discovery about the role of MEN1 mutations in neuroendocrine tumors, which suggests new treatment approaches for patients with MEN1 mutations.
The MEN1 gene is the most commonly altered gene in neuroendocrine tumors including carcinoids of the lung and patients with PNETs. Dr. Meyerson recently made key discoveries about MEN1 that suggest new therapeutic approaches for treating cancers with MEN1 mutations. Specifically, he 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. This project provides scientific rationale for a new class of targeted therapies for patients.