23 Sep 2023
August 2023: Research Updates
MEN1 Research Highlights
Publications related to MEN1 continue to increase, totaling over 500 in the last couple of years and implying that awareness of MEN disorders continues to increase. These studies explore the basic biology of the MEN1 gene and the menin protein that it encodes, as well as present case studies of patients and pilot results for new treatment options. One of the main challenges currently being addressed is why there is so much variability in disease progression in MEN1. Can we find biomarkers that identify the subset of patients with more aggressive disease? Perhaps such markers can reduce the controversy in the timing and extent of medical interventions. In addition, as in other scientific fields there is a palpable increase in the use of machine learning and artificial intelligence approaches to tackle problems related to MEN1.
Sincerely,
-ChatGPTJust kidding – this is really a human author, but we should be happy about the massive computing power being devoted to MEN1 research. For example, one recent study used computer models of the shape of the menin protein to simulate how particular MEN1 mutations might relate to their disease presentation, or the so called “genotype-phenotype correlation”:
1. Biancaniello, C., D’Argenio, A., Giordano, D., Dotolo, S., Scafuri, B., Marabotti, A., d’Acierno, A., Tagliaferri, R., and Facchiano, A. (2022). Investigating the Effects of Amino Acid Variations in Human Menin. Molecules 27, 1747.
As an MEN1 patient interested in research, I often wonder: with the recent rise of genetic therapies and CRISPR technology, how long will it be before we can “cure” MEN1? Since MEN1 patients only have one good copy of the MEN1 gene instead of two, will doctors be able to just give me another good copy (which has been successful in mouse models of MEN1)? Will it be possible to just edit out my faulty MEN1 gene and replace it with a functional one? Ethical issues aside, there are significant hurdles remaining to safely deliver genetic therapy without unintended effects. Furthermore, a prominent line of research in the past decade or so shows that things are not so simple as delivering more MEN1 gene or menin protein. It is now clear that the menin protein is not only a tumor suppressor in certain (mostly endocrine) tissues, but also can promote tumors in other tissues, for example related to certain forms of prostate cancer and leukemia. This research provides a reminder of the delicate balancing act that the body constantly plays to keep cancer at bay and emphasizes that any potential gene therapies related to MEN1 need to be thoroughly vetted.
Along this line of getting a more comprehensive picture of MEN1, for anyone interested in up-to-date review articles on MEN1 biology and patient care (albeit quite technical), or who would like to point their doctors to recent evidence, two noteworthy reviews were recently published from long-time clinical advisors to AMEND and AMEND USA:
2. Brandi, M.L., Agarwal, S.K., Perrier, N.D., Lines, K.E., Valk, G.D., and Thakker, R.V. (2021). Multiple Endocrine Neoplasia Type 1: Latest Insights. Endocrine Reviews 42, 133–170.
3. Pieterman, C.R.C., and Valk, G.D. (2022). Update on the clinical management of multiple endocrine neoplasia type 1. Clinical Endocrinology 97, 409–423.
As mentioned above, the advent of CRISPR “gene editing” is not safe in patients yet, but it has already proven very useful in manipulating cells in a dish (i.e. modified them to look like MEN1 cells), after which researchers can screen for thousands of interactions with the menin protein that can guide potential new therapies. One notable study from a team in China used this approach to identify a potential drug candidate for MEN1, leflunomide, that showed promising results in a very small group of patients and deserves further validation testing. Furthermore, this drug is already in use for arthritis and is considered relatively safe and inexpensive:
4. Ma, Y., Zhu, Q., Wang, X., Liu, M., Chen, Q., Jiang, L., Chi, Y., Zeng, Y.-X., Zhao, H., and Jiao, Y. (2022). Synthetic lethal screening identifies DHODH as a target for MEN1-mutated tumor cells. Cell Res 32, 596–599.
Several groups are now using related genetic technologies to develop “MEN1 cell lines” that can be studied in a dish. Similar to the way mouse models of MEN1 have supercharged research over the past decade, this could have a similar effect in speeding up the development of new treatments. The example paper below “reprogrammed” cells donated from an MEN1 patient to make stable cell lines that can be useful for developing new medicines:
5. Even-Zohar, N., Metin-Armagan, D., Ben-Shlomo, A., Sareen, D., and Melmed, S. (2023). Generation of isogenic and homozygous MEN1 mutant cell lines from patient-derived iPSCs using CRISPR/Cas9. Stem Cell Research 69, 103124.
Much work remains to be done, and I am very grateful for the researchers and funders that keep the ball rolling!
-Jason Keller
August 2023