Association for Multiple Endocrine Neoplasia Disorders

American Cancer Society MEN 2 Consortium - meeting update (December 2012)

Dr. Barry Nelkin, Professor of Oncology, Johns Hopkins University School of Medicine

Here is an update, from the annual meeting of the Consortium (University of Wisconsin, Madison, WI, December 5-6). This was one of the most inspiring MTC research meetings I’ve attended.


Background

As a reminder, the American Cancer Society MEN 2 Consortium is a group of researchers working on improving the therapy of MTC, and, in a growing number of instances, collaborating with each other to facilitate the research. It was started about two years ago, with a very generous grant from Mrs. Janet Mordecai. There are currently 10 researchers in the Consortium. The Consortium is led by Dr. Herb Chen, Layton Rikkers Professor of Surgery at the University of Wisconsin. Dr. Chen has an extensive basic and translational research program in MTC, as well as his clinical interest in MTC.



What everyone in the Consortium is Doing

I apologize that I couldn’t include all the details of the work, since a lot of the information is still unpublished. If you want to skip the science (bare bones summary: really promising things happening in MTC therapeutics, several groups identifying new therapeutic targets, several much needed new MTC model systems, plus groundbreaking epidemiology, clinical outcomes research, physician education), see the following section, “More about the Consortium,” below.

Dr. Ross Cagan (Professor and Associate Dean) and Dr. Tirtha Das (Postdoctoral Fellow), Mt. Sinai School of Medicine

Drs. Cagan and Das have a fly model (genetically modified Drosophila melanogaster) of RET-driven cancer. Dr. Cagan developed this model in collaboration with Dr. Sam Wells and Dr. Paul Goodfellow when they were all at Washington University. Obviously, this isn’t MTC, since flies don’t have thyroids, but it is a good model of the intracellular signaling mechanisms. The power and beauty of this model is that flies can be genetically manipulated very easily and rapidly, so it is easy to ask what other molecular targets are important in RET signaling; these may be therapeutic targets in the future. In addition, Dr. Cagan has set up a robotic research platform, so he can test thousands of pharmacological compounds and combinations per day (!) in this system. As proof of principle, vandetanib worked well to inhibit the RET-driven cancers. Using a similar fly system, Drs. Cagan and Das, in collaboration with medicinal chemists Drs. Kevan Shokat and Arvin Dar, have developed a series of compounds that inhibit RET and other molecular targets that they identified; they showed that these compounds are very effective in preclinical models of MTC (This study was published in Nature). They are exploring ways to move this to clinical development.

Dr. James Bibb, Associate Professor, University of Texas Southwestern Medical Center

Dr. Bibb is a neurobiologist. In the course of making a mouse model with a mutation implicated in neurodegenerative disease, he found that all of the mutant mice rapidly developed MTC!! The tumors regress when the product of the mutated gene is inhibited. Therefore, 1) this may be a useful mouse model of MTC, and 2) the gene that Dr. Bibb has identified may be a potential therapeutic target for MTC (more than incidentally, drugs that target this gene are already available and are in clinical development).

Dr. Daniel Ruan, Associate Surgeon, Brigham and Women’s Hospital

Dr. Ruan is working on combination therapies to treat MTC. In preclinical models, he has found that treatment of MTC with RET inhibitors can be greatly augmented by combination with other available drugs, and he has discovered the molecular basis for this. So we may soon see rational combinations including RET inhibitors.

Dr. Daekyu Sun, Assistant Professor of Pharmacy, University of Arizona

Dr. Sun is developing a new class of inhibitors to block RET gene expression, based on the physical structure of the RET gene. This is a novel approach, since all of the current inhibitors block the enzymatic activity of the RET protein.  Dr. Sun has developed a high throughput assay for such inhibitors, and has identified several potential “hits,” which must be further refined by medicinal chemistry.

Dr. Yawei Zhang, Associate Professor, Yale University

Dr. Zhang is an epidemiologist interested in thyroid cancer. As I told this group a few months ago, she plans to initiate an epidemiological study into factors that predispose to MTC (she already has a similar study ongoing in other thyroid cancers). This will probably be our best shot ever to discover these factors. The moderators of this site are very enthusiastic about this study, in which all of you will be invited to participate. There will be an online questionnaire, followed by a telephone interview.  Dr. Ball and I have discussed with Dr. Zhang the details of the questionnaire, and it looks very well designed. The update on the MTC study is 1) it is now approved by the Yale IRB; 2) Dr. Zhang is currently attempting to put the questionnaire online, to make it even more user friendly, 3) she hopes to have it available in about 2 months.

Dr. Jong-In Park, Associate Professor of Biochemistry, Medical College of Wisconsin

Dr. Park, using very elegant, cutting edge proteomic and biological techniques, has identified two proteins that appear to regulate the way MTC cells grow. In preclinical systems, he has shown that he can block growth of MTC by modulating these proteins. For one of the proteins, he has shown that this is also effective in an animal model of human MTC. He is exploring how to advance these findings to clinical development.

Dr. Elizabeth Grubbs, Assistant Professor of Surgical Oncology, M.D. Anderson Cancer Center

Dr. Grubbs, an expert MTC surgeon, is assembling an extensive database (GEN Registry) to determine the clinical and genetic predictors of outcome in MTC. She showed us some of her impressive initial findings. These may rapidly have high impact, practice-changing implications for MTC.

Dr. Barry Nelkin, Professor of Oncology, Johns Hopkins University School of Medicine

My project is to develop new models of MTC, based on implantation of MTC surgical specimens into mice, or development of new MTC cell lines, to characterize these models genetically, and then [we and others in the Consortium and the MTC field can] use them for development of therapeutic strategies. There are only two well characterized, widely available MTC cell lines, which is really suboptimal for research. I reported to the Consortium that there were two other MTC cell lines, from another lab, but we unfortunately just determined, by genetic testing, that these were not MTC. Meanwhile, we have two new MTC cell lines, developed in my laboratory, which we will characterize and be able to distribute soon. The main part of my presentation at the meeting concerned our characterization, by “next generation” DNA sequencing, of the mutations in MTC. We examined almost all the protein coding genes (~21,000 genes), in a series of 17 sporadic MTCs. Common mutations in this series were then examined in another 40 MTCs (about half sporadic, half hereditary). We found mutations in RET, HRAS, and KRAS in about 90% of the tumors; no tumor had more than one of these mutations. Very few other genes were found to be mutated in more than one tumor. This indicates that these three genes are likely to be the predominant “drivers” of MTC development. The study did not have the ability to tell whether these three mutated genes predict differences in the disease, but we may be able to tell this, to some extent, in the cell lines and mouse models. The sequencing results are in press at the Journal of Clinical Endocrinology and Metabolism.

Dr. Herb Chen, Chairman of the American Cancer Society MEN 2 Consortium,
American Cancer Society Research Professor, Chairman of General Surgery,
University of Wisconsin

Dr. Chen is an accomplished MTC surgeon. In his basic and translational research, Dr. Chen is working on intracellular signal pathways in MTC, which can be developed as therapeutic targets. In preclinical studies presented last year, Dr. Chen demonstrated that two of these pathways appear to be very promising targets for therapeutic development. Due to time constraints, we did not get to hear an update on Dr. Chen’s research on MTC.



More about the Consortium


Mrs. Mordecai’s and the American Cancer Society’s idea for this Consortium was truly visionary, and Dr. Chen has made it a model for research consortia everywhere, through his exceptionally creative leadership and ideas. These include: 1) as part of the Consortium, Dr. Chen is instituting a nationwide master’s program in endocrine surgery.  Many of you have noted that MTC surgery and clinical management is done optimally by only the few experts, and this program is designed to try to correct that, by training more experts in surgery. 2) The meetings have been used to emphatically encourage collaboration among the participants. It has worked! There are around 10 research collaborations among the groups, so far. 3) This year, Dr. Chen appointed an external advisory board of eminent thyroid cancer researchers, who attended the meeting and provided exceptional insights. The advisory board members are well known to all of you: Dr. Gil Cote (M.D. Anderson), Dr. Jim Fagin (Memorial Sloan-Kettering), and Dr. Matt Ringel (Ohio State). 4) There will be a Consortium website, describing the research, publications, Consortium researchers, etc. We hope to link to/from other thyroid cancer websites. I’ll update you when the website is ready.

This Consortium has provided a unique opportunity to advance MTC research. Dr. Cote noted that NIH has probably provided about 1 grant for MTC every 10 years (may be a little exaggeration – I’ve had a few NIH grants for MTC), but we have 10 grants at once in this Consortium. In addition, the Consortium has attracted researchers to MTC. This is not limited to the actual Consortium researchers, but includes our collaborators. Some of these collaborators are among the top names in science – e.g., I collaborated with Dr. Bert Vogelstein (world leader in identification of cancer genes and large scale sequencing to identify cancer mutations) for MTC sequencing, Dr. Cagan and Das are collaborating with Dr. Kevan Shokat (one of the top medicinal chemists in the world), and Dr. Ruan collaborates with Dr. Pier Paolo Pandolfi (one of the outstanding researchers in understanding the complexities of intracellular signaling in cancer cells). Getting these investigators interested in MTC is a significant advance for the field.

Finally, the American Cancer Society officials who attended the meeting were quite impressed. They didn’t have any research Consortium model like this, and they think it may be a paradigm for them to support in other cancers as well. [I hope that will translate into further support for this Consortium, so in another three years, we don’t have to disband…]