In the Clinic

On Cancer: Drug Reverses Radioiodine Resistance in Some People with Advanced Thyroid Cancer

By Media Staff  |  Thursday, February 14, 2013
Pictured: James Fagin James A. Fagin, Chief of Memorial Sloan Kettering’s Endocrinology Service

Many patients with advanced thyroid cancer have tumors that are difficult to treat because they are unable to absorb radioactive iodine, or radioiodine, the most effective therapy for the disease. Recent findings from Memorial Sloan Kettering researchers, published in the February 14 issue of the New England Journal of Medicine, may indicate a new treatment strategy for these patients.  

The phase II clinical trial found that selumetinib, an investigational drug that works by inhibiting a protein pathway called MAPK in tumor cells, reverses radioiodine resistance in some patients with advanced thyroid cancer.

“Blocking this key pathway increased the uptake of iodine, making radioiodine therapy potentially effective for patients who had a resistance,” says James A. Fagin, Chief of Memorial Sloan Kettering’s Endocrinology Service and senior author of the study. Dr. Fagin pioneered this research in cells and in mice.

Testing Selumetinib’s Potential

Therapeutic radioiodine is often given to patients with thyroid cancer after surgery to destroy any remaining cancer cells or thyroid tissue. Taken orally, usually only one or two doses of radioiodine are needed to treat a patient.

This therapy has been shown to increase survival in some patients with certain thyroid cancers that have spread to other parts of the body. Resistance to radioiodine can have an impact on a patient’s course of treatment.

Memorial Sloan Kettering researchers had previously demonstrated in cells and in mice that the MAPK pathway controls a cell’s ability to absorb radioiodine. As a result of this work, Dr. Fagin and his colleagues examined whether selumetinib, an MAPK pathway inhibitor, could reverse a patient’s resistance to radioiodine by inhibiting the signaling of particular genetic mutations in this pathway.

In the study, 20 patients with tumors resistant to radioiodine were given two doses of selumetinib every day for four weeks. To determine whether selumetinib reversed their tumors’ inability to retain radioiodine, researchers administered a form of iodine that, when absorbed, makes tumors visible on a PET scan. This diagnostic form of iodine has much less radiation than that of therapeutic radioiodine.

While most of the patients’ tumors were able to retain at least some of this diagnostic form of iodine, only eight patients absorbed a large enough amount to be eligible for radioiodine therapy. These eight patients, including all five of the patients with a mutation in a gene known as NRAS, were then given the therapeutic radioiodine.

During six months of follow-up, seven of the eight patients experienced either tumor shrinkage or a stop in tumor growth. All eight had a decreased level of serum thyroglobulin – a protein in the blood used to screen for advanced thyroid cancer – and none experienced serious side effects from selumetinib.

Determining the Benefit for Other Types of Advanced Thyroid Cancer

One advantage of selumetinib is that only a few weeks of therapy are required to improve a patient’s ability to absorb radioiodine.

“The initial results show promise for patients with a mutation in the RAS family of genes, particularly the NRAS gene, but the hope is that a larger clinical trial will shed light on whether selumetinib can be effective for people with other types of advanced thyroid cancer,” Dr. Fagin says.

Memorial Sloan Kettering will lead the international, multicenter phase III clinical trial of selumetinib, which will begin in mid-2013. The trial, which will be sponsored by AstraZeneca, will enroll patients who have recently had their thyroid gland removed – a procedure known as total thyroidectomy – due to thyroid cancer that has spread to nearby tissue or lymph nodes.

This study was supported by grants from the American Thyroid Association, The Society of Memorial Sloan Kettering Cancer Center, the National Institutes of Health (under award numbers CA50706 and CA72598), AstraZeneca, and Genzyme.

Comments

Dear Prof.

I am a medical doctor I did both my Master and Doctorate in oncology, I worked in Harvard University and I am now a clinical cancer reseracher in Jules Bordet Institute in Belgium.
With great interest I read today your impressive work with your team:
Selumetinib-Enhanced Radioiodine Uptake in Advanced Thyroid Cancer
( N Engl J Med 2013; 368:623-632).
I know that few MEK inhibitors such as PD98059 or Sunitinib increased NIS Na+/I- symporter protein protein levels..
I just thought it may be that Selumetinib enhanced Radioiodine uptake thought that pathway?

Best Wishes
Bissan Ahmed, MD, PhD
Clinical Research Associate
Service of Nuclear Medicine
Center of Tumors
Unit of Lymphology,
Institute Jules Bordet,
Université Libre de Bruxelles,
121, Bd de Waterloo, B-1000, Brussels,Belgium
Tel: 32-25413245
Fax: 32-2-5413224

Thanks for your comment, Dr. Ahmed. We spoke with Dr. Fagin, who says, "Selumetinib is an allosteric and highly specific inhibitor of MEK, which is in all likelihood its mechanism of action in these patients’ tumors."

Thanks for your reply, and your great efforts with your team for cancer patients.

Best Wishes
Bissan Ahmed, MD, PhD

Dear Dr. Fagin,
congratulations to your paper on successful "redifferentiation therapy" in patients with certain types of advanced thyroid carcinomas. I am Head of the Division of Endocrinology and Diabetology at the University Hospital of Freiburg in Germany, and worked at Mass. General Hospital and Harvard Medical School in Boston in the 90ies. Currently, we are treating a patient with advanced follicular thyroid carcinoma that has no radioiodine uptake as well. I am wondering whether there would be any chance to have access to either selumetinib on the basis of compassionate use or enroll the patient into another study of selumetinib. Any hint or support would be helpful. Of course, I will be happy to send the complete history of the patient at any time.
Thank you very much
Univ. Prof. Dr. med. Jochen Seufert, FRCPE, FACE
Division of Endocrinology and Diabetology
********************************************************
Department of Internal Medicine II
University Hospital of Freiburg
Hugstetter Str. 55
79106 Freiburg, GERMANY
Office: Clara Martinez, Diane Schopferer
Tel. +49-761-270-34200, Fax +49-761-270-34130

Thank you for your comment. We will forward this information to Dr. Fagin.

Dr Carl June at UPenn recommended that I ask if there would be any indication for treating a patient with anaplastic thyroid cancer with Selumetinib. If so, are there any trials ongoing addressing this? thank you

Hi David, Dr. Fagin will respond to your question directly via the email that you provided. Thank you for your comment.

Dear Dr. Fagin,
I was referred to a doctor Tuttle by my Endo back here in CT. I was told by his receptionist who took my call he no longer takes new patients. I asked her to help me and ask him who I can see for non avid theca, she said she never heard of that and said she would get back to me and she has not I had stage 3 pap with lymph node and skeletal muscle involvement. Now for the last year my blood test have indicated the cancer has returned (TGAB has gone up to 191) but thyca scans pet scans cannot locate the cells.I use to have all tests tg .01 and tgab -20. My total thyroidectomy was 5/09.
I had a total back reconstruction in February this year and still in recovery and will be for at least another year. My surgeon does not want me having any radiation that could go to the bone marrow and stop me fusing therefore stopping my recovery. Also travel is difficult so the closet treatment center to home would be best for me.
My endo here is stating there are only a few doctors that treat non-avid thyca. I am closer to NY than Kentucky and would like to come there for treatment or trials for this cancer that cannot be seen. I am so scared that I will loose the battle if this cancer is not found. Please can you help me or tell me who can now?

Sincerely,
Teresa

Teresa, we're sorry you've had trouble getting the information you need. If you'd like to make an appointment with someone at Memorial Sloan-Kettering, you can call our Physician Referral Service at 800-525-2225 or go to http://www.mskcc.org/cancer-care/appointment. Thank you for your comment.

I have no idea who to see that treats NON-AVID Thyroid Cancer?? Please help me because I can not deal with the long drive to just come in to someone who is going to tell me I have to make an appointment with someone else cause they don't deal with this. I cant believe this. Can I get a name?

Can I be a part of that study that deals with cells that do not take up Iodine?? Please?? Can you forward this to Dr. Fagan I can give you my doctors name that I see to get my file?

I have contacted the phone number given - it rang for a very long time before a busy signal came about.

Teresa, we are looking into this problem and as soon as we can we will send you a follow-up via private message to the email address you provided. We will also respond to your concerns and questions about seeing the correct specialist for your condition and about participating in clinical trials.

Dear colleague,
I also read your very impressive paper in the NEJM.
But may I remind that retinoic acids represent commercially available drugs with many publications showing that they can give biologic and/or metabolic responses and that these drugs might also represent ways to treat these patients. Using the same methdological protocol that you described, we have "offered" such treatments to our patients... with "satisfying" results in some.
We would be interested in partiicpating in your clinical trial with sulemitinib
Sincerely yours,
Prof Dr Pierre Bourgeois, MD, PhD,
Service of Nuclear Medicine,
Jules Bordet's Institute,
Université Libre de Bruxelles,
Brussels, Belgium

Pierre, we forwarded your comment to Dr. Fagin.

Dear Dr. Fagin
I commend him for his work on rediferentiation of malignant thyroid cells. I would like to know if you can attend a patient of Ecuador with dedifferentiated thyroid cancer with lung metastasis (resistant radiotherapy).
My patient wishes to be treated by you in the hospital kettering sloat

Dr. Vanegas, if your patient is interested in coming to Memorial Sloan-Kettering for treatment he or she can contact our International Center (1-212-639-4900) or go to the web page at http://www.mskcc.org/cancer-care/international-patients. Thank you for your comment.

Hi, this study looks promising and we should do more research to find cure for the iodine non avid persons like me. My stimulated Tg has risen to 38, but nothing picked up on the whole body scan. So this is a scary situation. Still decided to go for a higher dose of I 131 and hope something is absorbed.

The reason I am reaching out to Dr.Fagin is that I am myself a patient and also maybe interested in doing research on this cancer of mine. I know memorial Sloan Kettering hospital holds the patents for Thyrogen and I have some ideas to build up treatment in continuation of those patents...not sure if that is really feasible, but still would like to brain storm some ideas.

Suny, thank you for your comments. Our team continues to work actively to improve outcomes for patients with all stages of thyroid cancer. For your information, Memorial Sloan-Kettering does not hold the patent for Thyrogen.

Sir. I had cranioplasty sugery to remove a mass on from the top of my head. The mass was found to be a thyroid cancer. I had a partial thyroidectomy in 1998. Now I'm being advised to remove my thyroid completely. I know you can not say for sure but do you think radioiodine can be considered instead of removing the complete thyroid. Thank you for any assistance.

Deirdre, unfortunately we are not able to answer personal medical questions on our blog. If you'd like to make an appointment to speak with an MSKCC doctor about obtaining treatment here or to get a second opinion you can call 800-525-2225 or go to http://www.mskcc.org/cancer-care/appointment for more information. Thank you for your comment.

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