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Oncology Times:
doi: 10.1097/01.COT.0000437196.08121.e9
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Thyroid Cancer Research Boom: New Progress in Development of Targeted Treatments

Shah, Manisha H. MD

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Thyroid cancer is among the most curable forms of cancer—with 95 percent of patients cancer-free following surgery. But until 10 years ago, nothing much could be done for patients whose cancer had recurred or metastasized despite treatment with surgery and radioactive iodine. This type of cancer affects people of all ages, including young adults, and in the past people in their 30s and 40s were dying due to a lack of treatment options.

Now, though, increased knowledge of tumor genetics has led to an explosion of clinical studies, transforming the thyroid cancer treatment landscape. We have even seen major growth in the number of thyroid cancer studies presented at major medical meetings, particularly at the American Society of Clinical Oncology Annual Meeting. Years ago there were no studies presented, and now in recent times thyroid cancer has been well represented.

MANISHA H. SHAH, MD
MANISHA H. SHAH, MD
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Thyroid cancer is very different from any of its cancer counterparts in terms of patient population, treatment, and side effects, so there is a huge need for medical oncologists to specialize in this area to develop new, more sophisticated treatments.

This decade of discovery is sparking creativity among researchers. The National Cancer Institute and others are sponsoring clinical trials looking at new targets for treating thyroid cancer. Here at The Ohio State University Comprehensive Cancer Center–Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC—James), we are conducting significant research in this area as well.

My team is currently conducting three thyroid cancer clinical trials at OSUCCC-James:

  • A Phase II Study of Cabozantinib in Patients with Radioiodine-Refractory Differentiated Thyroid Cancer Who Progressed on First-Line VEGFR-Targeted Therapy (http://1.usa.gov/14MDUnR): The goal is to develop second-line therapy for patients whose cancers progress after currently available VEGFR-targeted first-line therapy, such as sorafenib, sunitinib, or pazopanib. Cabozantinib may be able to counteract the activity of proteins that help develop resistance. The study will pay particular attention to the response of cabozantinib in bone metastasis.
  • A Phase I Trial of GSK2118436 (BRAFi) and Pazopanib in Patients with BRAF-mutated Advanced Malignant Tumors (http://1.usa.gov/1bJhl86): This study is examining the side effects and best dose of the FDA-approved drugs dabrafenib (for melanoma) and pazopanib hydrochloride (for soft tissue sarcoma and renal cell carcinoma) when given together in treating patients with advanced malignant tumors. Dabrafenib and pazopanib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.
  • A Randomized Phase II Study of Single Agent GSK2118436 (BRAFi) vs. Combination Regimen GSK2118436 (BRAFi) and GSK1120212 (MEKi) in Patients with BRAF-Mutated Thyroid Carcinoma (http://1.usa.gov/15WKB7O): This trial will determine how well dabrafenib works with or without trametinib (also FDA-approved for melanoma) in treating patients with recurrent thyroid cancer. Dabrafenib and trametinib in combination may also stop the growth of tumor cells by blocking some of the enzymes needed for cell growth, but it's unknown whether dabrafenib is more effective when given with or without trametinib in treating thyroid cancer.

As the genomics revolution continues, thyroid cancer specialists are using this knowledge to enhance current research, and it's paying off. Based on the success of this new information related specifically to tumor genetics, research in this area continues to increase significantly (see box).

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Treatment Protocols

Although thyroid cancer can strike at any age, the prognosis is typically more favorable than that for other cancers.

The two major types of thyroid cancer are differentiated (papillary or follicular) and medullary thyroid carcinoma.

Although the differentiated type accounts for about 85 percent of all cases, there are currently no approved drugs for this type of thyroid cancer.

For medullary carcinoma, the rarer form of thyroid cancer, there are two approved drugs:

  • Cabozantinib (Cometriq), approved in 2012; and
  • Vandetanib (Caprelsa), approved in 2011.
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Typically, following surgery to remove the tumor and the use of oral radioactive iodine to kill the micromets, 95 percent of patients are rendered cancer free, but the remaining five percent need further treatment. For those five percent of patients, radioactive iodine can often be used again should cancer recur, and it usually then works for some time. But as the cancer progresses, patients can develop an iodine resistance and need more effective systemic treatments.

Enter the problem: Outside of radioactive iodine, the limited treatment options currently available to patients are not sufficient. It is critical that we develop more advanced therapeutics to improve the current survival rate for patients with advanced thyroid cancer of five to 10 years. Fortunately, with the increased number of clinical trials and a renewed interest in developing more innovative treatment options, attention is shifting in a more positive direction.

Patients with recurring thyroid cancers are still a challenge for endocrinologists and medical oncologists—who have more recently begun working together—due to a lack of resources and successful treatment options.

Currently available first-line systemic targeted therapy, such as VEGFR-targeted tyrosine kinase inhibitors (TKIs), have drawbacks of a relatively short duration of effectiveness (typically less than 18 months and a high frequency of chronic side effects that adversely affect patients' quality of life).

We clearly can do better, and researchers are working diligently to develop more effective second-generation treatments.

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Thyroid Cancer Genome

Increased knowledge of the Thyroid Cancer Genome has led to robust research in the last few years. For example, papillary is the most common type of differentiated thyroid cancer, and researchers have found that 40 percent of patients have the BRAF mutation. This gives researchers something to work with in the development of more targeted therapeutics.

With respect to research my team conducted in 2008, we discovered that nearly 80 percent of the trial's patient population has the BRAF mutation. Our team, therefore, is now focusing on targeting the BRAF-MEK pathway to develop an effective therapy.

In addition, researchers have found that medullary thyroid cancer can be caused by mutations of the RET gene, and the vascular endothelial growth factor (VEGF) plays a critical role in tumor growth. This information has been available for 20 years, but only recently have researchers started using this extremely valuable information in the clinic.

While two multikinase inhibitors (cabozantinib and vandetanib) that target the RET and VEGF receptors are approved for treatment of progressive medullary thyroid cancer, such therapies bring limitations similar to those discussed above, including a short duration of effectiveness and a high frequency of chronic side effects.

To counteract that, researchers are now testing more powerful RET-kinase inhibitor drugs in clinical trials. Without these genomic insights, we'd be back at the drawing board.

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OSUCCC-James' Thyroid Cancer Unit

I have been working with thyroid cancer patients since 2002, and at OSUCCC-James for the past 16 years, focusing on early-phase trials for thyroid cancer.

Our Thyroid Cancer Unit is the largest group of its kind in the United States and represents a unique collaboration among clinicians, researchers, and basic scientists—all striving to develop more advanced and effective thyroid cancer treatments.

Members of the multidisciplinary team include endocrinologists, medical oncologists, geneticists, pathologists, surgeons, pharmacologists, and molecular biologists. Through research and collaboration our team strives to do the following:

  • Identify genetic factors that cause the initiation of thyroid cancer cells;
  • Understand cellular changes that affect the growth and spread of thyroid cancer;
  • Analyze how different treatment agents affect thyroid cancer cells; and
  • Develop newer, targeted agents that will improve treatment strategies for thyroid cancer.

In the past, treating thyroid cancer patients was a much less collaborative effort, and therefore, not nearly as effective. Now, as crucial players such as medical oncologists and geneticists get involved and work together, patients are receiving a higher standard of care, and the quality of research has skyrocketed.

The good news is that many other cancer centers are also starting to create designated thyroid cancer units, which bodes well for the future of thyroid cancer research and the enhancement of available therapies. In fact, the International Thyroid Oncology Group (ITOG) has launched its very first multicenter clinical trial sponsored by NCI, which I am leading: Phase II Study of Cabozantinib in Patients with Radioiodine-Refractory Differentiated Thyroid Cancer Who Progressed on First-Line VEGFR-Targeted Therapy (http://1.usa.gov/14MDUnR).

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The Next Step

We have made exciting progress in the last 10 years, especially here at OSUCCC-James, but there is still a long way to go. We must keep this research momentum going to enhance treatment options for thyroid cancer patients and finally give this cancer the attention it deserves. Patients' lives depend on it.

Wolters Kluwer Health | Lippincott Williams & Wilkins

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