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Researchers Decode Molecular Action of Combination Therapy for Anaplastic Thyroid Cancer

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Key Points

  • HDAC inhibitors can increase activity of RhoB, which, once turned on, can stimulate the expression of two proteins: p21, which prevents cells from replicating, and BIM, which induces cell death.
  • Researchers found that only HDAC inhibitors that increase expression of BIM—such as vorinostat and belinostat—work with paclitaxel.
  • Researchers suggest that patient anaplastic thyroid cancer biopsies should be examined before an HDAC inhibitor is used with chemotherapy to see whether p21 or BIM protein are being produced in the tumor during treatment.

In their bid to find the best combination of therapies to treat anaplastic thyroid cancer, researchers at Mayo Clinic's Florida campus demonstrated that all histone deacetylase (HDAC) inhibitors are not created equal. In testing multiple HDAC inhibitors in combination with the chemotherapy drug paclitaxel—which has shown some benefit for this aggressive cancer—they found that class II HDAC inhibitors signal through a newly discovered pathway to promote synergy with chemotherapy treatment.

Aggressive Disease

The Mayo Clinic team has long sought to understand anaplastic thyroid cancer at a molecular level to find treatments that offer longer survival.

“Although anaplastic thyroid cancer is rare—accounting for only 1% to 2% of thyroid cancers—it is responsible for up to 50% of thyroid cancer deaths,” said John Copland, PhD, Associate Professor of Biochemistry/Molecular Biology and Professor of Cancer Biology.

The mortality rate for anaplastic thyroid cancer is almost 100%; the time from diagnosis to death can be measured in weeks to months. But when anaplastic thyroid cancer is found early, it is treated aggressively, and patients can survive for a number of years.

HDAC Inhibitors

The study, published by Marlow et al in Endocrine-Related Cancer, provides some surprising findings about HDAC inhibitors.

“Physicians and researchers should know that just using any of the many approved HDAC inhibitors for a patient's cancer may not offer the results one wants to see,” said Robert Smallridge, MD, an endocrinologist and Professor of Medicine.

“I doubt a single drug will ever work in this cancer, so it is a matter of finding which drugs in combination are going to be most effective,” said Dr. Smallridge.

HDAC inhibitors have been approved for use in blood cancers and are being tested for benefit in other cancers, such as breast, colorectal, gastric, liver, lung, and prostate cancers, which all overexpress specific HDAC proteins.

“HDAC inhibitors can increase activity of RhoB, a tumor suppressor that we had discovered earlier, that is switched off in anaplastic thyroid cancer,” said Dr. Copland. “We also know that this RhoB pathway, once turned on, can stimulate the expression of two proteins: p21, which prevents cells from replicating, and BIM, which induces cell death—both of which can help stop cancer growth.”

Study Findings

The focus of the study was testing whether different HDAC drugs work with paclitaxel to turn on RhoB, and what effect they had on p21 and BIM.

Researchers found that only HDAC inhibitors that increase expression of BIM work with paclitaxel, and two agents in their study did that: vorinostat (Zolinza) and belinostat (Beleodaq). Both are class II HDAC inhibitors. They found HDAC6 is specifically suppressed, leading to an increase in RhoB, and BIM is preferentially expressed due to RhoB's re-expression. They also showed that HDAC6 is overexpressed in patient anaplastic thyroid cancer tissues, indicating that class II HDAC inhibitors will be effective in patients.

The researchers also found class I HDAC inhibitors suppress HDAC1, which mostly upregulates p21 and sometimes BIM, but to a lesser degree. When p21 is produced, no synergy occurs with paclitaxel; therefore, there is no benefit of adding the HDAC inhibitor to treatment.

“Only vorinostat and belinostat always induced the BIM protein, always induced cell death, and always showed synergy with paclitaxel,” said Laura A. Marlow, a research technologist.

That suggests that patient anaplastic thyroid cancer biopsies should be examined before an HDAC inhibitor is used with chemotherapy to see whether p21 or BIM protein are being produced in the tumor during treatment, Dr. Smallridge said. Thus, BIM upregulation and protein expression should predict a response to therapy and synergy of the two drugs.

Dr. Copland concluded by saying that the study shows that molecular work decoding cancer-signaling pathways and the effect of agents on those pathways is possible—and necessary. “We now know which of the many HDAC inhibitors to try with anaplastic thyroid cancer. It makes sense that similar investigations would help other researchers who want to use an HDAC inhibitor to treat specific cancers.”

Dr. Copland is the corresponding author for the Endocrine-Related Cancer article.

This work was supported by the National Institute of Health and Medical Research; the Florida Department of Health Bankhead-Coley Cancer Research Program; Alfred D. and Audrey M. Petersen; the Francis and Miranda Childress Foundation Fund for Cancer Research; John A. and Bette B. Klacsmann Fund for Cancer Research on Mayo Clinic's Florida campus; and the Betty G. Castigliano Fund in Cancer Research Honoring S. Gordon Castigliano, MD, cancer research on the Florida campus.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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