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Supported by a grant from the U.S. Department of Defense (DOD), a “dream team” of University of Colorado Cancer Center researchers are joining forces to find more treatment options for thyroid cancer, a disease that causes more than 2,000 deaths each year.
CU Cancer Center members Rebecca Schweppe, PhD, Bryan Haugen, MD, and Jennifer Richer, PhD, have received a DOD Cancer Idea Award — a grant to support high-risk, high-reward research — to investigate the role of androgen receptors in thyroid cancers that develop resistance to BRAF inhibitors, a common medication used to treat the disease.
Room for improvement
In the type of thyroid cancer known as anaplastic thyroid cancer, there's a high prevalence of mutations in an enzyme called BRAF, which has approved therapies to target it, Schweppe says. “And while many patients respond to this treatment initially, they acquire resistance over time. There's another thyroid tumor type called papillary thyroid cancer, and those patients don't respond to BRAF therapy at all. We, as a field, need to improve these therapies for patients.”
In the DOD-funded project, the three CU Cancer Center investigators will look at the role of androgen receptors — proteins in cells that bind to the androgen hormone — in creating BRAF resistance and promoting the cancer’s spread.
“As part of our ongoing research, Bryan and I have identified a role for the androgen receptor in thyroid cancer,” Schweppe says. “My lab has data showing that when you treat with a BRAF inhibitor, the expression of the androgen receptor is increased. And Bryan has data showing that the androgen receptor is expressed in cancer-associated fibroblasts. So it may be playing a role not just in the cancer cell, but in other cells as well.”
To the test
Using a mix of in vitro studies and animal models, the researchers plan to test a BRAF inhibitor in combination with androgen receptor inhibitors, drugs that already are being successfully used to treat prostate cancer. Testing drugs that are already approved by the Food and Drug Administration (FDA), the researchers say, helps with the DOD’s aim of finding new treatments that can be rapidly translated into the clinic.
“We've done some experiments where we've added more androgen receptor to the cells, then we treat it with our BRAF inhibitor, and we see an increase in resistance,” Schweppe says. “That is clear evidence that the androgen receptor is directly promoting resistance.”
Moving toward a clinical trial
The DOD award is a two-year grant; if their research goes as planned, the three cancer center researchers hope to eventually move the study to a clinical trial to see how it works in humans.
“Overall, our data indicate that ‘If we block the androgen receptor, this will block both the pro-invasive and pro-growth aspects of cancer, and shut down resistance from an invasion, metastasis, and growth” Schweppe says. “That's where the data from all of our groups really came together for this grant.”
Haugen is especially interested in the effect of the new drug combination in men, who are more than two times more likely to die from thyroid cancer than women. Because testosterone is a primary androgen hormone, he says, targeting androgen signaling will likely have a greater effect in males.
“We think it could still have an effect in women, so we definitely want to test it,” he says. “It may not, but we think it's probably going to be more powerful in men.”
The trio of researchers has also applied for a grant from the American Cancer Society and a larger, translational grant from the DOD to move their study forward. Richer says the research is a great combination of all their skills.
“This is a perfect team, because my expertise is in hormone receptors, which act as what we call transcription factors, meaning that they can turn on and off other genes,” Richer says. “We have the clinical component in Bryan, and both Rebecca and Bryan have studied thyroid cancer in cell cultures and animal models for a long time. This is the beauty of being at a place like CU Anschutz, where basic scientists can collaborate closely with physician scientists to move things rapidly from the bench to the bedside and then back again to the bench.”
