Promising drug combination targets aggressive bladder cancers

A new study in mice by researchers at the Herbert Irving Comprehensive Cancer Center (HICCC) has identified a promising drug combination for treating muscle-invasive bladder cancer. Rosiglitazone and trametinib worked synergistically to not only induce tumor cell death, but also to shift aggressive tumor cells to a more benign molecular subtype.

The research team, led by HICCC member Cathy Lee Mendelsohn, Ph.D., hopes to move to clinical trials to evaluate the effectiveness of this combination therapy in human patients. The study was published in Nature Communications.

Meeting an urgent demand for bladder cancer treatments

“Despite recent advances, cystectomy remains the mainstay of treatment for patients with muscle-invasive bladder cancer,” says Mendelsohn, professor of urologic sciences (in urology) and of pathology and cell biology and genetics and development (in the Institute of Human Nutrition) at Columbia University. “More recently, we’ve gotten approval for checkpoint inhibitors, but they only work on a percentage of tumors. We just need more treatment options.”

Bladder cancer is the sixth most common form of cancer in the United States, with more than 83,000 new cases and 16,800 deaths each year. Most bladder cancers are non-muscle invasive, meaning they have not yet spread to the muscular wall of the bladder, and have a good prognosis.

However, up to 20% of non-muscle-invasive bladder cancers can progress to muscle-invasive bladder cancer, which has a five-year overall survival rate of about 50%. Although metastatic progression is not common, it is almost always fatal.

Since the early 2000s, the standard treatment for muscle-invasive bladder cancer has been neoadjuvant chemotherapy followed by surgery, sometimes combined with radiation therapy. In recent years, several immune checkpoint inhibitors, which work by releasing a natural brake on the body’s immune T cells, have been approved by the U.S. Food and Drug Administration (FDA). These immunotherapy drugs offer some patients another option (about 20% of people with advanced and metastatic disease will benefit), but response rates are still too low.

A new therapy to annihilate, then improve, tumors

Mendelsohn and his colleagues decided to take a different approach, using a drug combination that has shown potential against breast cancer. Studies in mice have shown that rosiglitazone combined with trametinib prevents both tumor growth and metastasis, transforming invasive breast cancer cells into fat cells. Rosiglitazone activates PPARG, a transcription factor that drives this transdifferentiation, and trametinib stimulates PPARG signaling in the tumor.

Instead of switching from tumor cells to fat cells, in muscle-invasive bladder cancer, the combination therapy transformed the tumor cells into a more benign subtype. Unlike basal/squamous tumors, luminal tumors generally have a better prognosis and may respond more favorably to certain treatments.

“In bladder cancer, there are two molecular subtypes. Luminal tumors grow in the lumen of the bladder and are relatively benign,” Mendelsohn says. “But basal/squamous tumors grow in the muscle and can metastasize, so they are much more dangerous.”

The researchers used autochthonous mouse models of muscle-invasive bladder cancer, meaning that the tumors develop from normal cells within a living organism. Unlike transplanted tumors, autochthonous mouse models mimic the natural course of tumor progression, from tumor initiation to metastasis. In mice treated with rosiglitazone plus trametinib, tumors shrank by an average of 91%, and in most cases, residual tumors were not detectable.

“When we give animals rosiglitazone or tremetinib alone, we slow the growth of the tumors, but we don’t eliminate them,” she says. “But if you give the two drugs together for a month, you induce apoptosis after about a week, and then what’s left of the tumor goes from a basal/squamous phenotype to a luminal phenotype.”

The results suggest that these FDA-approved therapies, rosiglitazone for type 2 diabetes and tremetinib for cancers including melanoma, non-small cell lung cancer, and thyroid cancer, should be further studied for the treatment of patients with basal-squamous cell muscle-invasive bladder cancer.

“We would need to adjust the doses and determine the minimum duration of treatment in humans,” Mendelsohn says. “But I hope we can adapt this combination therapy to some kind of clinical trial in the near future.”