Researchers at the Herbert Irving Comprehensive Cancer Center (HICCC) have identified a promising drug combination for treating muscle-invasive bladder cancer. The study, published in Nature Communications, found that rosiglitazone combined with trametinib induced tumor cell death and shifted aggressive tumor cells to a more benign subtype in mice.
Addressing Unmet Needs in Bladder Cancer Treatment
According to Cathy Lee Mendelsohn, Ph.D., a member of the HICCC and professor at Columbia University, current treatments for muscle-invasive bladder cancer, such as cystectomy and checkpoint inhibitors, have limitations. "We just need more avenues for treatment," she stated, emphasizing the necessity for innovative therapeutic strategies.
Bladder cancer is a significant health concern in the United States, with over 83,000 new cases and 16,800 deaths annually. While most cases are non-muscle-invasive and have a favorable prognosis, approximately 20% progress to muscle-invasive bladder cancer, which has a five-year survival rate of about 50%.
Synergistic Action of Rosiglitazone and Trametinib
The research team explored a novel approach using a drug combination previously studied in breast cancer. Rosiglitazone, which activates PPARG, and trametinib, which boosts PPARG signaling, demonstrated the ability to prevent tumor growth and metastasis in breast cancer models. In bladder cancer, this combination converted aggressive tumor cells into a more benign luminal subtype.
"In bladder cancer, there are two molecular subtypes. Luminal tumors grow into the bladder lumen, and they're relatively benign," Mendelsohn explained. "But basal/squamous tumors grow into the muscle and can metastasize, so these are much more dangerous."
Significant Tumor Reduction in Mouse Models
The study utilized autochthonous mouse models of muscle-invasive bladder cancer, which closely mimic the natural progression of the disease. Mice treated with the rosiglitazone and trametinib combination experienced an average tumor size reduction of 91%, with residual tumors often undetectable.
"When we give the animals rosiglitazone or tremetinib alone, you slow the growth of the tumors, but you don't get rid of them," Mendelsohn noted. "But if you give the two drugs together for a month, you induce apoptosis after about a week, and then whatever's left of the tumor shifts from the basal/squamous phenotype to the luminal phenotype."
Potential Clinical Translation
Both rosiglitazone and trametinib are FDA-approved for other conditions, including type 2 diabetes and various cancers. The researchers suggest further investigation of this combination for basal/squamous muscle-invasive bladder cancer.
"We would have to adjust the doses and figure out what's the minimum time we can treat in humans," Mendelsohn said, expressing hope for adapting this combination therapy into clinical trials in the near future.
