Cancer Center Research has been funded for two diabetes drugs taken by millions of Americans and believed to prevent lung cancer in some patients but could speed up cancer metastases in others, according to researchers at the University of Colorado Cancer Center.
The National Institutes of Health has just awarded these researchers a $1.4 million, five-year RO1 grant to learn why the same drug could have seemingly opposite effects.
“Based on our studies, it is possible that lung cancer in patients who are taking these drugs to treat their diabetes could progress more rapidly,” says Raphael Nemenoff, PhD, the UCCC researcher leading the work. “In the end, it is usually metastasized cancer that kills patients, not the original tumor, and these drugs appear to speed up that process in animal models of lung cancer.” Unknown Object
Specifically, Nemenoff’s team at the cancer center is examining the role of a protein called peroxisome proliferator-activated receptor (PPAR-gamma). Avandia and Actos — the commercial names for a class of drugs called thiazolidinediones (TZDs) taken by millions of people to treat Type 2 diabetes — activate this protein. These drugs already have come under scrutiny for increasing certain cardiovascular risk factors in patients.
A retrospective study conducted in 2007 showed that TZDs appeared to prevent the genetic changes that cause tobacco-induced lung cancer. Based on those findings, Nemenoff’s team assumed the drugs also could slow down lung cancer progression and metastases.
“That turned out not to be true. These drugs may, in fact, accelerate metastasis,” says Nemenoff, professor of medicine and pharmacology at the University of Colorado School of Medicine and a member of UCCC’s Lung Cancer Specialized Program of Research Excellence.
The TZD-class drugs appear to cause genetic changes that prevent cellular transformation and cancer initiation. But when these drugs activate the PPAR (gamma) protein in the surrounding tumor environment—the cells around the tumor, which include inflammatory cells, immune cells and fibroblasts—cancer progression and metastases speeds up. In a mouse model, Nemenoff’s group found that TZDs accelerated lung cancer metastasis to both liver and brain. Based on those findings, the NIH awarded the RO1 grant—the highest level of research grant available—to the cancer center to continue his investigation into the role of TZDs in cancer progression. The original work also had been funded by an NIH grant.
Because there currently is no effective screening for lung cancer, it typically is not diagnosed in patients until after it becomes symptomatic. If Nemenoff’s initial findings hold true, it would mean that diabetic patients with undiagnosed lung cancer could be on medicines that will cause their cancer to grow and spread much faster than normal. Since the work at the cancer center is being done in laboratory and mouse models, the findings are too early to draw conclusions for human treatment, Nemenoff cautions. If the drugs are proven to accelerate lung cancer progression and metastases, the next step would be to develop biomarkers that could be used to detect lung cancer early on in patients before they were put on these medicines.
This work is critical not just to understanding this drug, but to get a better understanding of the mechanisms involved in cancer metastases, Nemenoff says.
“Most new targeted cancer therapies are designed to shrink or kills tumor cells, but we also need to be able to block cancer progression and metastases,” Nemenoff says. “Our level of understanding of how cancer spreads is poor. If this project is successful, we will develop new targets that allow drugs to impair the metastases that kill people.”