Drugs that block NOTCH signaling in many cancers could be effective against ACC

Using a novel cell culture approach, Yale Cancer Center researchers have discovered critical vulnerabilities in adenoid cystic carcinoma (ACC), a rare and lethal glandular cancer with a high recurrence rate and few treatment options. The findings, published April 15th in the journal Clinical Cancer Research, offer data that ACC and similar cancers could be treated with already available drugs.

ACC most often occurs in the salivary glands but can originate in the breast, trachea, skin, or other sites. Survival rates at five years are close to 90% but drop significantly after that with just 40% surviving at 15 years after diagnosis. It is a slow-growing cancer that affects about 1,200 people each year, with few symptoms in early stages.

Aside from surgery, there are few treatments for ACC, which until now has proven largely resistant to radiation therapy. It is this resistance that prompted Yale researchers to develop a novel cell culture technique to isolate and study ACC cancer stem cells, known to be the root of tumor growth, aggressiveness, and resistance to chemotherapy and radiation, said co-senior author Sergey Ivanov, research scientist in surgery (otolaryngology).

"Within ACC cells, we found the especially aggressive cancer stem cells. As important, we found the Achilles heel of these cells, which is their addiction to NOTCH1, a signaling molecule that helps these cells to survive therapy and multiply," Ivanov said. "Fortunately, cancer stem cells can be killed by blocking NOTCH1 production."

The similarities between the ACC stem cells and cancer stem cells derived from other cancers such as melanoma, neuroblastoma, and glioma surprised the researchers, according to co-senior author Wendell Yarbrough, M.D., professor and chief of otolaryngology.

"Our study suggests that drugs, which are now used in clinical trials to block NOTCH signaling in a variety of cancers, could be effective against ACC," Yarbrough said. "Also, our study highlights that there are good targets for therapeutic development in ACC. These findings should form the basis for clinical trials."