Pancreatic cancer is the fourth most common cause of cancer-related deaths in the United States with a 5-year survival rate of less than 10%. Although it is defined by a small number of genetic alterations, efforts to pharmacologically target specific pathways have been unsuccessful.

Researchers have found that “squamous-like” pancreatic cancer, a subtype that impacts 15%-20% of patients, is driven by deregulation of epigenetic mechanisms, resulting in the loss of cell identity and development of highly aggressive and metastatic tumors.

A team at the George Washington University (GW) Cancer Center received more than $1.8 million from the National Institutes of Health to develop genetically engineered models to comprehensively study the role of COMPASS, a protein complex that epigenetically regulates cell fate decisions that drive the initiation and progression of pancreatic cancer. Understanding the role of the COMPASS complex may allow researchers to develop targeted therapies for the squamous-like pancreatic cancer.

“Due to early metastatic spreading, only a small percentage of patients benefit from surgical removal of the tumor,” said Alexandros Tzatsos, MD, PhD, assistant professor of anatomy and cell biology at the GW School of Medicine and Health Sciences and principal investigator on the study. “Even then, the overall prognosis remains dismal.”

In patients that don’t qualify for surgery, chemotherapy has marginally improved overall survival; however, it is also associated with adverse side effects. Thus, there is an unmet need to identify molecular vulnerabilities and treat pancreatic cancer patients based on their likelihood to respond to tailored treatments.

“Considering that rewired epigenetic circuitries are not present in normal cells, yet are essential in cancer, identifying and targeting the responsible enzymes may uncover an Achilles’ heel for the development of patient-tailored therapies,” Tzatsos said.

Thus far, screening of small-molecule inhibitors has revealed that COMPASS complex mutant pancreatic cancer is sensitive to the Bromodomain and Extra-Terminal family of inhibitors, suggesting a therapeutic niche that can be exploited in the development of personalized therapy.