Mar 01, 2019 8:00 AM

Martin McMahon, PhD, and Conan Kinsey, MD, PhD, in the lab
Martin McMahon, PhD, and Conan Kinsey, MD, PhD,

In late 2016, Conan Kinsey, MD, PhD, a fellow training to be a physician-scientist, approached Martin McMahon, PhD, a cancer researcher at Huntsman Cancer Institute (HCI), to discuss a research concept. Together, they set out to better understand a mystery in pancreatic cancer.

A gene named KRAS controls important functions in normal cell development. In pancreatic cancer cells, mutations in the KRAS gene send constant signals, causing the cell to keep making abnormal copies of itself. These signals are part of a chain of events called a cancer pathway—in this case, the KRAS>RAF>MEK>ERK pathway.

"There is a paradox in pancreatic cancer: we know this pathway is essential to how pancreatic cancer develops, but efforts to treat patients with drugs that block the pathway showed no clinical benefit," says Dr. McMahon.

Dr. Kinsey designed an experiment to examine what happens in pancreatic cancer cells when the KRAS>RAF>MEK>ERK pathway is blocked. He found blocking this pathway in cells leads to an increase in another cellular process known as autophagy.

"Autophagy is a process where cells recycle their components to generate new building blocks for cell metabolism," says Dr. Kinsey. "Somehow the process of autophagy was protecting pancreatic cancer cells from the drug that blocks the pathway."

With this knowledge in hand, Drs. Kinsey and McMahon reasoned that blocking KRAS on its own wasn't enough—but attacking both KRAS and autophagy simultaneously might produce the desired result.

The scientists engaged others at HCI to test this theory: oncologists, nurses, surgeons, pathologists, undergraduate and graduate students, imaging specialists, lab researchers, and clinical trial specialists. They used two drugs that had not been combined before to treat mice with pancreatic tumors. The results were promising.

In an unexpected turn of events, Dr. McMahon met a postdoctoral fellow, Kirsten Bryant, PhD, at a research conference in December 2017. Dr. Bryant presented a poster outlining work she was conducting in the lab of Channing Der, PhD, at the University of North Carolina Lineberger Comprehensive Cancer Center. Her findings were remarkably similar to Dr. Kinsey's research that was underway in Dr. McMahon's lab.

A few days later, Dr. McMahon called Dr. Der and explained the similarities. This might have started a race to publish first, but the scientists took an unusual and highly collaborative step. They recognized their independent studies were complementary and actually strengthened each other's conclusions. They made a plan to submit their work to a journal together and set up regular calls to discuss progress.

Some months later, a pancreatic cancer patient at HCI, who had exhausted all other treatment options, was able to receive the combination therapy Drs. McMahon and Kinsey designed. This allowed the scientists to get an early look at the potential clinical impact of their approach. Although the patient ultimately succumbed to the disease, he showed a striking response to the combination therapy and survived eight additional months—five of which were progression-free. This amounted to a 50 percent increase in typical life expectancy from time of diagnosis. The HCI study was recently published alongside the UNC Lineberger study in the journal Nature Medicine.

In less than three years, this idea progressed from concept to lab to clinical evaluation. A clinical trial to test the safety and effect of this drug combination in pancreatic cancer is now underway at HCI and planned at other sites around the United States.

"I have been working in cancer research for more than 30 years, and I have never participated in anything as exciting as this project," says Dr. McMahon.

Even with this excitement, they recognize the work is only beginning. A grant recently awarded to Dr. McMahon by the Pancreatic Cancer Collective, a collaboration of Stand Up 2 Cancer and the Lustgarten Foundation, will fund future work.

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