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Under the Microscope: Severing Cancer Cells’ Copper Communication Channels

New therapies are desperately needed for pancreatic cancer, one of the most deadly and difficult-to-treat types of cancer. The most common type of pancreatic cancer, known as pancreatic ductal adenocarcinoma (PDAC), has a five-year survival rate of less than eight percent.

“PDAC tumors are challenging because they can’t be detected early enough for surgical removal and don’t respond to standard chemotherapies,” said Donita C. Brady, Ph.D., Presidential Assistant Professor of Cancer Biology at the University of Pennsylvania Perelman School of Medicine. “In addition, 30 years of research into therapies targeting the KRAS gene mutation, which is present in 95 percent of PDAC tumors, has not yielded useful treatments.”

Today, a great deal of cancer research focuses on one of two areas: disrupting the proteins cancer cells use to send and receive messages; or finding ways to deprive cancer cells of energy to slow their growth. Brady’s research team is exploring a completely new approach by studying the role that dietary metals, such as copper, play in the signaling processes cancer cells use to communicate and survive.

Blocking copper suppresses tumors

With a V Foundation grant funded by the Stuart Scott Memorial Cancer Research Fund, Brady and her colleagues are studying PDAC tumors with the mutant version of the protein KRAS. The KRAS mutation turns on autophagy, a process in which cells digest themselves to fuel aggressive growth. While normal cells use autophagy to recycle nutrients and extend their lives when starved, cancer cells with mutant KRAS put the autophagy process into overdrive, allowing them to stay alive when extremely few nutrients are available.

“We have uncovered an entirely new role for the dietary nutrient copper in tumors with the KRAS mutation,” said Brady. “This nutrient is not only important for turning autophagy on but is also required to maintain the signaling that cancer cells need to survive. Getting rid of dietary copper can block both arms of this pathway.”

Because copper is found in a wide range of foods, from meat to vegetables, it is nearly impossible to avoid consuming it. However, small molecules that bind very tightly to copper, called copper chelators, can lower the amount of copper in the body. These drugs cost little and have been used successfully for years to treat rare genetic disorders in which patients accumulate copper in the brain and liver.

“We found that in mouse models of pancreatic cancer, combining chemotherapy with copper chelators completely suppressed tumor growth,” said Brady. “Our preliminary data is exciting because it shows that copper chelators do target the proteins that we thought they would and have an effect on cellular properties that cancer cells need to survive.”

More testing ahead

If these findings hold up after more experiments in mouse models, Brady said clinical trials could be designed to test copper chelators in combination with chemotherapy or as another option for pancreatic cancer patients who don’t respond to other treatments. The researchers are also studying how metals like copper may affect signaling in other types of cancers.

“This pilot funding from the V Foundation is letting us take preliminary data and grow it into a major focus of our research program,” said Brady. “This allows us to acquire the data we need to apply for research funding from other institutions, which is critically important with today’s tight funding climate.”