Amy Lee, PhD, has made it her mission to uncover new ways to block the growth of pancreatic cancer cells.

With a five-year survival rate of only 8 percent, pancreatic cancer remains a difficult cancer to treat successfully. The symptoms can be subtle or invisible, and the delay in diagnosis means treatment often does not begin until the cancer is advanced. Even after diagnosis, pancreatic cancer cells have a defense mechanism that makes it even harder to kill the cells.

Amy Lee, PhD, professor of biochemistry and molecular medicine at the Keck School of Medicine of USC and the Judy and Larry Freeman Chair in Basic Science Cancer Research, is leading a team of researchers that have identified a novel target to curb a key mechanism in pancreatic cancer development.

“Because pancreatic cancer is so hard to cure, one of things we want to define are some new targets — to figure out what is really making these cancer cells so difficult to kill,” Lee says.

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About 90 percent of pancreatic cancers are caused by a mutation in the gene called KRAS, Lee explains. There are few drugs known to destroy the mutant KRAS protein, making it very hard to kill. Moreover, pancreatic cancer is unique in that it is covered by a network of cells and fibrous proteins that behave like a hard crust, which acts as a barrier preventing drugs from penetrating into the cancerous cells.

“And there is yet another obstacle: The pancreatic cancer cells inside the crust are very stressed,” Lee says. “Under stress, these cells turn on a pro-survival defense mechanism that makes the cancer cells even harder to kill. Throughout my career, I have studied this pro-survival response.”

One of the major players in the pro-survival defense mechanism is the glucose-regulated protein 78 (GRP78). This protein is known to researchers as a very important tool in cancer’s defense mechanism — but its role in pancreatic cancer cells is still not clear. Lee’s lab has focused on studying GRP78 as a new target for pancreatic cancer, using genetic tools to understand its function in the development of cancer.

Using a mouse model with both normal levels of GRP78 and one with only 50 percent of GRP78 in the pancreas, Lee’s team added a mutant KRAS gene to initiate pancreatic cancer. The mouse with half the amount of GRP78 — which researchers previously determined would not affect otherwise normal organ development in mice — had a smaller incidence of cancer than the mouse with 100 percent production of GRP78, which indicates that GRP78 is required for cancer development, Lee says.

“It turns out that for the pancreas to go from healthy to cancerous, certain normal cells that produce digestive enzymes turn themselves into a different type of cells called ductal cells, which then become cancer cells,” Lee says. “What we discovered is that in the mouse with reduced GRP78, this conversion process is suppressed. Nobody realized this before. In addition, reduced GRP78 also impairs cancer cell growth signals.”

This discovery led Lee to propose GRP78 as a new target for blocking pancreatic cancer growth. Drugs that inhibit GRP78 are in clinical development for use in combination with other anti-cancer drugs, Lee says, which could result in a treatment that will suppress the development of pancreatic cancer as well as slow the growth of the cancer.

“In other words,” Lee says, “we can attack KRAS-driven pancreatic cancer through an entirely new method.”

This discovery is part of an emerging new direction in cancer research. Scientists are beginning to understand that in order for cancer to occur, one tissue has to transform into another tissue, Lee says. While this process is particularly relevant in pancreatic and breast cancer, it also may impact uterine cancer, which is regulated by a glucose-regulated protein called GRP94.

As researchers dive into uncovering the mysteries behind cancer development, Lee says the importance of fundamental basic cancer research cannot be understated.

“This research holds the key to new discoveries that can be translated to treat patients in the clinical setting,” Lee says. “An investment in basic cancer research is necessary to identify fresh approaches. I am grateful for the support from the Julia Stearns Dockweiler Foundation, the Freeman Chair and the National Cancer Institute for the support of this research, and the dedication of my research team.”

By Nancy Sokoler Steiner and Melissa Masatani