New research from the Keck School of Medicine of the University of Southern California (USC) shows new promise in the fight against one of the most lethal forms of cancer. Studies in mice with a mutation present in 90 percent of pancreatic cancer patients (the KRAS mutation) indicate that expressing only half the amount of the glucose-regulated protein GRP78 is enough to halt the earliest stage of pancreatic cancer development.
The study, funded in part by the NIH, suggests that because the protein is required for “switching” healthy pancreatic cells that produce enzymes to digest food into potentially cancerous cells, reducing the amount of this protein delays pancreatic cancer development and prolongs survival. The study is the first to establish the pivotal role of the protein in pancreatic cancer (PNAS 2017;114(20):E4020-E4029).
“Cancer cells are addicted to high levels of GRP78 for cancer development and growth. Our hope is that partially reducing or inactivating the protein by therapeutic agents could one day be an effective complementary therapy for pancreatic cancer and other cancers, while sparing other healthy organs,” said Amy Lee, PhD, Professor of Biochemistry and Molecular Medicine at the Keck School and the Judy and Larry Freeman Chair in Basic Science Research at the USC Norris Comprehensive Cancer Center, Los Angeles.
Lee, who was the first scientist to clone human GRP78, has since dedicated much of her research to investigating the protein's role in cancer progression and treatment. For her scientific contributions, Lee was honored by a MERIT award from the NCI and elected as Fellow of the American Association for the Advancement of Science.
“As developing drugs directly targeting the KRAS genetic mutation has been challenging, we are thrilled these findings indicate that we can attack KRAS-driven pancreatic cancer through an entirely new method,” Lee explained.
GRP78 is a stress-inducible protein that folds newly synthesized proteins and performs quality control in the endoplasmic reticulum (an essential component of human cells). During stress, a fraction of GRP78 is shipped out to the cell surface to perform additional growth and survival functions. Cancer cells, particularly those that survive treatment, typically undergo more stress than healthy cells, resulting in increased levels of GRP78 to help the cancer cells survive, grow, and develop therapeutic resistance.
A number of studies across cancer types have shown a relationship between highly elevated levels of the protein and increased risk for cancer recurrence or decreased survival. With GRP78 emerging as an attractive anti-cancer target, there is active development of potential treatments that can inhibit GRP78 activity or expression, including some that are in early-phase clinical trials with promising results. Certain food and herbs, including green tea and soy, contain natural compounds that can suppress the protein.
Patients and physicians alike are eager for more effective treatments for pancreatic cancer, as it is among the deadliest forms of cancer. According to the American Cancer Society, more than 53,600 people will be diagnosed with pancreatic cancer this year, and more than 43,000 people will die from the disease. The 5-year survival rate for early stage pancreatic cancer is only 12 percent, compared to 100 percent for breast cancer and prostate cancer and 92 percent for colon cancer.
“Translating any basic science discovery into clinical practice is a long process that requires substantial resources,” Lee concluded. “But given the notorious difficulties of treating KRAS-mutation related cancers, particularly in a disease as devastating as pancreatic cancer, this research provides hope and a novel approach. I am excited to put our theories to test in the clinical setting.”