New strategies for improving pancreatic cancer treatments

Pancreatic cancer
Promising preclinical results for a combination of a malaria drug and KRAS inhibitor resulted in a planned clinical trial in pancreatic cancer. (Manu5, http://www.scientificanimations.com/wiki-images/, [CC BY-SA 4.0 (https://creativecommons.org/licenses/by-sa/4.0)], via Wikimedia Commons)

Pancreatic cancer is so difficult to treat that the one-year survival rate across all stages of diagnosis is just 20%. Two discoveries announced on Monday—one related to a new combination treatment and the other to genetic testing—could improve the prognosis for patients with pancreatic cancer.

The potential new treatment strategy capitalizes on a natural process known as autophagy, in which cells recycle some of their own components to use as an energy source. Researchers at the University of North Carolina Lineberger Comprehensive Cancer Center figured out how to coax pancreatic cancer cells to become more reliant on autophagy, while at the same time blocking the energy pathway the cells need to survive.

The treatment combines hydroxychloroquine—a drug normally used to treat malaria and some autoimmune diseases—with a second compound that indirectly targets KRAS, a gene that’s frequently mutated in pancreatic cancer. In studies in mice and human cells, targeting the KRAS mutation with an FDA-approved MEK inhibitor made the cancer cells increasingly dependent on autophagy, which was then crippled by the hydroxychloroquine. The results were so promising that researchers at M.D. Anderson Cancer Center are now planning a trial in people, according to a statement.

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Researchers studying pancreatic cancer have long known that tumors with KRAS mutations exhibit increased autophagy. But trials testing hydroxychloroquine alone in patients were largely ineffective.

"Cancer cells have many options for energy—we know of at least four or five," said Channing Der, Ph.D., a professor of pharmacology at the UNC School of Medicine, in the statement. "And so if you take away one, the cancer cell can adapt and say 'OK, that's not a problem, I'll just increase the others.’”

Der’s team found that blocking KRAS cripples the ability of pancreatic cancer cells to use those other energy sources. They published their findings in the journal Nature Medicine. A similar discovery was also made by the Huntsman Cancer Institute, according to a letter published in the same issue of the journal.

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In a separate discovery, scientists led by the University of Pittsburgh School of Medicine studied the genomes of 3,594 pancreatic tumor samples and discovered that 17% of patients have genetic “signatures” that indicate they would respond well to existing chemotherapy regimens. What’s more, they found evidence of genetic abnormalities that can be inherited, including mutations in the BRCA gene.

The findings, published in the journal Gastroenterology, support two strategies, suggested lead author Aatur Singhi, M.D., Ph.D., a surgical pathologist at UPMC and assistant professor of pathology, in a statement. The first would be to match patients with the chemotherapy regimens that are most likely to work for them, and the second would be to test family members for a predisposition to pancreatic cancer, so surveillance strategies can be set up to catch the disease in its earliest stages.

Singhi previously led the development of a test called PancreaSeq to test pancreatic cysts and determine the likelihood they will develop into cancer. The Pitt team plans to add the biomarkers they discovered to the test.

"Every pancreatic cancer is different, and performing molecular profiling of each patient's tumor could help determine the best treatment options," Singhi said in the statement. “A one-size-fits-all approach isn't going to work. Therefore, we would like to make molecular profiling standard-of-care for patients with pancreatic cancer."

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