Capitalizing on a mutant p53 gene to fight pancreatic cancer

Human tumor cells from the pancreas
Fighting pancreatic cancer with a mutant form of p53 may prove effective, Stanford researchers suggest.

The p53 gene has long held interest in the oncology research community because of its proven role as producer of a tumor-suppressing protein. But harnessing the power of p53 in the treatment of cancer has been challenging. Several mutations of the p53 gene are known, and more than 1,000 other genes are affected by p53 status, making the path to tumor suppression difficult to define.

Now, scientists at the Stanford University School of Medicine say they’ve identified a pathway that allows the p53 protein to exert antitumor effects on pancreatic tumors—and a specific p53 mutation that strengthens this cancer-fighting capability.

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The Stanford team tested several individual p53 mutations on mice with predispositions to pancreatic cancer. They landed on one favorable mutation that supercharges the p53 gene and 100 genes that are affected by it. After just over a year, 40% of mice with normal p53 had died of pancreatic cancer, but none of the mice with the good mutation showed any signs of tumors.

The scientists then scrutinized the 100 downstream genes to try to figure out which ones were key to tumor suppression. They landed on Ptpn14, a gene that regulates a known cancer-promoting protein called Yap. The research was published in the journal Cancer Cell.

One of the key features of the particular p53 mutation that the Stanford team discovered is that it didn’t seem to cause any problems with embryonic development, as some mutant forms of the gene are known to do. Senior author Laura Attardi, Ph.D., professor of radiation oncology and genetics, called the mutant a “sweet spot” in cancer prevention. "Embryos can make it through development without any obvious effects, and then adult mice show greatly enhanced resistance to tumor growth."

But could the discovery point the way towards treatments for pancreatic cancer? Attardi believes that with more understanding of the p53-Ptpn14-Yap “axis,” it would be possible to invent a therapy that mimics the favorable mutation in p53. For example, a drug might be developed that inhibits Yap in tumors that lack p53.

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The promise of p53 continues to captivate biotechnology entrepreneurs and investors. New Jersey-based PMV Pharma has raised more than $100 million from investors to fund its pipeline, which targets nine cancers that have been tied to mutant p53, including hybrid serous ovarian tumors. The company expects to move into its first human trials next year.

Massachusetts-based Aileron Therapeutics collected $56 million in a June initial public offering, which will help fund the development of its lead compound designed to reactivate p53-mediated tumor suppression. It is being tested in several advanced solid tumors, as well as in peripheral T-cell lymphoma.

In pancreatic cancer, researchers are focusing on attacking tumors from many different angles. That includes capitalizing on metabolic pathways that might cripple the cancer. Last month, for example, scientists at Boston Children’s Hospital described how inhibiting the enzyme arginase 2 (ARG2) slowed pancreatic tumor growth in obese mice by preventing the cancer cells from metabolizing nitrogen.

The next step for the Stanford team is to determine whether the beneficial p53 mutant they uncovered may be relevant in mediating a wide range of other tumor types. "We want to know if this is a tissue-specific pathway,” Attardi said.