Three years ago, oncology researchers discovered that elephants have 20 copies of p53, a gene that’s essential to cancer suppression. Humans, by contrast, have just one copy of p53. The researchers, which included a team at the University of Chicago, concluded that elephants are especially resistant to cancer because of p53—but they didn’t know the exact mechanism by which the tumor suppressor gene works.
Now the Chicago team has uncovered a key part of that process: a nonfunctioning, or “zombie” gene. The gene, called LIF6, is activated in elephants by p53, after which it kills cancer precursor cells. They believe that the discovery, which they described in the journal Cell Reports, could boost efforts to develop drugs for people that target p53.
Cells that are unable to repair DNA damage often go on to become cancerous. Elephants are estimated to have 100 times as many of these cancer precursor cells than people do, but less than 5% of captive elephants end up dying from the disease. To try to figure out why that is, the University of Chicago team has been studying elephant cells.
The scientists discovered that in elephants, LIF6 makes a protein that zooms to the damaged cells’ mitochondria, or energy center, and pokes holes in it, which causes cell death.
“When [LIF6] gets turned on by damaged DNA, it kills that cell, quickly,” said senior author Vincent Lynch, Ph.D., assistant professor of human genetics at the University of Chicago, in a press release from the university. “This is beneficial, because it acts in response to genetic mistakes, errors made when the DNA is being repaired. Getting rid of that cell can prevent a subsequent cancer."
The team made the discovery by first inducing DNA damage in elephant cells and cells taken from smaller animals. The elephant cells died immediately, they observed. Then they tried blocking LIF6 protein expression, and the cells started to become cancerous. So they decided to try over-expressing LIF6 in cells from mice, which don’t normally have functional copies of the gene. All of the cancer precursor cells died.
Although p53 has been known as a tumor suppressor for quite some time, efforts to translate that knowledge into drugs have been slow to materialize. Still, interest in p53 research remains high. Startup PMV Pharma raised $74 million from venture capitalists last year to develop a pipeline of p53-targeted cancer drugs. Its approach is to use small molecules to restore the function of the gene in cancers marked by p53 mutations.
Aileron, which raised $56 million in an IPO last summer, is also targeting p53 with its lead product candidate, ALRN-6924. It’s designed to reactivate p53 tumor suppression by targeting two proteins. The drug is in early-stage clinical trials for advanced solid tumors and blood cancers.
Late last year, Stanford scientists announced they had found a p53 mutation that strengthens the ability of the gene to battle pancreatic cancer. The mutation regulates a cancer-promoting protein called Yap, they said. Their plan was to further study the mutation to determine if it's active in other cancer types.
The University of Chicago’s Lynch believes that the strategy employed by elephant cells to reawaken LIF6 could be translated to human oncology.
"Maybe we can find ways of developing drugs that mimic the behaviors of the elephant's LIF6 or of getting cancerous cells to turn on their existing zombie copies of the LIF gene," he said.