Lloyd Trotman journeys daily into the inner sanctum of cancer cells.
He analyzes their molecular machinery and potent energy production, but he does not stop there: The Cold Spring Harbor Laboratory cancer biologist’s explorations are revealing how a low-cost diabetes drug ultimately may quell the most lethal malignancies of the prostate.
In studying tumors that invade the walnut-sized gland, Trotman discovered a key genetic flaw in the most virulent forms of prostate cancer — those with a missing or mutated protein called PTEN.
When present, the protein slams the brakes on cancer growth.
“There is a loss of PTEN in many men who have aggressive variants of prostate cancer,” Trotman said. “So that loss is synonymous with a life-threatening form of the disease.”
The situation, he said, is found in about half of the men who die of prostate cancer. Many patients with aggressive forms of the disease also lack another brake, a key tumor suppressor called p53.
Trotman then found a way to make those cancers destroy themselves when exposed to a compound that first was isolated from French lilacs during the Middle Ages, now marketed as the top-selling diabetes drug, metformin.
The medication apparently undermines the mechanisms that aggressive prostate cancer cells rely on to produce energy and sustain themselves. It costs only pennies per dose.
If repurposed as a cancer treatment, it would be among the least expensive in an escalating pricing drama in which some cancer medications cost more than $450,000 for a one-time treatment.
Prostate cancer is a growing global health concern and a leading cause of cancer deaths among men. The American Cancer Society estimates that one in every 41 men in the United States dies of the disease, defining it as the second-leading cause of cancer deaths among men nationwide, after lung cancer.
Some prostate tumors, especially in older men, are indolent, growing so slowly that most men are more likely to die with the disease than of it.
It rarely is diagnosed before the age of 40, though some groups are at elevated risk. African-American men, for example, are at higher risk than white men. Others at high risk include anyone with a family history of the cancer.
Anecdotal evidence had long suggested that metformin might play a role in cancer therapy, because diabetics who were on the drug had lower rates of certain cancers.
But no one knew the precise mechanism of how metformin works in cancer cells until Trotman and his colleagues revealed their research on PTEN, published earlier this month in the journal “Cell Reports.”
It was a breakthrough for the prizewinning professor who received a 2014 Pershing Square Sohn Prize for Young Investigators in Cancer Research, given annually to six investigators in the greater metropolitan area exploring groundbreaking new paths.
The discovery that the absence of PTEN made prostate cancers more aggressive was the first piece in a large and complex puzzle, Trotman said.
When present and healthy, PTEN functions as a master tumor suppressor, keeping cancer at bay. But without it, combating prostate cancer becomes decidedly difficult, and sometimes futile.
“We were asking this question: How could we most effectively kill cells that have the mutation while sparing cells that do not? So we screened a lot of drugs and tested them in an unbiased way,” Trotman said. “What we found is that there is one type of drug that selectively kills those cells that have lost PTEN” — and that the drug leaves healthy cells unharmed.
Metformin, with its long and storied past, hails from a drug class known as mitochondrial inhibitors.
Trotman and his colleagues discovered the precise molecular mechanisms by which the drug forces aggressive prostate cancer cells to burn all of their energy and destroy themselves.
Mitochondria are tiny, bean-shaped powerhouses in most human cells (they are not in red blood cells). They provide the chemical energy necessary for every human activity — walking, running, lifting, even reading the words on this page.
Aggressive prostate cancer cells, lacking PTEN proteins, not only possess mitochondria, they covet them and go to great lengths to preserve them.
“Cells in general have two ways of generating energy,” Trotman said. “One is through the mitochondria, and the other is burning sugar. When you inhibit the mitochondria with metformin, cells are forced to burn sugar.”
Once cancer cells have burned all their fuel, they die, he said.
Missing PTEN suppressors have been found in other cancers, and small, inconclusive clinical studies have been conducted under the auspices of the National Cancer Institute to explore the role of metformin in cancer therapy.
The aims of these investigations have been to determine if metformin might be used as a cancer preventive in obese patients at high risk for cancer of all kinds, and who also had elevated blood sugar. Those doctors have not yet reported their results.
Dr. Gerald Bernstein of Lenox Hill Hospital in Manhattan, who was not involved with Cold Spring Harbor Lab’s research, said metformin probably works against cancer for many of the same reasons it helps to control diabetes.
“Metformin, at the present time, is the most commonly prescribed diabetic medication in the world,” said Bernstein, an endocrinologist and coordinator of the Friedman Diabetes Program at Lenox Hill. It was developed in Europe and prescribed for years before being approved by the U.S. Food and Drug Administration in the mid-1990s.
In diabetes, metformin reduces the amount of glucose — sugar — produced by cells in the liver. It also acts directly on the mitochondria by inhibiting respiration in the tiny bean-shaped pods.
“Most people who are on metformin, including myself, take the generic because it is perfectly effective and very inexpensive,” Bernstein said. The drug also is sold under the brand name Glucophage. Sixty tablets costs about $4 at prescription drug discounters, such as Walmart.
“Some of us think it should be in baby’s milk,” Bernstein said jokingly.
He added that metformin helps improve the integrity of blood vessels. And clinical studies also have shown that it can lower the risk of advancing from pre-diabetes to full-blown disease.
Trotman, meanwhile, is delving into the next part of the puzzle involving missing PTEN proteins, metformin and prostate cancer.
A looming scientific question is when it should be administered. Trotman noted that the drug probably would be best given when patients’ glucose levels are low, a point when there is little fuel left and no hope for cancer cells to cling to life.