The Cancer-Diabetes Connection
Before coming to Salk, he was already interested in a possible connection between the two diseases. As a postdoctoral fellow at the Harvard Medical School, he made the unexpected discovery in 2003 that LKB1, a gene causing 30% of lung cancers and 25% of cervical cancers was directly activating the enzyme AMPK, known to modulate diabetes and metabolism.
At this point, Dr. Shaw asked himself two seminal questions: “What did a diabetes gene have to do with cancer? And did the cancer gene have anything to do with diabetes?”
The answer turned out to be revelatory. AMPK is an ancient metabolic checkpoint that senses energy deprivation in the cells. Early in evolution, cells needed a sensor regulating their need for energy, and AMPK is found in organisms from simple yeasts to man and everything in between. AMPK responds to caloric restriction, exercise, hypoxia, low glucose, and metabolic hormones such as ghrelin or adiponectin.
In 2005, Dr. Shaw and his lab showed that metformin operates through LKB1 and AMPK to lower blood glucose. Since it is well-tolerated, it is the frontline treatment for type 2 diabetes with more than 120 million people taking it every day. However, as Dr. Shaw had postulated, at this time it was also becoming known that metformin reduces the risk of cancer in diabetic patients.
In 2008, now at Salk, Dr. Shaw and his lab discovered that AMPK directly shuts off a major oncogene called TOR, but it only does so when nutrients are low. This oncogene is the causal biochemical event in a number of human cancers, including kidney cancer, tuberous sclerosis, and LAM.
“LKB1 and AMPK act as a fuel gauge in our cells,” he explained in a recent interview, “and when energy is low, they instruct the cells to slow their metabolism. When tumor cells lack LKB1 or other parts of its pathway, they have, in effect, lost the sensor to know if their fuel levels are low.”