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Dec 26, 2013
Metabolism’s Unexpected Role in Cancer
A geneticist at the Salk Institute discusses his incredible discoveries.
Mitzi Perdue
The discoveries made in Reuben Shaw’s lab could influence how we treat diabetes, Alzheimer’s, and even aging itself. [© sheelamohanachandran - Fotolia.com]
The relationship between metabolism, cancer, and genetics was for decades obscured in part by chance, but in the last decade, the relationship has been rediscovered, also at least in part by chance. Reuben Shaw, Ph.D., a geneticist and researcher at the Salk Institute, is at the center of this story, and interestingly, the discoveries made in his lab have not only resulted in new targets for cancer therapy, but longer term, they’re also likely to influence how we treat diabetes, Alzheimer’s, and even aging itself.

Lost Information
To begin with the chance part of the story, what we now know to be true—that metabolism influences cancer—was well known at least 90 years ago. Back then, Otto Heinrich Warburg, a German physiologist, observed that tumor cells utilize glycolysis more than their normal counterpart cells despite being in normal oxygen conditions (the “Warburg Effect”). In 1931, Warburg won a Nobel Prize for his work on mitochondria. Subsequently he formulated the Warburg Hypothesis, that the cause of cancer is defective mitochondria.

In the 1980s, however, the discovery of “oncogenes” that directly caused cancer led researchers to believe that the Warburg Hypothesis for cancer causation was simply wrong. As the data on cancer-causing genes became both more comprehensive and more productive, cancer research switched to decoding genes, and a generation of researchers began ignoring metabolism as a factor.

Chance Intervenes
Things changed, however, when Dr. Shaw, who was trained as a cancer researcher at MIT and Harvard Medical School, was accepted at the Molecular and Cell Biology Laboratory at the Salk Institute. As Dr. Shaw puts it, “Salk is the only place that has a strong and deep history of cancer and diabetes research that also has the laboratories for both housed in one building. This means that some of the top people in the country get to interact fluidly, including not only sharing knowledge but also their tools and equipment.”

From Dr. Shaw’s point of view, the location of both the cancer and diabetes researchers in the same building meant that he was benefiting on a daily basis from the unique tools and discoveries of both the cancer and diabetes researchers at Salk and the cross-fertilization of these two fields. He was therefore able to pursue his investigations of the connections between the two diseases in ways that might not have happened if he were in a silo-type building where all his colleagues were researching cancer alone or diabetes alone.

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.”

Interfering with Cancer’s Sweet Tooth
Knowing that cells lacking LKB1 had lost their fuel gauges, Dr. Shaw wondered if this could be an entry point for disrupting tumor growth. Dr. Shaw already knew that factors such as exercise and calorie restriction could stimulate AMPK’s signaling ability, but were there, he wondered, drugs that could accomplish the same thing? Interestingly, the answer is yes.

The drugs metformin and phenformin both inhibit mitochondria; however, phenformin is nearly 50 times as potent as metformin. Dr. Shaw and his postdoctoral fellows tested both metformin and phenformin as chemotherapeutic agents in mice genetically engineered to mutate different cancer genes in adult lung cells, which results in the mice developing advanced-stage lung tumors. Only in mice lacking the LKB1 cancer gene did Dr. Shaw and his team observe that, after three weeks of treatment with phenformin, there was a major reduction in tumor burden in the mice.

Cancer’s Achilles’ Heel
Knowledge of this leads to a profound impact on therapies for cancer because, as Dr. Shaw now knew, it was possible to interfere pharmacologically with this pathway. Disruptions of the “fuel sensing” mechanism means that with cancer cells, they could cause nutrient and oxygen deprivation. This had the medically important effect of signaling AMPK to arrest cell growth. The cancer cells would be influenced to cease proliferating.

But that’s not the end. The other side of the coin of being able to induce a faulty fuel-sensing mechanism is that the cancer cells may act as if it they have all the energy and nutrients they need, even when they don’t. This results in the continuation of cell growth, and in the absence of fuel, the cells continue dividing until they run out of all energy stores and die.

Possible Clinical Trials
“These studies,” he said, “are the tip of the iceberg. We are in the midst of decoding new links between metabolism and cancer that are going to result in new druggable targets. They are likely to be important in treating many different cancers, and they may also be effective for other diseases such as type II diabetes. In the future we may find that aberrations in these same pathways and the metabolic disturbances that result may underpin neurodegenerative diseases and other broad disease categories as well.”

A lot is at stake. The 90-year-old Warburg Hypothesis, re-evaluated by Dr. Shaw and his colleagues, could have an outsize impact on modern medicine. Let the clinical trials begin!