In the 1920s, the German researcher Dr. Otto Warburg discovered that cancer cells rely heavily on a process known as glycolysis to produce energy.

Dr. Warburg, a Nobel Prize winner, also found that cancer cells did this even when there was sufficient oxygen available for a far more efficient, oxygen-dependent energy-production process used by many normal cells, called oxidative phosphorylation. The paradox came to be known as the "Warburg effect."

Dr. Warburg believed that this "aerobic glycolysis" was at the root of cancer development, but his theory never caught on.

Over the last decade, however, there has been a resurgence of interest in learning more about cancer cell metabolism - how cancer cells produce energy and use it to grow and divide.

Cancer cell metabolism hasn't traditionally been "considered as part of the cancer problem," says Dr. Craig Thompson, scientific director at the Abramson Family Cancer Research Institute. But the renewed interest in it, he believes, "gives us a number of new avenues to investigate to see whether it can be exploited for therapeutic benefit."

And Dr. Thompson isn't the only one. A growing cadre of researchers is now delving deep into cancer cells' energy-production machinery, with the hope of finding effective ways to short-circuit it.

Tumor cells' glucose problem

The renewed focus on energy production and Warburg's discoveries from 80 years ago is an ideal case in point.

"More and more, multiple groups are looking at the molecular mechanisms behind the Warburg effect, because it's consistently observed in tumor cells," says Dr. Peng Huang, an associate professor of molecular pathology at the University of Texas M.D. Anderson Cancer Center. "Certainly, in both cell culture and animal models, we see the cancer cells' increased dependence on glycolysis."

Both glycolysis and oxidative phosphorylation begin with the ingestion of glucose by a cell. The difference resides in how the cell transforms that raw material into energy - in the form of a complex molecule called ATP - and the efficiency with which it does it. Oxidative phosphorylation can produce as much as 18 times more ATP per molecule of glucose than glycolysis.

This inefficiency leads tumor cells that are reliant on glycolysis to take up a tremendous amount of glucose. This reliance forms the basis for the now widespread use of PET scans that involve the glucose analog FDG for the detection of a number of different cancer types.

Researchers like Drs. Huang and Thompson believe tumor cells' addiction to glycolysis might represent a bona fide Achilles heel: Disrupt glycolysis and tumor cells won't be able to produce enough energy to survive. Data from laboratory and animal model studies support this belief.

But the question remains: Why do tumor cells rely on a less efficient energy-production process when they don't have to?

"It's still a matter of debate," says Dr. Huang.

Several theories have been proposed to explain this. One suggests that genetic mutations have damaged the tumor cells' mitochondria, where oxidative phosphorylation takes place, so the cell switches to an alternative energy-production pathway. Another argues that it's an adaptation that gives the cell a survival advantage once a tumor becomes larger and oxygen - but not necessarily glucose - becomes far less abundant.

Dr. Thompson admits that it's complicated and requires more intensive study.

"We need to look more closely at issues like which signaling pathways tumor cells are using when they just want to survive for the day, or if they want to engage in growth and proliferation," he says.

Mucking up the machinery

Efforts to exploit this potential tumor cell weakness are moving ahead full steam, with glycolytic inhibitors already in human clinical trials or headed in that direction.

One company, Threshold Pharmaceuticals, has based its entire therapeutic enterprise on what they call "metabolic targeting." Two of its products are currently in clinical trials, including 2DG, a glucose analog being investigated in combination with docetaxel in a phase I trial.

Because tumor cells are so hungry for glucose - particularly those that are in hypoxic regions of a tumor and are more likely to be resistant to standard chemotherapy agents - 2DG is readily taken up by tumor cells, says the scientist who developed it, Dr. Ted Lampidis.

Once inside, explains Dr. Lampidis, a professor of cell biology at the University of Miami Sylvester Cancer Center, the agent competes with regular glucose to be synthesized into ATP. However, because of the slight difference in 2DG's makeup compared with glucose, that synthesis never happens, starving the cell of energy.

"We've made tremendous progress from developing the concept of 2DG to getting it into the clinic," he says. "I see now that there's a real possibility it's going to work."

The phase I trial is almost complete and plans are under way to launch a phase II trial.

Another agent, 3-BrPA, completely eradicated large, highly glycolytic tumors in one animal model and markedly shrank similar tumors in another model. The agent's target, explains Dr. Peter Pedersen, a professor of biological chemistry at the Johns Hopkins University School of Medicine - who along with Dr. Young Ko, is moving it through preclinical studies - is an enzyme called hexokinase that is bound to the surface of mitochondria but plays a key role in both glycolysis and oxidative phosphorylation. Dr. Ko, who discovered the agent's potent anticancer activity, calls 3-BrPA a "total energy blocker."

Most recently, they've been investigating 3-BrPA's effect on different cancer cell lines.

"Once inside [the tumor cell], it's like a Trojan horse," Dr. Pedersen explains. "You see dissipation of ATP very quickly. But if you do the same thing to a hepatocyte [an important and abundant liver cell], for example, it hardly has any effect."

A number of companies have approached Dr. Petersen's lab about taking 3-BrPA into clinical trials.

By Carmen Phillips