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When German biochemist Otto Warburg first postulated connection between cancer cells and metabolism in the 1920s, he likely would not have anticipated that his ideas would make a comeback some 90 years later. However, that is exactly what is happening.

“We've known for a long time that cancer cells were metabolically different than normal tissue,” says Lewis Cantley, PhD, director of the Weill Cornell Cancer Center at New York- Presbyterian Hospital, Weill Cornell Medical College in New York City, and a leading researcher in cancer cell metabolism. “We have the same questions today as we did 90 years ago, but now we have the tools to answer why.”

In 1924, Warburg (who would go on to win the Nobel Prize in Physiology in 1931) made the observation that cancer cells ate glucose at a much higher rate (up to 100% more) compared with normal tissue, and that they metabolized it differently as well, converting it to lactate rather than carbon dioxide. That discovery, known as the Warburg effect, dominated cancer research until the middle of the 20th century, when the discovery of oncogenes and tumor suppressor genes took center stage for the next 30 years. Now, thanks to new technology, scientists are beginning to understand that these genes actually control metabolism and switch cells on into different modes of growth, many of which follow the Warburg effect.

“The field has really blossomed in the last 5 to 10 years,” says Chi Van Dang, MD, PhD, director of the Abramson Cancer Center of the University of Pennsylvania in Philadelphia, who has conducted research in metabolism and cancer since the 1990s. “We're now able to see how genes change the metabolism of cells, and we are beginning to exploit those differences to develop new ways of treating cancer by targeting metabolism.”

New Tools and Research

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  2. New Tools and Research
  3. Lifestyle Factors
  4. References

Among the new technologies that are enabling more sophisticated analysis of metabolic levels are large-scale DNA sequencing and the ability to measure metabolic intermediates in a cell or perform flux analysis (the rate at which a metabolite is produced during a bioprocess), as well as better bioinformatics. Through such tools, scientists now can analyze thousands of pieces of data simultaneously rather than one at a time, Dr. Cantley says.

Many major pharmaceutical companies are dedicating large research divisions to the study of cancer and metabolism, whereas journals are publishing an increasing number of articles on the topic. A new open-access journal, Cancer & Metabolism, is dedicated exclusively to the field. Dr. Dang, who is co-editor of the journal, says, “We want to be a little more adventurous with this journal, yet keep the quality very high. Researchers don't need to have the entire story developed; we want to open the field up and be at the edge of discovery, which is always a little more turbulent.”

He cites an example of the emerging field of metabolomics, which aims to detect metabolism on a single-cell basis. It is still a new technology that is continually changing, and many other journals would require substantial feasibility to support the publication of studies focused on it, he adds.

Dr. Cantley notes that another reason why the field has taken off is that it provides an opportunity to develop new drug targets. Protein kinases (ie, BCR-ACL in chronic myelogenous leukemia and human epidermal growth factor receptor 2 [HER2] in breast cancer) have dominated the cancer field over the past decade because they are effective drug targets; however, he adds, “they have sort of saturated out.” At the same time, it is difficult to target transcription factors such as the protooncogenes Myc and Ras. Conversely, metabolic enzymes, such as protein kinases, can serve as potential drug targets.

Dr. Cantley, along with fellow leading cancer researchers Tak Mak, PhD, and Craig Thompson, MD, founded Cambridge, Massachusetts-based Agios Pharmaceuticals, which is working to develop drugs that target metabolic enzymes, including cytosolic isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2). Mutated versions of IDH1 are a common feature of a major subset of primary human brain cancers (gliomas), whereas mutated IDH2 has been noted in subsets of acute myelogenous leukemia.

Dr. Cantley and his colleagues have been investigating the role the metabolic enzyme glutamic-oxaloacetic transaminase 1 (GOT1) plays in the development of pancreatic cancer, as well as the enzyme phosphoglycerate dehydrogenase's amplification in many breast cancers and melanomas.[1, 2] “The focus in deciding what to target in clinical trials is to try to understand the event to which the cancer is addicted,” he says. “In the kinase field, that has been well established, but the question is whether we can identify metabolic enzymes that when mutated or amplified can be good targets for intervention.”

Dr. Cantley and others have coined the term “oncometabolite” for enzymes that cause high levels of molecules that then allow epigenetic changes in cells, causing them to become transformed. The goal is to target the enzymes and reverse how the mutations are driving the tumor.

In recent years, researchers also have found strong connections between diabetes, obesity, and cancer. Studies have demonstrated that people who are obese or have type 2 diabetes have higher rates of cancer, particularly those of the endometrium, colon and rectum, and breast. Scientists theorize that cancer may be fueled by insulin, higher levels of which are associated with both obesity and type 2 diabetes.

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We have the same questions today as we did 90 years ago, but now we have the tools to answer why. —Lewis Cantley, PhD

Recent epidemiological studies have suggested that the diabetes drug metformin, which lowers both insulin and glucose levels, also lowers the risk of cancer. A growing amount of research is focusing on the drug's impact on cancer. One example is an ongoing phase 3 clinical trial comparing metformin with a placebo in patients with early-stage breast cancer. Led by medical oncologist Pamela Goodwin, MD, of the University of Toronto in Ontario, Canada, the 5-year study seeks to determine whether metformin improves disease-free survival, overall survival, and various quality-of-life endpoints. She and her colleagues theorize that metformin's effect on decreasing insulin levels reduces signaling through the PI3K (phosphatidylinositide 3-kinases) pathway, which is a growth/proliferation pathway in patients with breast cancer.

The antimalarial drug chloroquine is another agent that is currently being investigated because it appears to interfere with autophagy, says Dr. Dang.

Lifestyle Factors

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  2. New Tools and Research
  3. Lifestyle Factors
  4. References

Still other investigators are exploring the lifestyle side of the metabolism equation. Rowan Chlebowski, MD, a medical oncologist with the Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, for example, has been involved with studies on how lifestyle interventions (including weight reduction and increased physical activity) can reduce the risk of cancer. “Many areas related to lifestyle factors, such as insulin, glucose, and hormone levels, as well as inflammation, can potentially stimulate or accelerate cancer growth when they get outside a certain range,” he says. “We're trying to bring them back in control, and you can either do that pharmacologically through drugs like metformin or through lifestyle interventions.”

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We're now able to see how genes change the metabolism of cells, and we are beginning to exploit those differences to develop new ways of treating cancer.—Chi Van Dang, MD, PhD

Dr. Chlebowski led the Women's Intervention Nutrition Study, which sought to determine whether dietary fat reduction would improve disease-free or overall survival in patients with earlystage breast cancer. The study found a 24% reduction in disease recurrence among women who received the intervention for 5.5 years, but did not note a survival difference. He and his colleagues are attempting to perform another 5-year follow-up study on these patients. “As the population, particularly in the US, becomes more and more sedentary and more and more overweight, we're seeing an increase in these growth factors that we didn't see as part of the evolutionary norm for hundreds of thousands of years,” Dr. Chlebowski says, adding that breast and colorectal cancers were very unusual diseases 100 years ago.

References

  1. Top of page
  2. New Tools and Research
  3. Lifestyle Factors
  4. References