Cancer as a Metabolic Disorder

I received an inquiry via Twitter “Has anyone thought about using a sugar medium (similar to PET scans) to deliver chemo drugs?”

Although no one would use PET scans nor the PET reagents as therapy, the question is actually profound. There is a growing recognition that cancer is not a genetic disease but instead a metabolic disorder. One could not attend a lecture at the American Association of Cancer Research without there being reference to Otto Warburg’s 1956 paper “On the Origin of Cancer Cells” that described the metabolic basis of human malignancy.

Despite our myopic focus on cancer genomics, there is a growing recognition that cancer represents dysregulated energy metabolism. The high utilization of glucose, a hallmark of malignantly transformed cells, (and the target of PET scan diagnostics), in part reflects the process of aerobic glycolysis, whereby cells provided ample oxygen nonetheless eschew the efficiency of mitochondrial oxidative phosphorylation in favor of seemingly inefficient lactate production.

Into this new realm of biochemically driven developments, a growing number of therapeutic agents that target glucose metabolism are finding their way into the clinic. To the dismay of some, the mutations that our molecular biologists identify are increasingly found to represent intermediates of cellular metabolism, forcing many to go back to relearn biochemistry. Thus, the avidity for glucose represented by uptake of the PET scan reagent F18 fluorodeoxyglucose by tumor cells, is a diagnostic application of what, in the future, may provide meaningful therapeutic opportunities.

About Dr. Robert A. Nagourney
Dr. Nagourney received his undergraduate degree in chemistry from Boston University and his doctor of medicine at McGill University in Montreal, where he was a University Scholar. After a residency in internal medicine at the University of California, Irvine, he went on to complete fellowship training in medical oncology at Georgetown University, as well as in hematology at the Scripps Institute in La Jolla. During his fellowship at Georgetown University, Dr. Nagourney confronted aggressive malignancies for which the standard therapies remained mostly ineffective. No matter what he did, all of his patients died. While he found this “standard of care” to be unacceptable, it inspired him to return to the laboratory where he eventually developed “personalized cancer therapy.” In 1986, Dr. Nagourney, along with colleague Larry Weisenthal, MD, PhD, received a Phase I grant from a federally funded program and launched Oncotech, Inc. They began conducting experiments to prove that human tumors resistant to chemotherapeutics could be re-sensitized by pre-incubation with calcium channel blockers, glutathione depletors and protein kinase C inhibitors. The original research was a success. Oncotech grew with financial backing from investors who ultimately changed the direction of the company’s research. The changes proved untenable to Dr. Nagourney and in 1991, he left the company he co-founded. He then returned to the laboratory, and developed the Ex-vivo Analysis - Programmed Cell Death ® (EVA-PCD) test to identify the treatments that would induce programmed cell death, or “apoptosis.” He soon took a position as Director of Experimental Therapeutics at the Cancer Institute of Long Beach Memorial Medical Center. His primary research project during this time was chronic lymphocytic leukemia. He remained in this position until the basic research program funding was cut, at which time he founded Rational Therapeutics in 1995. It is here where the EVA-PCD test is used to identity the drug, combinations of drugs or targeted therapies that will kill a patient's tumor - thus providing patients with truly personalized cancer treatment plans. With the desire to change how cancer care is delivered, he became Medical Director of the Todd Cancer Institute at Long Beach Memorial in 2003. In 2008, he returned to Rational Therapeutics full time to rededicate his time and expertise to expand the research opportunities available through the laboratory. He is a frequently invited lecturer for numerous professional organizations and universities, and has served as a reviewer and on the editorial boards of several journals including Clinical Cancer Research, British Journal of Cancer, Gynecologic Oncology, Cancer Research and the Journal of Medicinal Food.

4 Responses to Cancer as a Metabolic Disorder

  1. Dr. Nagourney

    My understanding is that “aerobic glycolysis” is an oxymoron. Glycolysis is “anaerobic” and not “aerobic.” The Warburg hypothesis was simply that tumor cells had a metabolic abnormality which made them rely more on glycolysis than on aerobic (Krebs Cycle) metabolism, the principle behind PET scans. You inject radioactive glucose, which is preferentially taken up by tumor cells, as glycolysis can only use glucose to create energy (ATP).

    Non-tumor (normal) cells use more aerobic, Krebs Cycle activity, which burns fat, in addition to glucose; so the relative uptake of radioactive glucose by normal tissue (compared to tumor tissue) is relatively greater and tumors show up as “hot” spots. So glycolysis is always anaerobic, not aerobic. One does not have to qualify glycolysis as being anaerobic.

    And then there is the thought that cancer cells burn through much more glucose – that’s visible on FDG PET scans – than normal cells. But not all cancers show up on FDG PET scans, because some use glutamine metabolism rather than glycolysis, or they could depend on another nutrient, amino acid glycine. Researchers know very little about how the body regulates glycine metabolism, yet its contribution to tumor cell proliferation only increases the evidence that changes in metabolism are a cause of cancer, not just a consequence of it.

  2. Neil Feldman says:

    Greg, I thought it was considered “aerobic” because even in the presence or restoration of adequate oxygen the tumor cell will not revert back to OxPhos (Oxidative Phosphorylation – i.e. normal respiration of oxygen). I thought that anaerobic glycolysis was what happens when a normal cell temporarily lacks sufficient oxygen (i.e. as, perhaps, during a strenuous workout by muscle cells) but then returns to normal respiration once sufficient oxygen is restored to the cell.

    Also, I think you meant to say that the relative uptake of radioactive glucose by normal tissue (compared to tumor tissue) is relatively LESS and tumors show up as “hot” spots.

  3. robert nagourney says:

    I thank you for your interesting comments. Warburg described “aerobic” glycolysis, as the preferential process of glucose consumption and metabolism through to lactate (glycolysis) in tumor cells, despite the apparent adequacy of O2. Thus, the glucose molecule capable of providing 36 ATP via oxidative phosphorylation yielded a mere 2 molecules of ATP per molecule of glucose. The seeming paradox may reflect many processes, one of which is the need to pass glucose to the pentose shunt. A related area is the use of amino acids to replenish Kreb’s cycle intermediates, as the pyruvate pathway to acetyl-CoA is diminished. This is known as anaplerosis and is in part reflected by glutaminolysis to alpha-ketoglutarate. This is a wonderful area of investigation and will certainly provide many therapeutics options in the future. Thank you.

    • Ralph Moss says:

      You might want to let your readers know about Thomas Seyfried’s comprehensive book, Cancer as a Metabolic Disease (2012) and about the work of Pete Pedersen of Johns Hopkins.

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