The term cancer generally refers to a large number of diseases arrayed across a broad continuum known as malignant neoplasms. This spectrum of pathology has a few basic commonalities: abnormal cells that divide and proliferate rapidly and uncontrollably and have the ability to invade tissue and spread (metastasize) distantly through blood and lymphatic systems. Cancers represent the second leading cause of death in the United States (CDC 2014).
The spectrum of treatment approaches and regimens for cancer is vast and larger even than the diversity of specific types and subtypes of disease. There are the long-standing approaches involving surgery, radiation, and conventional chemotherapies. There are targeted therapies directed at specific signaling pathways, including monoclonal antibodies, usually against tyrosine kinases (TKs). Tyrosine kinase inhibitors (TKIs) can be drugs in chemotherapeutic cocktails. They are also naturally occurring compounds that serve as “brakes” to various biologic pathways; for example, curcumin (in turmeric) and hematoxylin (in homoisoflavonoids) are potent TKIs. The noted antibodies can block pathologic TKs or angiogenins. There are specific hormone-blocking agonists that inhibit the tumor-growth-promoting effects of reproductive steroids. “Biologic” or immunotherapies are designed to repair or stimulate; cytokines, vaccines, and radio immunotherapy round out the adjunctive biologic armamentarium.
Hematopoietic autologous and allogeneic stem cell transplantation together with chemotherapy and radiation have revolutionized the treatment of leukemias, lymphomas, multiple myeloma, germ cell, and other pediatric tumors. Other strategies involve high-intensity ultrasound/hyperthermic, photodynamic, cryo- and laser-based procedures, nanoparticle delivery systems, and genomic editing. These have become elements of the cancer management tool kit.
What is conspicuous by its relative absence in both the research and clinical literature is a primary treatment strategy based upon nutrition. However, there appears to be an area of emerging and very intriguing work that is worthy of attention, support, and expansion. Recent investigation, exemplified by the work of researchers at the Abramson Cancer Center of the University of Pennsylvania, ushered in a new approach to treating cancer at the level of cellular nutrition. This approach may also be relevant for general pre- and post-operative nutritional support in patients who do not suffer from malignancy but who are faced with what amounts to autocatabolic illnesses.
The biomedical research at this center recognized the extreme bioenergetic needs of cancer cells in general and, in particular, the survival of rapidly proliferating cells under nutrient-deprived conditions. Solid tumors, both malignant and benign (i.e., endometriomas, fibromas, and lipomas), are often poorly vascularized, leading to regions of hypoxia and nutrient deficiency (Goel et al. 2011). Angiogenesis alone, in the microenvironment of a neoplasm, emerges as a very desirable target either for optimal antibody blockade or via blockade of requisite nutrient/precursor metabolism (Le et al. 2012).
Among the most intriguing nutritional studies to date are those focusing on L-glutamine. This is a naturally occurring nonessential amino acid that is the most abundant free amino acid in human muscle and plasma. Its role in normal metabolism includes protein synthesis, nitrogen donation, and transport (in support of anabolic/anaplerotic processes), carbon donation (replenishing the TCA cycle), and gluconeogenesis. In addition, L-glutamine serves as a precursor of nucleotide bases and glutathione, modulates acid-base regulation, and appears to be critical in gut mucosal cell energetics. In cancer cells, glutamine appears to be necessary for activation of target of rapamycin (TOR) kinase, as a primary mitochondrial substrate, for maintenance of mitochondrial membrane potential, and in support of nicotinamide adenine dinucleotide phosphate production (Wise and Thompson 2010; Gleeson 2008).
TOR, initially identified in the yeast Saccharomyces cerevisiae, is a member of the phosphatidylinositol kinase–related kinase (PIKK) family. This family includes an array of DNA-dependent protein kinases, some of which act as tumor suppressor genes. Its name arises from the fact that TOR binds the bacterial macrolide rapamycin when it is complexed with FKBP12—a peptidyl prolyl isomerase. TOR pathways are widely expressed systems that respond to growth factors that recruit or activate downstream effectors that in turn support biosynthesis or uptake of nutrients and amino acids (DeBerardinia et al. 2008).
Thus glutamine as a putative activator of TOR presents an appealing target for new clinical strategies to detect, monitor, and reduce cancer. In the current taxonomic language, the metabolic functions of glutamine identify it as a critical nutrient with surprising roles in supporting and disabling the metabolic hallmarks of malignancy. This is, of course, but one potential mechanism for the nutritional management of cancer. The more exciting and potentially important message is that medical nutritional avenues of attack on at least some malignancies may represent an effective intervention in the war on cancer.
Roger Clemens, DrPH, CFS,
Univ. of Southern California School of Pharmacy,
Los Angeles, Calif.