Glutamine antagonist tested on monkeys shows promise against brain cancer
Glutamine is a non essential amino acid that acts as a principle nutrient for cancer cells to survive and proliferate. While many cancers show altered glucose metabolism, and this can be managed to a degree with metabolic therapy, it is critical to not forget the role of glutamine in brain cancer. In some cases glutamine appears to even be utilised as the preferential fuel source for these tumours.
'... in many cancer cells, glutamine is the primary mitochondrial substrate and is required to maintain mitochondrial membrane potential and integrity as well as support of the NADPH production needed for redox control and macromolecular synthesis.' (Wise and Thompson, 2010)
It is true that cancer cells have substantially higher demand for glucose, as defined by Otto Warburg in the 1920's, however we must not forget the work of Harry Eagle, who in 1955 was the first to highlight the essential requirement for glutamine for these proliferating cells, over and above that of any other amino acid. (Eagle, 1955)
Cavalheiro, E. A. and Olney, J. W. (2001). Glutamate antagonists: Deadly liaisons with cancer. Proc Natl Acad Sci U S A. May 22; 98(11): 5947–5948.
Eagle H. (1955). Nutrition needs of mammalian cells in tissue culture. Science. 122:501–514.
Martins, I. (2016). New Drug that Crosses Blood Brain Barrier May Improve Immunotherapy for Brain Tumors. Immun-Oncology News.
Raise, R. et al. (2016). Discovery of 6-Diazo-5-oxo-l-norleucine (DON) Prodrugs with Enhanced CSF Delivery in Monkeys: A Potential Treatment for Glioblastoma. J. Med. Chem. 59 (18), pp 8621–8633
Wise, D. R. and Thompson, C. B. (2010). Glutamine Addiction: A New Therapeutic Target in Cancer. Trends Biochem Sci. 2010 Aug; 35(8): 427–433.
The glutamine conundrum:
Harry Eagle was the first to observe the essential role of glutamine as an energy substrate in several cancer cell lines in vitro.
In a recent study using monkeys as test subjects, a 70 year old drug (6-diazo-5-oxo-l-norleucine (DON, 1)) has been adapted to cross the blood brain barrier without the concerning levels of toxicity which have frustrated pharmaceutical companies in the past. Researchers behind the study (scientists from Johns Hopkins Drug Discovery and the Kimmel Cancer Center's Bloomberg~Kimmel Institute for Cancer Immunotherapy) have suggested that the drug could generate a more preferential metabolic environment which can enhance the action of immunotherapy treatments.
I believe it is perfectly feasible that this drug could enhance efficacy of the ketogenic diet.
'The glutamine antagonist 6-diazo-5-oxo-l-norleucine (DON, 1) has shown robust anticancer efficacy in preclinical and clinical studies, but its development was halted due to marked systemic toxicities. To enhance DON’s therapeutic index, we utilized a prodrug strategy to increase its brain delivery and limit systemic exposure. While these dual moiety prodrugs exhibited rapid metabolism in mouse plasma, several provided excellent stability in monkey and human plasma. The most stable compound (5c, methyl-POM-DON-isopropyl-ester) was evaluated in monkeys, where it achieved 10-fold enhanced cerebrospinal fluid to plasma ratio versus DON. This strategy may provide a path to DON utilization in glioblastoma multiforme patients.' (Raise, 2016)
Scientists attempted to block glucose uptake to the brain with glutamine antagonists for many years with little success.