A window into the future of cancer treatment
Metabolic drugs target different pathways in the cells, such as glycolysis or oxidative phosphorylation, which provide cells with energy, or glutaminolysis, which is important in the processing of the aminoacid glutamine. However, these processes aren’t specific to cancer cells, they take place in other cell types in our body too, so during treatment, cell types other than cancer cells are impacted as well. The changes they undergo are structural and functional and generally can affect tumor growth.
The first metabolic process targeted by cancer drugs is glycolysis. It generates ATP (a form of energy) for a cell and is important in energetically demanding proliferation of cancer cells. Pyruvate is the main product of glycolysis and is converted to lactate, which further proceeds to cellular pathways. Attenuation of glycolysis would therefore drastically compromise the biosynthesis of a cell. While this is preferable in cancer cells, as it reduces their viability, inhibition of glycolysis would supress anti-tumor immune response in cell types other than cancer cells. The inhibition of glycolysis also crucially affects T cells and endothelial cells. That leads to vessel disintegration and metastasis – both counterproductive to the treatment. A solution to that would be only partial inhibition of glycolysis, which might result in vessel normalization and better response to combinatory therapy.
Another important metabolic process within a cell is oxidative phosphorylation – a system of multiple respiratory complexes at the inner membrane of mitochondria. Like glycolysis, phosphorylation is an important producer of ATP as well. In cancer cells, this process is usually inhibited because of lower mitochondrial DNA or mutations but phosphorylation still promotes the growth of tumors, since it enables the synthesis of some amino acids and nucleotides. Also, cancer cells with elevated activity of oxidative phosphorylation are more drug-resistant – a sign that inhibition of this process would effectively fight the tumors. Metformin, a substance currently used in the treatment of diabetes, has been studied as an inhibitor of oxidative phosphorylation. However, it has a negative impact on vessel formation and immune cells – both needed for an effective fight against the disease.
Another process targeted by metabolic drug therapy is a tricarboxylic acid cycle (TCA) which connects oxidative phosphorylation and cellular metabolism by producing intermediates that affect the degradation of epigenetic marks on chromatin and therefore tumorigenesis. Another metabolic process targeted by the cancer treatment is glutaminolysis, which helps with the increased metabolic needs of rapidly proliferating cancer cells by glutamine synthesis. Since glutamine deprivation is toxic, a more specific targeting and combination therapy is needed in this case, otherwise healthy cells in TME would be damaged extensively.
Without a doubt, every cell needs amino acids. Because of that, there is ongoing research to find out how to apply this in cancer treatments. The deprivation of asparagine (one amino acid) was studied first, but its effects on TME would be too extensive if it was inhibited. On the contrary, selective inhibition of the uptake of another amino acid, methionine, by cancer cells, but not immune cells might be a very effective way to boost anti-tumor immunity. Fatty acids, another essential component of a cell, are an alternative source of energy when glucose is limited, which is very important for the proliferation of cancer cells. Their blockage decreases tumor growth but again worsens vessel permeability.
Nucleotide targeting therapy has been widely used in the treatment of some tumor types for decades. It is one of the most common treatments, which targets the metabolism of the cancer. Unfortunately, it is dangerous for immune T cells. Nucleotides, the building blocks of DNA and RNA, are present in all body cells and their inhibition is general and doesn’t affect only the tumor. Inhibition of nucleotides has an unwanted effect on immune cells as well as other body cells. That can result in many side effects, such as hair loss or digestive problems. New approaches, that would reduce the effect on the cells of the immune system, could improve this year’s proven tumor treatment approach.
The research shows, that when developing metabolic cancer treatments, the effect on the tumor microenvironment has to be taken into account. An effective cancer treatment might be so-called combinatorial metabolic therapy, which targets oxidative phosphorylation and fatty acid metabolism. What’s more, it would be beneficial to focus on transporters specific for cell types, which would prevent the treatment from harming the “good” cells in our body as well. These are very promising opportunities for future metabolic anti-cancer strategies.