An example of a widely studied gene that has turned out to be vital to tumor metabolism is the MYC oncogene that encodes a transcription factor with a well-known role in cell cycle progression. It turns out, said Dr. Dang, that “MYC opens up the fuel line to drive cell growth; it drives genes that import nutrients into cells and metabolize nutrients to make the building blocks for the growing cell.”
Many of the growth factor signaling pathways that are commonly dysregulated in cancer don’t just regulate cell growth and proliferation, but are also intimately involved in dictating the response to nutrients. A prominent example is the PI3K/Akt pathway; among the most highly mutated pathways in human cancer, it acts as a master regulator of glucose uptake.
Some researchers propose that alterations in growth factor signaling pathways drive cancer formation because they allow the cell to flaunt the rules of the dinner table. Essentially, instead of acting like a cell that forms part of a multicellular organism, taking cues from the surrounding cells about when and how to respond to nutrients, cancer cells are able to ignore these signals and take up whatever nutrients they can find. This may also explain the observation that cancer development is closely linked to obesity and diabetes.
Targeting metabolism
These discoveries have led researchers to consider the possibility of targeting metabolism to prevent cancer cell growth. Some commonly used chemotherapy drugs have a metabolic mechanism of action; the antifolates methotrexate and pemetrexed, for example, target one-carbon metabolism.
Although no metabolism-based small-molecule drugs are approved yet, many are in preclinical development, and some are beginning to move forward into clinical trials. Dr. Dang highlighted the development of drugs targeting metabolic enzymes: “Drugs being developed against the mutant enzymes IDH1/2 have demonstrated clinical responses in acute myelocytic leukemia, and other drugs, such as CB-839 – an inhibitor of glutaminase – are undergoing clinical studies.”
Several existing drugs have also been repurposed in the fight against cancer, including some not previously thought of in this context, such as the antidiabetic drug metformin, which has shown significant promise. Dr. Dang concluded: “The future outlook is the generation of a new class of drugs that could, in combination with other drugs, result in better clinical treatments for cancers.”