International Business Department           Liu Bojia           October 11, 2023

  The concept of "starving" cancer cells is not new; scientists have known that cancer cells need higher levels of energy metabolism in order to satisfy their savage growth, so by blocking the energy intake pathways of cancer cells, it is expected that cancer cell growth can be inhibited.

  But which energy pathway to block? Earlier, people would focus on glucose, because sugar metabolism is necessary for rapid cell growth, and blocking the glucose supply would deprive cancer cells of an important source of energy. In recent years, however, more and more experiments have revealed that glucose is not the only thing that cancer cells can't use.

  As cancer cells become denser, blood vessels become difficult to supply, and oxygen and glucose become progressively scarce. At this point, cancer cells will begin to adjust their energy source strategies, as a study by a team of Johns Hopkins University researchers, which was published in the Proceedings of the National Academy of Sciences, has pointed out that statins also have a killing effect on cancer cells due to blocking their uptake of proteins. Last year, another study in Science also confirmed that tumours use proteins and amino acids as a back-up energy source to ensure survival when sugar is scarce.

  In a new study in Nature Cancer, researchers from New York University tested a new way to "starve" cancer cells in pancreatic ductal adenocarcinoma (PDAC), which, according to the paper, converts glutamate to glutamine with the help of the enzyme glutaminase, which can be utilised by the cancer cells to help them grow.

  Thus, a molecule that blocks this pathway could be effective in "starving" cancer cells, and DON happens to be a class of glutamine mimetic molecules that can block all the metabolic pathways glutamine is involved in, but that also makes it highly cytotoxic. Dracen Pharmaceuticals has designed and developed a prodrug, DRP-104, based on DON, and it has been shown to block glutamine metabolism in cancer cells in clinical trials in patients with non-small cell lung cancer.

  Compared to DON, DRP-104 tends to be more activated in tumours and binds enzymes paired with glutamine. In an in vitro cellular assay, DRP-104 could rapidly cause a metabolic crisis in cancer cells, resulting in the inhibition of cancer cell growth. The researchers then selected a group of PDAC mouse models and gave some of them DRP-104 treatment for 7 days as a cycle.

  According to their observations, the PDAC tumours in the mice treated for 2 cycles were significantly smaller than those in the control group, and they detected high levels of glutamine in the tumour cells, suggesting that this glutamine was accumulating without being consumed by the cancer cells.

  At the same time, the DRP-104-treated mice also showed basically no metastatic foci in the liver, which means that the invasive metastatic ability of the cancer cells was also weakened. This process did not cause changes in the immune system, and the researchers found that the number of infiltrating T-cells in the tumours of the mice was very low regardless of whether or not they had been treated with DRP-104, and that DRP-104 acted completely independently of the immune system.

  Of course, the cancer cells were not imperceptible to this change; upon realising that glutamine could not be utilised, they activated an ERK kinase-related signalling pathway to compensate, and the stronger the signals from this pathway, the more likely the cancer cells were to become resistant to DRP-104.

  To this end, the researchers found an existing ERK signalling pathway inhibitor, trametinib, which they paired with DRP-104 in a way that further improved survival in PDAC mice than DRP-104 alone. This also offers a new approach to 'starving' cancer cells, noted study co-author Professor Alec Kimmelman, "We have known that cancer cells switch energy sources in the past, but have not been able to derive clinically useful therapies from this. By blocking glutamine metabolism in cancer cells, we may be able to help more patients in the future."