The relationship between cellular energy metabolism and oncogenesis was first described about 100 years ago by Otto Warburg and his colleagues, who discovered that tumour cells shift their glucose metabolism to favour increased rates of anaerobic glycolysis and lactose fermentation independently of oxygen availability, a phenomenon known today as the Warburg effect Warburg et al., 1927, J. Gen. Physiol. At the time, many misinterpreted these observations to mean that cancer was caused by defective mitochondrial respiration and metabolism, including Warburg himself Warburg, 1956 Science. This initial lack of understanding resulted decreased the interest and it was further overlooked with the rise of molecular oncology and cancer genetics in the late 1980s. With ground-breaking new -omics technologies we have much better insights into cancer metabolism which we did not have only a decade ago. We can use powerful metabolomic analyses to identify novel therapeutic targets, such as MTHFD2, which is recognised to be a key cancer-specific metabolic enzyme Jain et al., 2012 Science .
Watch how NASA describes one-carbon metabolism in the video. Our drugs are targeting cancer cell specific proteins so we don’t expect to have any vision alterations.
One-carbon metabolism is key to generate building blocks required to sustain proliferation and maintain redox balance and therefore its upregulation in cancer cells is unsurprisingly common. In particular the de novo serine and mitochondrial folate pathways are identified as the most important in cancer. Actually, this is not entirely new. The altered folate metabolism in cancer cells was among the first metabolic pathways to be targeted for cancer therapy, with pioneering studies by Sidney Farber in the late 1940s demonstrating that the folate analog aminopterin was capable of inducing remission in children with acute lymphoblastic leukemia Farber et al., 1948, N Engl J Med. These observations gave rise to new folate analogs, or antifolates (e.g., methotrexate and pemetrexed), drugs which inhibit one-carbon metabolism and are remains today as best-in-class treatments for many cancers. So, our current advanced -omics methods show that what they discovered by hard work in 1940ties was actually very important and key as treatment for cancer. No wonder these old fashion drugs are still used as front-line anti-cancer treatments. At one-carbon, we know that we can do better as we now have all detailed -omics data and superb structure based medicinal chemistry at hand. We are pioneering the next generation of working anti-cancer drugs.
DNA DAMAGE RESPONSE (DDR)
The loss of growth control mechanisms in cancer cells result not only in abnormal growth but also damage to macromolecules such as DNA. The damaged DNA becomes a big issue when trying to replicate (divide) the DNA, causing something we call replication stress. If the replication damage is not repaired the cell will die. DNA repair ensures that the cancer cell survives, but at the same time often mis insert the wrong DNA building block (nucleotide). The mis insertion of the wrong base results in mutations that further transform the cancer cell to become more malignant.
The strategy we use is targeting the DNA repair and DNA damage response (DDR). Then the cancer cell can no longer repair the DNA damage and dies. This works in a similar way to chemo- and radiotherapy that also cause DNA damage to kill cancer cells. The difference is that chemo- and radiotherapy also cause damage to normal cells, resulting in severe side effects. As normal cells have fewer DNA lesions than cancer, inhibiting DNA repair will specifically target the cancer cells, while sparing the normal cells and not generate serious adverse effects.
PARP inhibitors is an example of a DDR inhibitor that inhibits DNA repair, which is well tolerated with many patients being on a daily maintenance treatment for >10 years. Having a daily treatment with chemotherapy for 10 years would not be possible.
Under normal circumstances, MTHFD2 does not exist in adult healthy tissue; it is present only in embryos before cells mature into specialized organs. In embryos, MTHFD2 is important for fast growth because it provides the building blocks for all the DNA being assembled in the new cells. These DNA building blocks, called nucleotides, are part of the reason pregnant women are encouraged to take more folic acid – the embryo’s MTHFD2 requires folic acid to make nucleotides. Cancer cells, like embryonic cells, divide extremely fast and find it convenient to reactivate MTHFD2 in order to make more DNA building blocks to support their fast growth. MTHFD2 is an oncofoetal protein, being expressed during embryogenesis, silenced in adult cells and then re-expressed in cancer. Since MTHFD2 is not important in normal cells we envision that MTHFD2 inhibitors will be well tolerated and at the same time effective in causing replication stress in cancer cells.