Project PFKFB3 (solid tumors)

PFKFB inhibitors – reducing cancer’s energy supply

Background
In most tumors that are more than a couple of millimeters in size there is a lack of oxygen, due to the fact that the formation of blood vessels does not match the growth of the tumor. To cope with this oxygen-deficient environment it has been found that the tumor changes its metabolism so that it primarily uses glycolysis (breakdown of sugar), irrespective of how much oxygen is available. This is known as the Warburg effect.

Since glycolysis is a less efficient way of generating energy than that of normal cells (oxidative phosphorylation in the cell’s mitochondria), the oxygen-deficient environment means that the cancer cells divide at a slower rate. This in turn means that traditional chemotherapy and radiotherapy, which are particularly effective on cancer cells that divide, are less effective at killing cancer cells in oxygen-deficient tumors. Since oxygen-deficient environments are linked to the development of particularly aggressive cancer cells, which are believed to lie behind the recurrence of previously treated cancers, it is particularly important to develop drugs that effectively reconfigure the cancer’s metabolism by reducing the cancer’s glycolysis without severely damaging the energy supply to the healthy body.

Kancera’s project is based on the fact that a specific inhibition of the enzyme PFKFB3 results in reduced metabolism and cell growth in oxygen-deficient cancer environments. PFKFB3 is linked to this through the fact that it is highly up-regulated when there is an oxygen deficiency through the protein HIF (Hypoxy Induced Factor). Inhibiting PFKFB3 is expected to starve and weaken the tumor cells by reducing their glycolysis and cell division. This overcomes the current problem of tumors’ resistance to radiotherapy and chemotherapy. Since PFKFB3 is generally found in tissues that are occasionally exposed to oxygen deficiency, there is good reason to assume that Kancera’s PFKFB3-targeted drug will primarily affect the tumor while healthy tissue is left less affected.


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