Glioblastoma multiforme is one of the deadliest forms of brain cancer (GBM). Only 28,000 new cases are diagnosed each year in the EU and the US; despite treatment, the median survival time is only one year. Only 3% of GBM patients survive more than five years, and less than 30% of adult GBM patients survive one year after diagnosis. As a result, GBM is also known as the Terminator. Currently, the standard GBM treatment includes surgery as the first step, followed by radiotherapy and chemotherapy.
Fluorescent photosensitizer (PS) drugs, which are commonly used in photodynamic therapy, can be beneficial during GBM surgery. PSs include protoporphyrin IX (PpIX), a 5-aminolevulinic acid (5-ALA) metadrug administered exogenously in the biochemical heme cycle. Because of structural and functional variations close to the GBM tumours, the prodrug 5-ALA of PpIX accumulates very specifically in GBM lesions, providing precise guidance for GBM resection. Both the American Food and Drug Administration and the European Medicines Agency have approved this method of GBM resection. Exact tumour removal can significantly improve patient survival.
Researchers from Greece and Norway discovered 5-ALA to be a photosensitive drug as well as an inhibitor of the glycolytic enzyme lactate dehydrogenase (LDH) This is a significant discovery because cancer cells do not obtain most of their energy from respiration, instead they rely on the breakdown of glucose. Cancer cells may die if glycolysis is halted because they will no longer be able to obtain the energy they require from other sources.
Since 5-ALA accumulates ten times more in GBM tumours than in normal cells, it also serves as a potent inhibitor of LDH and subsequent glycolysis. This could prevent GBM cells from properly metabolising “sugar,” ultimately resulting in cell death. This discovery opens the door to new treatments for GBM and possibly other cancers.
Research team leader Dr. Theodossis Theodossiou stated, “We are delighted to have uncovered this alternative property of 5-ALA. The fact that 5-ALA is approved for the detection of malignant gliomas and GBM makes our findings more valuable and easier to apply in the clinic. For detection purposes, 5-ALA is only applied to patients for a few hours, which is not enough to kill the cancer cells by glycolysis disruption. However, prolonged administration for one or several days could lead to surprising, even curative results, in a disease which is currently incurable and lethal.”