A drug cocktail to bust brain tumours
that could be effective at treating every patient with a particular
type of brain cancer that typically has a dismal prognosis.
Scientists at Wake Forest University Baptist Medical Center have been examining glioblastoma multiforme (GBM) tumours, to try and decipher which proteins in particular help these cancers to prosper. GBM tumours are often resistant to current treatments, including chemotherapy and radiation therapy. The mean survival rate of patients with GBM is about 14 months and has improved only slightly over the past decades. The dream of personalised medicine is that, one day, we might be able to test both an individual's gene signature and their tumour itself and only give them drugs that target those particular proteins. However, the Wake Forest team here have taken a different approach; they wanted to find out if a cocktail of just a few drugs could be used to treat every single patient with GBM. They analysed the 'molecular signature' of GBM and identified three proteins present in elevated levels in these cancers. These were interleukin 13 receptor alpha 2 (IL-13R-alpha), ephrin receptor A2 (EphA2) and Fos-related antigen 1 (Fra-1). Although each one could be targeted with an individual anticancer drug, how useful a cocktail of these drugs would be would only become clear once the researchers found out how often these proteins appear together. These latest results have now been published in the journal Clinical Cancer Research. They examined 76 specimens of brain tumour, including 46 GBMs, and nine normal brain samples and discovered that every GBM tumour examined had at least one marker present and 95 per cent of the tumours had at least two. "This finding offers a unique opportunity for treatment," said Dr Waldemar Debinski, director of the Wake Forest Brain Tumor Center of Excellence. "Without any pre-therapy testing, we would know for sure that at least one of these targets is highly present in each patient and that the patient is suitable for the combination of off-the-shelf drugs. It is like having a crystal ball." In a recent issue of Molecular Cancer Therapeutics, the researchers reported developing a potent treatment targeted to EphA2. A drug against IL-13R-alpha is currently being tested alone in a phase III clinical trial, with second-generation drugs already in development. The Wake Forest team is working to develop a drug to target Fra-1 and Debinski predicts that the cocktail could be tested in patients within five years. The EphA2 drug, which would be delivered by catheters directly to the tumour, was created by chemically linking a protein that binds to EphA2 with a modified bacterial toxin. "Developing molecularly targeted therapies using genetically engineered bacterial toxins represents an attractive option that may improve outcomes," said Debinski. In the laboratory, the treatment potently killed all of the over-expressing EphA2 cells within 48 hours. It was also effective at reducing tumours in mice. Debinski has also developed a drug that targets IL-13R-alpha and the team set about comparing them. "Both were extremely effective and highly potent," said Debinski. "Some of the tumour cells responded to the IL-13 cytotoxin, some responded to EphA2-targeted cytotoxin and some responded to both. This illustrates why we need a cocktail to cover as many patients as possible." The fact that the three markers were not found in healthy brain tissue suggests that the proteins are highly suited as targets for therapies designed to kill cancer cells and spare healthy brain tissue. The third marker, Fra-1, is believed to control malignant features of brain tumour cells, such as the development new blood vessels. An additional benefit of targeting the three proteins is that the drug cocktail affects cellular signalling pathways, including epidermal growth factor receptor VIII, which is known to control the expression of all three proteins. "With the drug cocktail we may be taking care of cancer cells that are really important for tumour survival," said Debinski. "It may be the best of two worlds." He also believes that the drug combination may also prove beneficial to those with breast, pancreas and prostate cancers, which also have high levels of these proteins.
