New laboratory-based research from US based Johns Hopkins University School of Medicine shows that a combination of drugs holds promise for paediatric low-grade gliomas (pLGG), the most common childhood brain tumour. These slow-growing tumours can sometimes be completely removed by surgery, but many are in parts of the brain where surgery is simply too risky to undertake. The chemotherapy drug carboplatin can be used for children with these tumours that are either completely or partially inoperable, or have returned after initially successful surgery. Whilst this at first shrinks or slows the tumour, more than 50% of treated tumours eventually progress and require additional therapy.
Researchers determined to find a cure for this challenging subset of low-grade gliomas discovered that the tumours often display activation of a signalling pathway called mammalian Target of Rapamycin (mTOR), which drives the growth and survival of the cancer. This gave them the idea of combining a drug known to inhibit the action of mTORC1 complex, a common form of mTOR, with the cisplatin that is already approved for use in these patients. The drug is called everolimus and was used alongside carboplatin to treat paediatric low-grade glioma cells in the laboratory, as well as a mouse model of this tumour type, to test their theory.
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Results were impressive, as all cell lines treated with this drug combination showed either slowed growth or increased levels of cell death. This was because everolimus prevented the conversation of two amino acids (building blocks of protein) called glutamine and glutamate from being converted into a powerful antioxidant called glutathione, which can detoxify these chemotherapy drugs and hence protect cancer cells from being damaged. With less glutathione available, this drug combination was able to cause greater DNA damage and increased levels of programmed cell death (apoptosis) within the tumour cells than could be achieved with either drug alone.
Thankfully, the research team has already undertaken a clinical study on everolimus and shown it to be safe to use in paediatric low-grade glioma, so the next step of taking this drug combination into a clinical trial will hopefully be relatively easy to achieve. However, it will be key to first identify the patients who do have this increased activity of the mTORC1 complex and are therefore suitable to be given the drug, which can be done by genetically testing tumour samples gained via a biopsy.
This is the basis of personalised medicine: rather than giving a drug to large numbers of patients who may or may not respond, these targeted drugs are only offered to those with the right genetic markers that are relevant to the way the particular drug works. In the past, chemotherapy drugs have been unable to tell the difference between a healthy cell and a cancer cell, but instead have simply targeted cells that are rapidly dividing: a hallmark of cancer. This is why their side effects can be so devastating, because all cells of this type are affected and hence, for example, patients’ fast-growing hair follicles are affected and hair is lost. These exciting new drugs are much more specific in their effects, holding great promise for the future.
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