Cancer Factsheet: Glioblastoma and the Need for Targeted Cancer Therapies

What is Glioblastoma?

Glioblastoma is the most common and aggressive form of brain tumour. It is an extremely fast-growing cancer which has no known cure. Glioblastomas are named for the cells they form in; glial cells. Though the brain is best known for having billions of neurons, 90% of brain matter is made from glial cells. Originally scientists believed that glial cells simply formed the ‘stuff’ that neurons sit in whilst they are busy firing signals all day long — glia is Greek for ‘glue’. All scientists knew about glial cells was that neurons liked them. Stick a neuron in a petri dish without a glial cell and it dies. Pair it with a glial cell, however, and it has no complaints.

More recently it has been discovered that there may be more to glial cells than we first believed. In fact, their behaviour is remarkably similar to that of neurons. Potassium, involved in firing neurons, can cause a certain type of glial cell (an astrocyte) to exhibit an electrical potential, just as a neuron does when it sends a signal for something to happen. Experiments since then have led to the discovery that astrocytes respond to and release neurotransmitters (technically gliotransmitters), and can communicate with other astrocytes and neurons through ‘calcium waves’. Glial cells are vitally important for neurons to function, and may actually moderate the entire process. This study published in Nature has shown how glutamate, released from glial cells, modulates neural firing.

As you can imagine, when something goes wrong with glial cells it can have a devastating effect on brain function. Many glioblastomas originate from astrocytes, these neuron-like glial cells, and this may go some way to explain why these tumours have such a drastic impact on a patient’s health.

: A human astrocyte

Glioblastomas can form in two ways:

Primary tumours develop spontaneously and account for 90% of glioblastomas
Secondary tumours develop from previous low-grade (slow-spreading, normal-looking cancer cells) tumours

Though secondary tumours generally lead to a slightly better prognosis than primary tumours, outcomes are not good. Less than 10% of patients survive past the first five years after diagnosis, and the median survival rate (where an equal number of patients do better and an equal number do worse) for patients with glioblastoma is just 12 to 18 months.

What is the treatment for glioblastoma?

Treatment for glioblastoma is variable, however the majority of cases are first treated with surgery to attempt a resection, where as much of the tumour is removed as possible. This is a very difficult procedure, not only because brain surgery always carries a much greater risk than many other invasive procedures, but because glioblastomas are diffuse. This means they develop cancerous tendrils which worm their way into areas of the brain which are difficult for surgeons to access. When surgeons cannot be sure that they have extracted all the tumour cells, surgery is usually followed up with a ‘traditional’ cancer treatment such as chemotherapy or radiotherapy.

In some instances, these treatments are combined into chemoradiotherapy using the chemotherapy agent Temodar (active agent: temozolomide). This is the standard of care for glioblastoma as recommended by the National Comprehensive Cancer Network (NCCN) and the European Society for Medical Oncology (ESMO). Despite having the backing of two prestigious scientific organisations, chemoradiotherapy only has limited effectiveness. After 6 months, only 54% of patients experience no disease progression. In one study looking at a more intensified chemoradiotherapy schedule, 70% of patients experienced no progression at 6 months. Unfortunately, the median overall survival of these patients was still no more than 16 months from diagnosis. In other words, half of glioblastoma patients died in the first 16 months of their disease.

So how can treatment outcomes be improved?

Due to the short life-expectancy associated with glioblastoma, there is an urgent need for more effective treatments. Thankfully scientists have begun developing targeted treatments which can be tailored to specific tumour and/or patient profiles.

Many glioblastoma patients have mutated genes which impact both on the expected course of disease and the effectiveness of treatment. IDH is one-such gene. IDH provides instructions for the synthesis of an enzyme called isocitrate dehydrogenase 1, which is important for breaking down fats for energy and protecting cells from potentially harmful molecules. IDH is mutated in many cases of glioblastoma and this is one instance of a helpful mutation. Most patients with this mutation are diagnosed with secondary glioblastoma, the more slow-growing tumour-type, and they can expect to survive longer than patients without the mutation. IDH mutation has been recognised as an early event in glioma tumour formation, and there is some suggestion that it may be responsible for the classification of primary vs secondary tumours.

As well as mutations, genes can also be affected by amplification (i.e. too many copies of DNA within a gene are created) and overexpression (i.e. when a gene’s instructions are given too frequently). The Epidermal Growth Factor Receptor (EGFR) gene, for instance, is amplified in ~50% of glioblastoma cases and causes the overexpression of the EGFR protein. This protein leads to cell proliferation, motility and survival. Though there is somewhat conflicting evidence as to its effect in glioblastoma, research indicates that EGFR overexpression can lead to a poorer outcome for patients.

Two drug-types have been developed which can counteract the effects of EGFR overexpression. EGFR is found in abnormally high levels on the surface of glioblastoma tumours, and can be used like a lighthouse to attract antibody-drug conjugates, which bind to the surface of a tumour cell like an antibody, burrows inside and releases a toxin which destroys the cell. Another drug-type is the monoclonal antibody, which block the action of the EGFR, reducing the ability of the tumour cells to proliferate and thrive.

Unfortunately, the vast majority of new drugs for glioblastoma are only available through clinical trials. Nevertheless, there is hope that in the foreseeable future these drugs will come to market to drastically improve life-expectancy and treatment outcomes for patients all over the world.

Cancer is a very complex disease area, and this overview is not exhaustive. For further information, I encourage you to check out following links: