You may have heard the tragic news that broke hell under the feet of Senator McCain (R-AZ) and his family on Wednesday. According to several sources, Senator McCain biopsy taken from his recent medical examination revealed to be classified as “glioblastoma multiform” (or GBM) for short.
I am not a brain cancer specialist but I have been doing some collaboration with a research group focused on GBM and I know all too well what does it mean and what is the prognosis. This is a type of tumor I would not wish my fiercest archenemy to get. I thought it would maybe help me to make a lay summary on GBM and explain why the BBB in that case is one of our fiercest challenge for drug delivery.
1. What is glioblastoma multiforme?
Glioblastoma multiforme (aka GBM) is a primary brain tumor characterized by its heterogeneity. However, we assume that GBM is originating from tumor astrocytes. Astrocytes are an important cell type of the macroglia, outnumbering neurons from 3:1 to 5:1. For a long time, astrocytes were considered as “glue cells”, playing only a function of scaffold and nourishing cells to neurons.
However, in the last 50 years, astrocytes have been shown to play much more important roles including the induction of the blood-brain barrier phenotype, regulation of the cerebral blood flow, modulation of neuronal cell activity, ability to form a parallel signaling network and also to play an important function in terms of protection of the brain during diseases.
The World Health Organization (WHO) classify GBM as a grade IV brain tumor (https://link.springer.com/article/10.1007/s00401-016-1545-1), meaning this type of cancer is classify as highly aggressive. Because the brain is a very soft tissue, tumor cells can easily proliferate, migrate and invade the surrounding healthy tissues.
The cause of GBM remains unclear, however we know that some GBMs are evolved from other types of brain tumors that have a lesser malignancy like lower-grade astrocytomas (grade II) or anaplastic astrocytomas (grade III). GBM is considered the most common type of primary tumor (not caused by metastatic cells) but also remains pretty rare with a case of 2-3 new patients diagnosed with the condition for every 100’000 inhabitants. There is a possible sexual dimorphism, as men are more likely to be affected than women (3:2 ratio), with an increased risk with age (https://www.ncbi.nlm.nih.gov/pubmed/17373878).
There is no particular risk factor associated with GBM. So far, we assume it has a strong genetic background, as several genes have been associated with GBM including some abnormalities (including loss of DNA in a chromosome domain) on the chromosome 10, mutations in various genes including TP53 (tumor suppressor gene, its function is to repair cell DNA or to induce cell death by apoptosis if it fails to repair), MDM2 (pro-survival gene, its function is to promote cell survival), EFGR and PDGFRα (these are two receptors that induce cell growth, cell proliferation and cell survival upon stimulation by growth factors).
Also noteworthy, there has been speculation and a perpetuated myth that wireless cell phones activity are associated with an increased risk of developing brain tumors. There is no reliable studies (both on epidemiological standpoint and on animal models) that can show an association between the use of cell phones with increased risk of brain tumors.
2. What are the treatments and prognosis for patients with GBMs?
This is where I cannot have much optimism. GBM is a very aggressive type of cancer. The average survival rate is about 18 months, with less than 5% of patients making through the 5-year milestone.
Like any type of cancer, there are different options proposed: radiation therapy, surgery and chemotherapy.
Surgery is commonly practiced but have several challenges: Firstly, it is very hard to identify GBM tissue from the healthy tissue by naked eye during surgery. The neurosurgeon has to rely on the MRI cliches to resect the tumor tissue. Secondly, the neurosurgeon wants to maximize the removal of tumor tissue but also he/she wants to limit the damage to the surrounding healthy tissue to not induce further brain damage. Thirdly, GBM is prone to form glioblastoma stem cell-like cells (GSCs) that share several features with stem cells. These cells can tolerate very aggressive environment and can rapidly proliferate. This is one of the common complication occurring in GBM patients. After you remove the tumor and see no trace of it under the MRI, you conclude it got eliminated. Only to find out three months later that the tumor grew back in size and started to invade more brain tissues.
Chemotherapy arsenal for GBM is very limited. So far, temozolomide is the way to go for GBM. However, 50% of the patients will not respond to temozolomide due to a mutation in the MGMT gene capable to inactivate it (http://www.sciencedirect.com/science/article/pii/S2352304216300162). Other anti cancerous agents including EGFR inhibitors (e.g. lapatinib) fail to show any activity to the presence of a pathological form of the blood-brain barrier (BBB) called “brain-tumor barrier” (BTB). This abnormal form of the BBB involve interactions with brain tumor cells. For a long time, the scientific community thought that BBB surrounding brain tumors was leaky and therefore accessible to chemotherapeutics. However, we know that indeed there is a BTB that can act as a barrier for the penetration and delivery of drugs into the tumor region.
There are some new avenues and approaches to target GBM but they are still very experimental. Amongst them, the possibility to use oncolytic viruses like a modified form of the polio virus capable to set brain tumor cells into “auto-destruction” mode. The second avenue explored is possible use of immunotherapy. The rationale behind is to help the immune system “to learn” about the tumor cells as foreign agents and strike them. There are some success using antibodies targeting tumors and also by reprogramming patients own cells (CAR-T cell therapy).
The diagnosis of GBM is probably one of the most difficult one a neurologist or neurosurgeon has to set, as it has a very poor prognosis. Let’s be honest, it is not looking good and for someone like Senator McCain that has been facing death several times during his military duties this is probably the toughest one to overcome.
3. Concluding remarks
This is why we need to foster research in brain tumors, this is why we need funding to help research findings, this is why we need clinical trials to pick the most promising drug candidate to fight this type of cancer, this is why we need to have a public health policy that ensure healthcare coverage for everyone can have access to treatment to beat the odds and not have to decline treatment because of the huge costs associated that health insurance may simply refuse to share the burden.
I am so embarrassed to say that right now the only thing we can provide Senator McCain and anyone with GBM and their relatives are our sympathies and our wishful thinking. This is why I have colleagues, peers working days and nights, weekends to bring on a “silver bullet” capable to annihilate such condition.
If you are looking to help, the best I can advise is to support research by donating to association like ABTA (http://www.abta.org) that focuses on funding research on brain tumors. Also considerate to let your voice heard and support healthcare policies that ensure an universal coverage of the population regardless of their age, gender, socio-economic status. Because refusing treatment by fear of letting your most loved ones with a humongous amount of debt should be the last of your worry.