A Crab in the Brain. Searching for a Treatment of Glioblastoma

The word “cancer” comes from the word karkinos, Greek for crab. Hippocrates, the Greek physician, observed how some tumors spread with “legs” to neighboring tissue, just as the movements of a crab. The brain is a fascinating and complex organ that directs many of the body’s vital functions such as thinking, moving, feeling, and breathing. It is made up of neurons and glial cells. Although it can be affected by different diseases, one of the most serious problems it faces is glioblastoma (figure 1), the most common and aggressive type of malignant brain tumor in adults. This tumor can originate from astrocytes, a type of glial cell that is key to the proper functioning of the brain.

Figure 1. Analogy between glioblastoma and an evasive crab. 

Historically, cancer has been associated with crabs. The crab’s limbs symbolize the extensions of the tumor that invade healthy brain tissue, mimicking the way a crab clings and moves, which is similar to glioblastoma that is capable of infiltrating aggressively, making it difficult to eliminate completely

GLIOBLASTOMA: THE LETHAL CRAB
Glioblastoma has made headlines by claiming the lives of celebrities such as German soccer player Stephan Beckenbauer, Canadian drummer Neil Peart, and Cuban singer Celia Cruz; all of them died after being diagnosed with this aggressive brain tumor.

From birth, we all have a small risk of developing a brain tumor, about 0.6 percent, and it is higher in men than in women (Lapointe, Perry & Butowski, 2018). The only confirmed risk factor for glioblastoma is having been exposed to radiation to the head, usually as part of the treatment for other kinds of cancer​​ (Braganza et al. 2012). Interestingly, people with allergic diseases such as asthma or hay fever appear to be at lower risk (Kaur et al., 2019). In very few cases (about two percent), this tumor is associated with rare genetic syndromes (Khattab & Monga, 2023; Alegría-Loyola, Galnares-Olalde & Mercado, 2017). But if you are wondering about the impact on the brain of cell phone use, several studies have found that there is no relation between that and the development of brain tumors.

HOW DOES THE CRAB SHOW UP?
The symptoms of a patient with glioblastoma depend entirely on the exact place where it develops (Price et al., 2024), but the most common are headache, nausea or vomiting, confusion or decreased brain function, memory loss, personality changes or irritability, equilibrium problems, urinary incontinence, vision problems such as blurred vision, double vision or loss of peripheral vision, speech difficulties, and seizures, especially in people with no history of epilepsy (figure 2; see also https://www.mayoclinic.org/es/diseases-conditions/glioma/symptoms-causes/syc-20350251).

Figura 2. Most common symptoms in glioblastoma.

The way in which this type of tumor manifests depends completely on the site where it originates. However, it generally presents headache, nausea, dizziness, vomiting, speech problems, confusion, personality changes, blurry vision, and mobility problems

The average age of diagnosis for glioblastoma is 60 years; however, in Mexico it is 50.1 years (Mondragon-Soto et al., 2022; Van T Hek et al., 2023), a shocking fact. Why is this difference possible? We don’t know, but it is important to note that the statistics in Mexico are not as complete as in other countries. In the specific case of glioblastoma, the data reported come from three primary care centers: the National Institute of Neurology and Neurosurgery, the National Cancerology Institute, and the ABC hospital. These health centers receive patients from different states; however, we lack a national database where information from the entire country can be concentrated.

THE GLOBAL AVERAGE AGE OF DIAGNOSIS FOR GLIOBLASTOMA IS 60 YEARS; HOWEVER, IN MEXICO IT IS 50.1 YEARS

FIGHTING THE CRAB IN THE LAB
The conventional treatment of glioblastoma is the surgical resection of the largest tumor volume, followed by radiotherapy and chemotherapy; however, even with this treatment, patient survival is 14.6 months on average (Price et al., 2024). One of the most important aspects we have to consider when thinking about the treatment of glioblastoma is the presence of the blood-brain barrier, a set of tightly knit cells that control the transport of molecules in and out of the central nervous system (Sweeney et al., 2019), which makes it difficult to design drugs that have the ability to reach the tumor site.

In the search for new therapies, we have observed that joining forces is a promising option. In other words, combining drugs that attack the main survival pathways of cancer cells generates an additive or synergistic effect between them​​ (Ferreira et al., 2020). 

In our laboratory we have studied the role of a molecule commonly associated with reproduction, but which could play a key role in the development of glioblastoma: the progesterone receptor (PR) (Arcos Montoya et al., 2021). We found that when this receptor is activated, either by the progesterone hormone or by signals inside the cell, it can encourage tumor cells to multiply, migrate, and become more invasive. To better understand this phenomenon, we design studies in cell cultures and animal models. We observed that by blocking the action of PR with a drug called mifepristone (known mainly for its use as an abortive), tumor cells reduced their viability depending on the dose of the drug. In animal models, the treatment managed to reduce tumor volume by more than 50 percent (figure 3) (Arcos-Montoya et al., n. d.).

Figura 3. reconstruction of rat brains with brain tumors treated with mifepristone

In the laboratory we investigated the effect of progesterone receptor blockade on tumor development in a rat model. The image shows the reconstruction of three brains, the right hemisphere is seen in yellow, the left hemisphere is magenta, and the tumor of three rats is seen in blue: A) without treatment, B) with intermediate dose of mifepristone, and C) with high dose of mifepristone

But perhaps the most hopeful finding comes from a pilot study in eight glioblastoma patients, who received mifepristone in combination with current therapy and showed a marked improvement in their quality of life and extended survival to more than 400 days, exceeding usual expectations.

This project, carried out in collaboration with UNAM’s Faculty of Chemistry, the National Institute of Neurology and Neurosurgery, and the National Cancerology Institute, proposes to reposit an already approved drug for a new indication: to combat the relentless crab in the brain. The value of this strategy is that it is a drug with a well-known safety profile, which accelerates its possible clinical application. Currently, we are investigating how sex hormones and the differences between men and women influence the progression of glioblastoma, with the aim of developing more effective and personalized therapies against this devastating brain enemy.

Although various research groups around the world continue to search for a therapeutic target to annihilate the terrible crab in the brain, there is still no cure for this condition.

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