Science besieges brain tumors: researchers are looking for ways to combat malignant cells, juggling drugs to the brain and investigating how to detect warning signs early. They have not given up their efforts, but the results of recent years are not very encouraging and the prognosis, both for primary tumors and for metastases in that area, is usually unfavorable. In this scientific journey against cancer in the brain, all the winds blow against it: it is an organ that is difficult to access, tumors there do not usually give symptoms until they are very advanced and, when it comes to administering drugs to stop the proliferation of tumor cells , scientists collide with the blood-brain barrier, a kind of vascular wall that makes it difficult for drugs to reach the brain.
Brain tumors are rare. According to the Spanish Society of Medical Oncology (SEOM), tumors that originate in the central nervous system (primary tumors) represent 2% of all cancer in adults and up to 15% of those in children under 15 years of age. But there are also brain metastases, which is the spread in the brain of tumors that started in other parts of the body: they end up appearing in almost half of the patients with a specific type of lung cancer, they also suffer from it between 15% and 25 % of women with a primary breast tumor and between 5% and 20% of people with melanoma.
Óscar González, 40, has been battling a glioma with a mutation in the IDH gene, a type of brain tumor, since 2013. It was one night, during his working day in a paper mill in Tarragona, when the cancer manifested itself in the form of a strange fainting spell. There began a journey of hospitals, tests, diagnoses and a string of treatments and operations: an intervention, radiotherapy, antiepileptic drugs, another surgery, four chemotherapies, corticosteroids and, since 2018, a drug directed against a specific mutation found in his tumor . “I have always had and still have the tumor,” says González, but, after successive therapeutic failures, the latest treatment, which he accessed through a clinical trial, has been “wonderful,” he says: “You go from preparing for what worse, to see that you are going to get better and that the tumor is reduced by 60%”.
His oncologist in Vall d’Hebron, María Vieito, explains that this treatment was “the last option, the last cartridge” and it is working: “What remains of the tumor is very residual and who knows if it is a tumor or not, but not they usually disappear [del todo]. This type of drug blocks an important growth pathway for brain tumors and theoretically, if you stop blocking the pathway and any tumor cells remain, they can relapse.” González will continue with the treatment. Just in case.
Each tumor has its own story. “There is a very strong tumor heterogeneity: each one is different, has different mutations and changes to adapt to the niche where it is found,” advances Joan Seoane, ICREA research professor and co-director of the Preclinical and Translational Research Program at the Vall d’Hebron Institut d’ ‘Oncology (VHIO). A primary brain tumor is not the same as a metastasis; it is also not the same in children as in young or elderly adults; A glioma with an IDH mutation, with which patients can live for many years, has nothing to do with a glioblastoma, which is one of the most aggressive brain tumors and has an average life expectancy of 15 months.
The only thing they agree on, that is, is the complexity of the therapeutic approach due to the “special characteristics” of the brain, points out María Martínez, president of the Spanish Neuro-oncology Research Group: “The brain is designed as something to be protected, like a sanctuary, and that makes it difficult to access and get treatment.”
Due to its vital importance, as the operations center of the human body, the brain is highly protected from the outside. “It has to be,” insists Manuel Valiente, head of the Brain Metastasis Group at the National Cancer Research Center (CNIO). Essential functions depend on it for the proper functioning of the organism and if it fails, almost everything fails. But the counterpart of that protective isolation is that, when they paint coarse and a tumor appears in that organ, their therapeutic approach is an odyssey. “The blood-brain barrier protects against the entry of toxins because the brain has almost no regenerative capacity. That is the price to pay so that neurons are not damaged. But from a therapeutic point of view, there is an unresolved issue: they want to insert drugs and they do not fit well”, explains Valiente.
The blood-brain barrier is formed by the cells of the blood vessels of the brain, which are closely linked to each other and make it difficult for compounds that are in the blood to pass through, says Seoane: “You can have a drug that, perhaps, works on the tumor in the lung or in melanoma, but it doesn’t work as well in brain metastases because the drug doesn’t get there.”
One of the focuses of scientific research is precisely to find a vehicle that crosses this barrier, but there is no silver bullet. Seoane and his team have found a promising compound in this field for brain metastatic melanoma with specific mutations: in a preclinical study published in the journal CancerResearch, has found that C1a, an inhibitor of the BRAF gene, can cross this vascular wall and penetrate the brain. It is also being tested with ultrasound, Valiente points out, to get the medicines inside.
Difficult surgical access
In addition to the difficulties in delivering therapies against the tumor, there is also the fact that the brain is an area with difficult surgical access, assumes Martínez, who is also an oncologist at the Hospital del Mar in Barcelona: “We cannot perform a surgical approach as we would like. Localization is difficult and even when we find small tumors by chance, they have already infiltrated the parenchyma [el tejido funcional del cerebro], which makes complete resection very difficult: in other parts of the body, the tumor is usually a round ball and when you operate, you leave the margins clean; but in the brain, these malignant cells get into the brain tissue, they have branches that grow along the pathways of the brain.”
The cancer cells of primary brain tumors, explains Valiente, also have a “great plasticity, they have more capacity to develop resistance” and the tumors are very heterogeneous, which is linked to the difficulty of approaching the cancerous mass. Everything plays against.
The lack of early diagnostic tools doesn’t help either. Primary brain tumors do not usually metastasize outside that area, but are detected when clinical symptoms are evident. “Many are indolent and since the brain does not hurt, it grows until it affects you,” says Seoane. An epileptic seizure, loss of strength or character changes may be the warning signal, but when they come to light, the tumor is usually already advanced.
The liquid biopsy of cerebrospinal fluid allows the detection of brain tumor cells through a sample of this substance, which is extracted through a lumbar puncture. It allows to diagnose and molecularly analyze that tumor, even. But the technique is more complex than a blood test and cannot be used for population screening, Valiente maintains: “It is a surgical extraction. Cannot pose a screening population with her.
The therapeutic arsenal is, in any case, very limited. “The standard treatment is, first, to try to make the possible surgical resection and then, radiotherapy and chemotherapy with temozolamide, which we have been doing for 15 years. We know a lot about the biology of therapeutic targets, we see evidence in phase I and II, but we reach phase III and fail. The key will be the combination of targeted therapies and immunotherapy”, predicts Martínez.
But immunotherapy, which has revolutionized oncology, has not yet taken hold in brain neoplasms, especially in primary tumors, because they are “locked inside the brain,” says Valiente, and there are hardly any immune cells in their environment. “In metastases, there is more infiltration of immune cells and they are more candidates for immunotherapy: it has been seen that it has worked when these metastases are starting to grow, when they are not clinically relevant. But when they give symptoms, immunotherapy no longer works as well. We believe that there are cells that are protecting the tumor when it grows”, he points out. His CNIO group is investigating how to block this local immunosuppression.
Precision medicine, with treatments aimed at each patient, prevails in oncology, but much remains to be done in brain tumors, Valiente admits: “Glioblastoma is the most frequent and the most lethal. It is a black box in oncology. We have been using the same treatment for 15 years and not much progress has been made”. And in brain metastases, although there has been a little more therapeutic progress —15% respond to targeted drugs—, it also has a poor prognosis. “Metastasis continues to be a scourge and we don’t know how to treat these patients well”, regrets the CNIO researcher.
Given the starting circumstances, every little scientific breakthrough is a huge success. Seoane and his team have just published in the magazine Molecular Cancer Therapeutics promising results in preclinical phases with an immunotherapeutic drug against glioblastomas that have a specific mutation in the EGFR gene (present in 25% of this type of brain tumor): in in vivo and in vitro samples of tumors from patients, researchers have demonstrated that a biospecific antibody, which helps to recruit cells of the immune system to attack tumor cells, achieves a regression of glioblastoma. The therapy is still in very early stages, but scientists are already recruiting patients to start a phase I clinical trial.
Martínez also celebrates that radiopharmaceuticals are being investigated, which are like vehicles that carry the radioactive molecule and release the substance in the brain. Targeted therapies against specific mutations and combinations of chemotherapy and radiotherapy with other drugs are also under study. There is even a study that combines cannabinoids, she points out: “The key is to learn more about the intrinsic and acquired resistance of the tumor”, resolves the oncologist at Hospital del Mar. Valiente, for her part, calls for “more research resources”, but admits more interest than before in this field: “It seems that in brain metastasis things are appearing little by little. Historically, for example, patients with brain metastases were considered end-stage and were excluded from trials, so there are many drugs that we don’t know if they work and haven’t been tested.”
The experts consulted are optimistic. “We are starting to scratch the periphery of brain tumors. Targeted therapies are beginning to enter areas of brain tumors that are more minority, such as pediatric brain tumors”, celebrates Vieito. Seoane is committed to exploring the role of the immune system, delving into “detailed knowledge of the enemy” – its metabolism, its resistance and interaction with its environment and the immune system, for example – and continuing to search for specific drugs: “We are not going to treat all tumors [a la vez]but small towns, yes, we can”.
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