Lucía's legacy: samples from her rare tumor shed light on this cancer's resistance to treatment

Lucía García was just eight years old when she was diagnosed with a rare, highly aggressive, and incurable brain tumor . It was a diffuse intrinsic brainstem glioma (DIPG), a very rare cancer—barely twenty cases are diagnosed each year in Spain—but capable of outwitting the immune system and escaping all available treatments. The girl died a year after her diagnosis, but she left behind a legacy that can lay the groundwork for changing the prognosis of a devastating disease: samples of her tumor, donated by her family, have allowed science to study the aggressiveness of this cancer and also investigate potential therapeutic targets to destroy it.

“Samples from Lucía's tumor have been very useful. Clinical trials using this tumor have been justified,” says Ángel Montero, head of the pediatric cancer treatment group at the Sant Joan de Déu Research Institute in Barcelona. Specifically, this researcher has used samples from the girl's tumor and those of other patients to reveal DIPG's tricks to outwit the immune system. In a recent article published in the journal Neuro-Oncology Advances , researchers at Sant Joan de Déu have discovered that this tumor strengthens the blood vessels around it to prevent any treatment from penetrating and also secretes proteins that camouflage it from the immune system.

Lucía was eight years old when she began experiencing strange headaches. They were nonspecific, but persistent. They became increasingly frequent. Doctors hypothesized it could simply be something with her vision. But one day, her parents noticed that her tongue was also starting to twitch and one of her eyes was making strange movements, and they took her to the emergency room. An MRI revealed the truth and the worst possible prognosis: a brain tumor was causing all of this.

The little girl was admitted to Sant Joan de Déu Hospital in Barcelona that same day to begin treatment, but the doctors were frank with the family from the very beginning, recalls Alfonso García, Lucía's father: "They explained the disease to us and also a little bit about the sequence of what would happen. And they nailed it." There are no curative treatments , and life expectancy after diagnosis is less than two years.

Andrés Morales, director of care at the Pediatric Cancer Center at Sant Joan de Déu, says that a diagnosis of DIPG is "one of those rare situations" in which the medical team sits down with the family and explains from the outset that there is no curative treatment. "When we determine it's a high-risk DIPG, we know that in nine out of 10 cases, the patient will die within the first two years. And they die with the loss of neurological faculties. Mortality is almost universal, and the family also sees the patient deteriorate. It's very hard," Morales points out.

More than a decade has passed since that first time Lucía and her family crossed the doors of Sant Joan de Déu, but Montero still has vivid memories of the little girl, of visiting his laboratory, of the hopes placed in a clinical trial in which the little girl participated—he is not a doctor, but he was present when they tested an anti-tumor vaccine on her. The youngest was also one of the first patients to undergo a brainstem biopsy at the hospital, he recalls: “Her tumor was our fourth biopsy. And it was very important because we were able to obtain that tumor, immortalize it in the laboratory, amplify it, study it, and use it for many studies and share it with dozens of international laboratories. This tumor is present in approximately 40 or 50 laboratories around the world,” Montero emphasizes.

Lucía couldn't see it, but thanks to the samples of her tumor—taken at diagnosis, but also after her death—science has been making inroads into understanding this strange cancer. Montero explains, for example, that by having tumor tissue samples from the beginning and end of the process, it was possible to see the difference between an untreated tumor and how those malignant cells evolved over time and after receiving various treatments—the girl underwent chemotherapy and radiotherapy, in addition to the experimental anti-tumor vaccine. "The main finding is that almost nothing changes: the initial tumors are very devoid of immune cells, and the final tumors persist, devoid of immune cells. Nothing has happened there. What's the reason? We're unable to reach those tumors with any treatment. And that's the key," the scientist points out.

Lucia's tumor is in approximately 40 or 50 laboratories around the world.

Ángel Montero, scientist at the Sant Joan de Déu Research Institute in Barcelona

Along with donations from another thirty families, the little girl's brain tissue samples have also helped Montero and her team delve even deeper into the behavior of this tumor and unravel why these malignant cells do not respond to any treatment.

By analyzing brain tissue, cerebrospinal fluid, and blood samples from patients with DIPG, and by conducting in vitro experiments with human cells and animal models, the team of scientists at Sant Joan de Déu revealed that tumor cells distort everything around them. "The importance of these biopsy cells is that they can grow in the laboratory. What we have demonstrated is that if we then put them in contact with other cells in the brain, which are theoretically normal cells, such as macrophages [a type of immune system cell], we see that everything that touches the tumor becomes malignant, becoming protumoral," Montero explains.

Researchers have discovered that tumor cells secrete two proteins that change their surroundings to escape the immune system. “The tumor secretes substances into its microenvironment that cause macrophages to become pro-tumoral. That is, suddenly these macrophages don't notice anything and actually inactivate any lymphocytes that might get there,” he explains. Furthermore, these substances cause blood vessels to become more sealed, impenetrable: “If the blood vessels in our brain are already especially well sealed so they don't get poisoned by anything, in the presence of a tumor, these blood vessels are even more isolated: they are even more tightly sealed so that chemotherapy doesn't enter, and they secrete proteins that inactivate lymphocytes. In other words, even worse,” the scientist laments.

Potential therapeutic targets

According to this research, the tumor entrenches itself behind a very robust wall of molecular mechanisms. But Montero, although aware of the complexity of this disease, remains optimistic: "We have two potential therapeutic targets to further attack. We now know that these blood vessels and also the pericytes [cells found in the vessel walls] secrete a protein called B7H3. And there are anti-B7H3 therapies on the scientific market. In other words, now you know the enemy and know what can attack it. So, on the one hand, I think anti-B7H3 therapy, considered an immunotherapy, has a great future, and there are researchers in Seattle already investigating it. On the other hand, the blood-brain barrier is more intact." "Therefore, we need to develop drugs that are chemically modified to be able to penetrate it," the scientist reflects.

For Morales, all these findings "are doors that are opening and must be explored." But he measures his expectations. "There is a gap between research and clinical practice. It is in the translation to clinical practice where we encounter the difficulty. It is an extremely complex process. Despite our increasing understanding of tumor biology , treatment has not changed significantly in recent years. After nearly 300 clinical trials, the survival curve has moved very little. Although it now appears that immunotherapy may work in a subgroup of patients," he notes.

Alfonso García and Noelia Gómez, parents of little Lucía, place all their hopes in their daughter's legacy. "Faced with this disease, as a parent, you feel powerless. You can't do anything. Absolutely nothing. This, at least, is something. And you think that if it hasn't helped us avoid losing our daughter, at least it will help other families in the future," García admits. "Perhaps there's still a long way to go before a cure for this disease is found, but research can benefit many other illnesses, and that's very valuable to me," the mother adds.

That first visit by Lucía and her family to Montero's laboratory left a scientific mark that has yet to be finalized. Samples of the little girl's tumor continue to travel to laboratories around the world, but during the little girl's illness, her brother, Sete , who was 10 at the time, also discovered "a world of science that I didn't know existed," say the parents. And something took root there, because today the young man is studying Biotechnology at university and has just completed a research stay with Montero, in the same laboratory that he first visited with his sister a decade ago.