Cancer-Causing Supergenes

“The current therapies for brain tumors in children aren’t yet good enough,” says pediatric oncologist Ana Guerreiro Stücklin. Although far fewer children die of brain tumors today than they did 20 years ago, it is still 20 to 30% of sufferers. “Survival chances have improved,” says Guerreiro Stücklin, “but not as markedly as for other types of cancer, such as leukemia and kidney tumors.”

Some particularly aggressive brain tumors in children, such as high-grade gliomas and diffuse intrinsic pontine gliomas, are not yet curable, says the oncologist. They are relentless and continue to grow despite radiotherapy and chemotherapy.

Treating brain tumors is particularly difficult because they are complex and affect the central nervous system. This means that they are more difficult for conventional treatments to reach – operations in vital areas may be highly risky, the blood-brain barrier blocks certain medications, and the tumors often do not have clear contours, instead growing diffusely into the brain tissue. On top of that is the fact that “there are many different types of brain tumors in children,” says Guerreiro Stücklin, who is also an SNSF Eccellenza Professorial Fellow.

Despite these obstacles, traditional therapies such as surgical interventions, chemotherapy and radiotherapy remain the most important treatment methods. “We have to get the best out of everything that is available to us,” says Ana Guerreiro Stücklin, “and we must continually improve the therapies so that we can treat tumors more successfully while minimizing the side effects.”

As well as improving existing therapies, it is important to continually develop new ones, stresses the neuro-oncologist. “We’re conducting several clinical studies that bring innovations and new treatments to our patients.” As part of such early phase clinical trials, children are able to access new therapies that are still in development. This is important, particularly for patients whose existing treatment options are insufficient.

Ana Guerreiro Stücklin treats children with cancer and at the same time carries out research into new therapies. In this way, she bridges the gap between basic research and clinical practice. This is important to her, she says, as to make progress in the treatment of cancer “researchers have to understand what clinicians need in order to better treat patients. At the same time, it becomes clear during treatment which therapies work and which don’t.” This feedback is key for research and for the development of clinical studies.

Besides the continuous improvement of existing therapies and treatment protocols, Guerreiro Stücklin works in an area that is particularly promising in understanding and combating the development of brain tumors: so-called gene fusions. Scientists first discovered this phenomenon in the 1980s, when they saw under a microscope that parts of damaged genes fused to make new ones, which then developed into cancer cells.

This showed that cancer can develop not only from damage to genetic material but also through the actual creation of something new. Nowadays, genome sequencing allows us to see in much more detail what is going on at the genetic level. “Genome sequencing revealed that many tumors which looked identical were in fact biologically completely different,” says Guerreiro Stücklin.

This also applies to gene fusions, which can be characterized more precisely. “We see that parts of two genes fuse into a new ‘supergene’,” explains Guerreiro Stücklin, “this produces an aggressive protein which drives the growth of tumor cells.” These fusions work like a switch. Once switched on, cancer cells form and their growth is stimulated. Gene fusions are therefore interesting to researchers, says Guerreiro Stücklin, as they provide an ideal target for therapies. If the therapy manages to block the fusion protein, it is possible to fight the tumor without damaging healthy cells.

Gene fusions occur primarily in children in their first or second year of life when their brains are developing very rapidly. Such carcinogenic gene fusions do not only occur in the brain, but also in other types of tumor, such as leukemia and sarcoma. Research into gene fusions is therefore important for the whole of cancer biology, says Guerreiro Stücklin: “Our research findings on this tumor type could also make therapies possible for other types of cancer.” The good news is that, according to initial studies, gene fusions respond very well to targeted therapy.

Are gene fusions the lever with which highly aggressive forms of cancer can be treated? Ana Guerreiro Stücklin explains: “Many aggressive brain tumors are not driven by gene fusions. But if new biological findings open up opportunities to fight cancer, we will pursue them.” Combining knowledge from clinical practice and from research to make something better is how we advance medicine, she says.