Six years ago, a team of researchers at Columbia University led by Antonio Iavarone and Anna Lasorella announced the discovery of a fusion between two genes, FGFR3 and TACC3, which is responsible for 3% of glioblastoma cases, the most aggressive and lethal of brain tumors (see related interview on the Aspen Italia website). Now they have gone a step further, identifying the mechanism triggered by this gene fusion and effectively determining what drives the growth of some types of cancer. These findings, which have just been published in Nature, were made possible by a careful and personalized study of tumors, in which bioinformatics and big data analytics played a pivotal role.
How did you come to identify the mechanism triggered by the fusion of the FGFR3 and TACC3 genes?
In 2012, we discovered the existence of this fusion, noting its existence in 3% of patients with glioblastoma. This research, published in Science, was part of a larger study of gene sequences that we are still working on today. Following our discovery, the same gene fusion was described by many other studies that detected its presence in the majority of human tumors, always with an incidence of between 2-4% of cases. In short, that gene fusion between FGFR3 and TACC3 is probably the one most frequently described in cancer cases so far.
However, our latest study, published in Nature, reveals this fusion’s mechanism of action, which was previously unknown. In practice, this gene fusion induces the production of energy, causing cancer through the activation of cellular energy metabolism. Energy production occurs by means of the uncontrolled stimulation of the activity of certain subcellular organelles, called mitochondria, which are the cell’s energy control units. This is undoubtedly a very complex and completely hitherto uncharted mechanism, which we have succeeded in identifying thanks to a highly innovative platform of integrated computational and experimental technologies.
What clinical implications does your latest discovery have?
We now know how to tackle certain tumor cases, because we know what the tumor does to grow and expand. The concept of personalized medicine demands a thorough examination of the tumor: today, we are able to identify cases in which the gene fusion described by our studies takes place, and we have the weapons to block the mitochondrial metabolism, which involves inhibiting the production of energy capable of fueling the tumor. At the moment, we continue to use drugs capable of targeting the fusion protein. In mice, however, we have experimented with antimetabolic drugs that block the mitochondrial metabolism. We hope to be able to use them soon in human patients as well, as an additional line of defense, especially as various forms of drug resistance have been encountered with targeted drugs.
What tools are needed for this personalized approach to treating cancer?
The latest molecular techniques available are increasing the therapeutic opportunities for treating tumors, and this is because the disease can present different characteristics between individuals. Indeed, every patient is a project when you have the tools available to study them. In fact, even if a gene fusion like the one described in our studies is not found, a meticulous analysis could find others equally cable of being targeted.
However, it is first necessary to very carefully preserve tumors right from the time they are removed in the operating theater. Freezing them and creating a tumor bank allows them to be analyzed and interpreted, thanks to the efforts of bioinformatics experts. Such analyses, if conducted on a large scale, can reveal interesting trends in the population. Here we enter the field of big data analytics, a fundamental tool for medicine. Our studies at Columbia show the results of tests carried out on American patients, but different populations may present different trends. At the moment, for example, we do not know the genetic context of tumors in Italy, because there are no centers that can conduct studies of this nature.
Can the expertise and infrastructure required to offer this kind of treatment be found in Italy?
It is possible, but advanced research centers are needed that can apply the technologies and deploy them in real time for patients. The creation of centers of great international worth is essential for these facilities to attract the best scientists in the world – from doctors to big-data specialists – and funding from big pharmaceutical companies. This is the only way that innovative studies can be conducted. In my opinion, it is more a question of will than costs. Indeed, research centers of a high international standard bring many benefits, because the investment is rewarded with attraction of funding not only for research, but also for clinical studies. For now, hopes have been pinned on the Human Technopole, though in my opinion this project needs to open itself up to the wider world, with greater involvement of the international scientific community. In any case, given how important it is to know the geographic characteristics of a given population, Italy must build more research centers of this kind, not just in Milan but also in the South. Indeed, what’s needed for personalized medicine are not the so-called “mercy dashes” to far-off places, but rather quality facilities within communities.
