A group of scientists tried to find the explanations using an approach that combines mathematical models and laboratory experiments
One of the most promising therapeutic strategies for cancer patients consists of molecularly targeted therapies: by delivering the drug specifically to tumor cells that bring a certain target to the surface, the so-called target therapy they guarantee greater precision and less toxicity than traditional chemotherapies. Their effectiveness is often limited by development of tolerances and resistances by tumors, which can thus give rise to metastases. Understanding how cancer manages to get around the obstacle was the goal set by the Italian researchers who published a study in the authoritative scientific journal. Nature Genetics
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An approach that combines mathematics and biology
The development of metastasis and resistance to therapy I’m the main one cause of relapses in cancer patients: in some cases the rapid relapse, and due to genetic alterations already existing in the tumor mass before the administration of the treatment. In others, however, the tumor reappears after a long time, even years after diagnosis, and the reasons are still not clear. The ability to prolong the effectiveness of a treatment to date is limited by the lack of knowledge of the multiple mechanisms that lead to the development of resistance. A step forward in this direction has been made by the researchers of IFOM, University of Turin, University of Milan and Candiolo Cancer Institute FPO IRCCS, led by Marco Cosentino Lagomarsino and Alberto Bardelli, thanks to the support of the AIRC Foundation and an ERC grant from the European Union. The interdisciplinary group, made up of physicists and biologists, investigated the resistance to molecularly targeted therapies from a quantitative point of view and with a novel approach that combines mathematics with biology. More precisely, thanks to mathematical tools, tumor cells have been characterized in their various subpopulations, reaching excellent levels of detail and depth.
In the wake of the Nobel Prizes
We have adopted a method very similar to the one originally used, in 1943, by Salvador Luria and Max Delbrck to study the development of resistance in bacteria – says Marco Cosentino Lagomarsino, of IFOM and University of Milan -. That pioneering experiment gave a impulse fundamental to modern experimental genetics and proved crucial to the development of molecular biology, to the point that the two scientists received the Nobel Prize for Physiology and Medicine in 1969. The same approach had so far been used in a very limited way in human cells, probably due to its complexity. the duration of the required experiments. In fact, it is necessary to sample and characterize many cells, in our case obtained from patients with colorectal cancer, both during drug treatment and in normal growth conditions. The results obtained with the laboratory experiments were enriched by the mathematical analyzes and vice versa – explains Alberto Bardelli – and the collaboration was essential for the success of the project. On the one hand, preliminary theoretical considerations based on mathematical models allowed us to design the experiments in an optimal way for our purposes. On the other hand, the results of the experiments in genetics and molecular biology have allowed us to apply mathematical models to think about innovative treatment protocols, which could lead in perspective to a reduction in resistance to therapies.
Cancer cells go to sleep
What did the researchers highlight in the laboratory? We have observed that molecularly targeted therapies induce the transition to one in cancer cells state of hibernationmaking them able to temporarily tolerate the treatment – he says Mariangela Russo, first author of the article, of the University of Turin and Candiolo Cancer Institute -. These cells, called “persistent” cells, being tolerant to therapy, potentially have time to acquire genetic mutations that make them able to replicate in the presence of the drug, thus causing a relapse of the disease. Our studies have allowed us to understand that therapy induces a significant increase in the ability of persistent cells to mutate: not only do persistent cancer cells have time to develop mutations in their favor, but the therapy makes this process faster. What answers did the mathematical models provide? They allowed us to more accurately interpret and predict the behavior of cancer cells during treatments – he replies Simone Pompei by IFOM, who co-first authored the article and developed the mathematical models used -. In this way we calculated that persistent cells mutate up to 50 times faster than cancer cells. This means that persistent cells, even if present in small numbers, carry a high probability of recurrence. What are the next steps? In addition to bringing a greater understanding of the molecular mechanisms underlying resistance to therapies, the results obtained in the study open up new possibilities for preventing the onset of resistance and preventing the development of metastases – conclude Cosentino Lagomarsino and Bardelli -. In the future, doctors could modulate the doses and times of administration of anticancer drugs in order to minimize the likelihood of disease recurrence. But there is still a long way to go.
July 20, 2022 (change July 20, 2022 | 18:09)
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