Colon cancer, found to be a possible “culprit” when chemo doesn't work

With 48,100 new cases registered every year, colorectal cancer is the second most frequent type of cancer in our country and is also second in the little-coveted ranking of the most lethal, despite there being an effective way to diagnose it early and save your life. life: screening (offered free in Italy to all people between 50 and 70 years old) with the Sof test, to search for occult blood in the faeces.

Seven out of ten Italians, however, do not carry out the test which would allow them to avoid almost 90% of cases, given that colorectal carcinomas develop from adenomas or polyps which take years, on average about ten, to transform into forms malignant. If diagnosed in the early stages, when the tumor is small, surgical removal may be sufficient to definitively cure the patient.

Current therapeutic strategies

«Very often, however, chemotherapy is also prescribed, which continues to have a very important strategic value – explains Alberto Bardelli, scientific director of IFOM (the Foundation Institute of Molecular Oncology) -. It can be used before or after the operation, combined or not with radiotherapy. Unfortunately, not all patients achieve the desired results and one of the greatest challenges of scientific research is understanding what helps cancer cells to resist therapies.”

«Numerous chemotherapy drugs are available in the clinic, some of which share the common mechanism of damaging the DNA of tumor cells, crumbling it piece by piece, until the tumor remains without “instructions” and regresses – continues Bardelli, full professor at the University of Turin —. But it's about drugs that can also affect normal cells, causing side effects that may preclude continued treatment. Furthermore, not all intestinal cancers respond to the same drug from the beginning. Optimizing the therapeutic choice to maximize clinical benefit and reduce collateral toxicity is essential. Currently, however, there are still no univocal criteria for choosing the right chemotherapy for the right patient.”

A new study

A team of Italian researchers, united by a collaboration between IFOM and the Department of Oncology of the University of Turin and coordinated by Bardelli, has found a new strategy for selecting treatment of colorectal cancer patients, adopting an innovative change of perspective. Rather than focusing only on the tumor to predict the possible response to chemotherapy, researchers studied what surrounds it, that is, the set of bacteria that populate the intestine: the so-called microbiota. The new study was published in the scientific journal Cell Reports Medicinethanks to the support of the AIRC Foundation and an ERC grant from the European Union.

The microbiota and colibactin

«The microbiota represents an incredible set of microorganisms that live in the intestine – clarifies Bardelli -. If everyone were a star, the microbiota would be 100 times the size of the Milky Way. The microbiota performs many important and positive functions for our body, but there are some bacteria that promote the development of cancer. In particular, it is known that some species of Escherichia coli and other intestinal bacteria are capable of producing a specific toxin, called colibactin, which has been found enriched in a fraction of colorectal tumors. This toxin is capable of causing the transformation of normal intestinal cells into cancerous ones by inducing mutations, i.e. alterations in the sequence of their DNA: the same target as chemotherapy drugs commonly used in clinics. We therefore asked ourselves if there could be a correlation, that is, if exposure to the toxin could thus influence the way in which tumors respond to treatment.”

Laboratory simulation

«We had the idea of ​​going beyond the study of tumor cells alone to understand how they can be guided by the micro-environment that surrounds them – continues Alberto Sogari, AIRC researcher of the Department of Oncology of the University of Turin and first author of the study – . It wasn't easy because this change of approach required the idea of new experimental protocols. With the help of microbiologists from Professor David Lembo's group of the Department of Clinical and Biological Sciences of the University of Turin, we have grown colorectal cancer cells and colibactin-producing bacteria in the laboratory, thus simulating what happens in the intestine.”

The researchers used both cell lines and so-called organoids, innovative patient-derived models that recapitulate the three-dimensional structure of the tumors of origin, and studied the functional impact of colibactin on cells with sequencing technologies and cutting-edge bioinformatic analyses.

The “gym” of tumors

«We thus discovered that colibactin works as a sort of “gym for tumors” – says Sogari -: this toxin trains tumor cells to bear a constant load of DNA mutations, getting used to them. And so, when we start treatment with a chemotherapy drug with a similar mechanism widely used in the clinic, irinotecanthe tumor is already “trained”: by learning to tolerate the mutations caused by colibactin, the tumor also learns to tolerate the damage caused by chemotherapy, thus becoming resistant.”

Choose the most effective treatment

The study therefore opens up new perspectives. In fact, researchers have observed that tumors trained by colibactin can also respond to other chemotherapy approaches which act with a different mechanism. Colibactin, therefore, may be the key to selecting the appropriate therapeutic strategy to target these tumors more effectively. In the field of precision oncology it is increasingly important to stratify patients in order to personalize the treatment as much as possible.

«Our results show how important a 360-degree integrated approach is, which looks at the tumor and its surroundings, to discover new biomarkers, i.e. new criteria for selecting the right drug for the right patient – ​​concludes Bardelli -. Starting from our pre-clinical results, we began to analyze the presence of colibactin in clinical samples from patients at the Niguarda Hospital in Milan, in collaboration with Salvatore Siena and Andrea Sartore-Bianchi, to correlate the toxin to the clinical response to drugs. We have already obtained some first encouraging results.”

The researchers' next step is now validate this approach on larger, more representative cohorts of colon cancer patients.

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