Mitomycin C and immune response: a new perspective for bladder cancer treatment in a study by Humanitas University

A research of great medical interest, leading to important progress in the treatment of bladder cancer. An important study lead by Dr Bianca Oresta, researcher at Humanitas, has recently been published in Science Translational Medicine. The study was able to identify the action mechanism of mitomycin C, a chemotherapeutic drug which has been used to treat bladder cancer for more than 50 years.

Professor Maria Rescigno, Professor of General Pathology at Humanitas University and Vice Rector responsible for research, explains: “We started this work knowing that mitomycin works in 40% of patients. Half of the patients, therefore, have a relapse after treatment. We asked ourselves what the reason for such an outcome was”. The answer has to do with the way the drug kills the cancer cells by activating the immune system. This is known as immunogenic death, a mechanism that releases mitochondrial DNA which triggers a signal that prompts the immune system cells to ‘eat’ the dead cell. “This new mitomycin mechanism has never been described before,” continues Prof. Rescigno. “In other words, if the tumour cell expresses a certain protein in the respiratory chain, it will undergo immunogenic death. If not, death will not be immunogenic. Patients who respond to mitomycin are precisely those who present this marker.

The study started with a retrospective approach: it was verified that patients who had responded to mitomycin in the past had the marker, and vice versa. “Then we switched to a prospective study. The hypothesis: patients without a marker will not respond to mitomycin. This was indeed the case,’ Rescigno points out. This means that it is possible to predict the treatment response, and thus monitor patients at risk of relapse and choose alternative therapies. “We want to go further, and study whether it would be advantageous to administer the drug even before removing the tumour”, Rescigno continues. “Now it is common practice to operate, then to wash the area with mitomycin, which acts on cells that may have escaped surgery inside the bladder. The idea is to administer the drug even before surgery and therefore trigger the immune response beforehand”.

For Dr Bianca Oresta, 29, a Humanitas researcher with an AIRC scholarship, this is the second scientific publication on the subject since her PhD. Before this one, she published another one related to the study of the bladder microbiome in patients with bladder cancer. “The initial question dates back to a colon cancer study in 2016. We had already questioned how chemotherapeutic agents could stimulate the immune response, known as immunogenic cell death, by awakening a specific response against the tumour.” “This time we observed that many patients relapse after mitomycin treatment. Very often the tumour recurs within a year, which is a problem for the patient and for the healthcare system”. Thanks to the collaboration with the Urology Operative Unit, directed by Prof. Giorgio Guazzoni, the study was also carried out on tumour tissue taken from patients.

“The publication is of great satisfaction, this work has accompanied me throughout my PhD and we managed to complete it in a very difficult year,” says Dr. Oresta. The study has opened up new perspectives: “We’ve proposed a new clinical trial: having discovered this mechanism and how it works, we aim to identify biomarkers that will allow us to understand beforehand whether the patient will respond or not, and thus direct the course of treatment”.