Ieo-UniMi, hopes against genetic anomaly, cancer’s Achilles heel

Scientists from the European Institute of Oncology (IEO) and the University of Milan have demonstrated that 2 classes of anticancer drugs already used in clinical practice can target a genetic ‘Achilles heel’ common to several types of tumors. This is aneuploidy, i.e. the presence in diseased cells of a number of chromosomes different from that of healthy cells, which is found in approximately 90% of solid tumors and 75% of blood tumors. The results are the fruit of 2 large-scale studies supported by the Airc Foundation for Cancer Research and were published in ‘Nature Communications’ and ‘Cancer Discovery’.

The discovery was made by a team coordinated by Stefano Santaguida, group leader of the Laboratory of Genomic Integrity of the IEO and professor of molecular biology at the University of Milan, in collaboration with the laboratory of Uri Ben-David (University of Tel Aviv, Israel) and with the participation of centers of excellence including the National Cancer Institute (Bethesda, USA), the Broad Institute of MIT and Harvard (Cambridge, USA), the Max Planck Institute for Molecular Genetics (Berlin, Germany) and the Center for Genomic Sciences of the Italian Institute of Technology (IIT, Milan).

The new data – explains a note – are part of a previous study, the results of which had been considered very relevant by the oncology community. The same group had in fact contributed to demonstrating that aneuploidy can be a target for anticancer drugs: a weak point of the disease, vulnerable even in tumors that resist molecularly targeted drugs, directed against specific alterations. “Until now, however, this important hallmark of cancer has never been clinically exploited as a treatment target – Santaguida emphasizes – because until recently the tools needed to reproduce and cultivate purely aneuploid cells in the laboratory were lacking. Tumor cells are in fact characterized by genetic chaos due to various anomalies, including aneuploidy. For years, several research laboratories have been trying to generate systems in which aneuploidy could be studied individually, that is, without the presence of other alterations normally present in tumor cells. The aim was to analyze this characteristic and understand how to attack it. For the first time at IEO, we have succeeded in developing cells in culture exclusively with aneuploid karyotypes. We have thus been able to create clones of aneuploid cells and study them to understand their vulnerabilities, that is, which processes they need to survive and which can therefore be exploited as therapeutic targets”.

“We were the first to achieve this result – explains Marica Rosaria Ippolito, first author of the two articles and a research doctor at the European School of Molecular Medicine, thanks to the studies carried out at the Laboratory of Genomic Integrity of the IEO – thanks to the use of various ‘omic’ techniques, latest-generation approaches that allow us to have a global vision of the activities of a cell or tissue, including DNA sequencing techniques, genomic screening and proteomic analysis. We also used high-resolution microscopy techniques, in which our laboratory has had very solid experience for several years now”.

“We have thus discovered – reports Santaguida – that aneuploid cells are affected both by chemotherapy drugs that induce DNA damage and by PARP inhibitors, the molecular target drugs used for example in the treatment of ovarian and breast cancer. These are drugs that are effective in cases of BRCA mutation and other genetic deficits that alter the mechanisms of repair of DNA damage. The results obtained with aneuploid cells generated in the laboratory have been validated on samples obtained from patients. We are therefore confident that our studies will soon offer new treatment options for the large group of aneuploid tumors”.