Breast cancer, protein discovered that increases risk of metastasis

Forcing cancer cells to starve by alternating their metabolism. A strategy that is not new – and which had not yielded great results so far – but which could instead prove to be very useful in one in 5 patients with breast cancer. The discovery is Italian, made by researchers from the European Institute of Oncology (IEO) thanks to the support of the Airc Foundation, and the strategy we are talking about is based on drugs called anti-metabolics, such as methotrexate.

The researchers led by Salvatore Pece, full professor of General Pathology at the State University of Milan and Director of the Hormone-Dependent Tumors and Stem Cell Pathobiology of the IEO, have identified a new mechanism at the origin of the progression towards metastatic disease and growth uncontrolled tumor, which involves the CDK12 protein. If expressed in an exaggerated way – as occurs in over 20% of all breast cancers – it causes a cascade of events that make the tumor aggressive and resistant to conventional chemotherapies. If on the one hand the presence of CDK12 at high levels is the driving force of the disease, on the other it becomes a biomarker that reveals a weak point.

The tumor marker that was missing

“It has been known for about a century that cancer cells have a different metabolism from healthy ones”, explains Pece: “The use of anti-metabolic drugs was among the first strategies put in place to fight cancer, in particular cancer. breast. However, the enthusiasm for these drugs on the part of oncologists has progressively diminished due to the lack of markers to accurately identify patients able to selectively and effectively benefit from these therapies. In our studies we have integrated the data obtained in experiments with laboratory animals with the retrospective analyzes of different clinical cohorts of patients. The results solve the problem as they clearly indicate that high levels of CDK12 constitute a biomarker that can be used to select patients to be treated with anti-metabolic therapy using a drug, methotrexate, already available in the clinic for the treatment of breast cancer “.

How drugs work

How do these drugs work? They prevent cells with high CDK12 expression from “overusing glucose to fuel the metabolic pathway of the folate cycle. This, in turn, supports cell replication and metastatic spread ”, explains Maria Grazia Filippone, researcher supported by the Umberto Veronesi Foundation. This study – published in Nature Communications – marks one of those times when it is possible to move from basic research to clinical application. Studies will now be started in metastatic patients with elevated CDK12 levels and in whom chemotherapy has not been found to be effective. “If the results confirm these data – concludes Paolo Veronesi, Director of the IEO Senology Program – it will be possible to provide these patients with a concrete therapeutic perspective”.