A new hope for the treatment of more aggressive breast cancers arises from the research of a group of researchers of theEuropean Institute of Oncology (IEO) coordinated by Salvatore Pece, Full Professor of General Pathology at the State University of Milan and Director of the IEO “Hormone-Dependent Tumors and Stem Cell Pathology” Laboratory. 

The results of the study, supported by AIRC Foundation for cancer research, were recently published in the journal Nature Communications.

Treats aggressive breast tumors: the Italian study

The research group has discovered an unprecedented molecular mechanism, based on the action of the CDK12 protein, which, if activated, alters the metabolism of cancer cells, promotes uncontrolled growth and progression towards metastatic disease. 

"This is a new strategy to fight cancer by attacking its particular metabolism," he explained Maria Grazia Filippone, researcher supported by Umberto Veronesi Foundation - This interferes with the ability of tumor cells with high CDK12 expression to exaggerate glucose to feed the metabolic pathway of the folate cycle. This in turn provides the necessary constituents for DNA replication, supporting cell replication and metastatic spread ”.

At the origin of the whole process is the CDK12 protein, which, if expressed in an exaggerated way - as occurs in more than 20% of all human breast cancers - causes the cascade of events that make the tumor aggressive, resistant to conventional chemotherapies. and at risk of metastasis. 

"The presence of CDK12 at elevated levels on the one hand is the driving force of the disease, but on the other - underlined Professor Salvatore Pece - becomes a tumor biomarker and a point of vulnerability. Thanks to this biomarker it is in fact possible to identify tumors to be targeted with anti-metabolic drugs, thus depriving the tumor cells of the energy necessary for their multiplication and essentially forcing them to starve ”.

Prof. Salvatore Pece

Advances in scientific research

"It has been known for about a century that cancer cells have a different metabolism than healthy ones," said Salvatore Pece.

However, oncologists' enthusiasm for these drugs has progressively diminished due to the lack of markers to accurately identify patients who can selectively and effectively benefit from these therapies. 

“In our studies - explained Pece - we integrated the data obtained in experiments with laboratory animals with the retrospective analyzes of various clinical cohorts of patients with breast cancer. 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 breast cancer clinic ".

From research to clinical application

The team of researchers, coordinated by Salvatore Pece, went beyond the discovery.

Scientists have shown, also at a clinical level, that tumors with high levels of this protein are particularly sensitive to anti-metabolic therapies based on methotrexate.

This extraordinary result "represents one of those rare moments of research in which, after many years of study, it is possible to move from basic research to concrete application in the clinical setting", underlined Professor Pece.

If the results of clinical studies on patients with high levels of CDK12 who have not responded to other types of chemotherapies confirm the findings of the Italian research, it will be possible to provide these patients with a therapeutic perspective with protocols that include the use of antimetabolic drugs such as methotrexate. 

“This study is a source of great satisfaction for us - concluded the Professor Salvatore Pece - not only for its scientific value but also for its clinical results. IS in fact, one of those rare moments of research in which, after many years of study, it is possible to pass from basic research to concrete application in the clinical setting. In fact, we have both drugs already immediately available for the treatment of patients, and a new marker of tumor aggression and metastatic risk which is, at the same time, a new target for targeted therapy ".