Support from the European Research Council (ERC) will enable Marek Mráz to advance the development of new GAB1 protein inhibitors – substances that appear to be a promising avenue for more effective treatment of acute myeloid leukaemia, one of the most aggressive forms of cancer. The ERC Proof of Concept grant helps researchers determine whether the outcomes of fundamental research can be applied in the real world.
Mark Mráz’s research team at CEITEC MU and University Hospital Brno has long been working on the mechanisms that allow tumour cells to evade the effects of treatment. Originally, his laboratory focused on chronic lymphocytic leukaemia (CLL), whose cells are able to circumvent standard therapy by rebuilding cell signalling pathways. However, when testing new substances developed under a previous ERC Starting grant, they encountered a surprising effect: inhibitors targeting the GAB1 protein, which helps tumour cells survive, showed significant efficacy not only against CLL, but also against acute myeloid leukaemia (AML) and certain other leukaemias and lymphomas.
AML is one of the most serious haematological diseases and often affects young people. Sadly, despite available treatment, more than half of patients die within a year of diagnosis. Scientists have discovered that the GAB1 protein is crucial for the survival of leukaemia cells, as well as for the adaptive processes by which tumour cells defend themselves against other treatments. They have also found that blocking the protein disrupts these processes.
“Targeting GAB1 is a complex issue because it is not a kinase, a type of enzyme which is the most common target of anti-cancer drugs,” explains Mráz. “It is a protein that functions as an ‘aggregation’ centre within the cell and helps to connect and amplify signals between different regulatory pathways. Targeting this type of protein therefore requires a different and more technically demanding approach compared to drugs based on kinase inhibitors. When developing GAB1 inhibitors in collaboration with medicinal chemists at the Faculty of Science, we have to work with a different strategy to disrupt their key role in tumour cells.”
The recent ERC Proof of Concept grant, which is awarded exclusively to researchers who have previously been successful in obtaining one of the main ERC grants, represents a major step forward for the team. It will enable them to develop and test second-generation inhibitors, expand preclinical data, assess the potential for using inhibitors in clinical practice, and establish collaborations with industrial partners.
Building on Marek Mráz’s team’s previous acquisition of a US patent for substances that block the function of the GAB1 protein, this project may represent an important step towards a new type of therapy for patients with AML and other haematological malignancies. However, the journey from laboratory discovery to an effective medicinal drug can be long and arduous. It requires extensive testing, significant investments and a lot of patience.