First, the development of a new method of analysing cancer biomarkers and then a new prodrug, i.e. a molecule that attacks cancer cells and destroys them, are the focal areas of the activity of Prof. Marcin Poręba from the Faculty of Chemistry of Wrocław University of Science and Technology. Our researchers received a grant for their research from the National Centre for Science.

Professor Marcin Poręba and his colleagues intend to develop a new method for analysing single tumour cells in the context of the activity of individual proteases (proteolytic enzymes). In his work, he is going to use a mass cytometer – today’s most modern instrument enabling the analysis and diagnosis of cellular samples and advanced proteomics. In Poland, we have only one such apparatus – at Wrocław University of Science and Technology. The device examines samples using mass spectral analysis of metal atoms, which are used as markers in this method.

Prof. Poręba's work is made possible by a 2.5-million grant from the National Centre for Science under the Opus + Lap programme. It will take four years and has been divided into three phases.

First, the researchers will create chemical markers equipped with metals for specific enzymes: proteases and protein kinases – two main groups of enzymes that, depending on the situation (biological context), serve a pro-cancer or anti-cancer role in the cell. It will be crucial to prepare these markers for the largest possible group of proteases and kinases.

– At a later stage, we’ll use them in different biological systems, namely on cancer cells taken from breast cancer patients. Thanks to mass cytometry, we will know the distribution of these enzymes’ activity and compare this information with the clinical picture of the disease, i.e. detailed information from doctors, e.g. on markers they consider or the possibility of hormone therapy – says Prof. Poręba. – This is how we will develop a kind of “cancer cell fingerprint”, which will let us move on to the next stage of our project.

That will consist in developing antibody-drug conjugates that will become activated only with selected enzymes. The result will be a solution to deliver and activate the drug in cancer cells.

– Antibody-drug conjugates are currently one of the fastest-growing fields of oncology, but the vast majority of those that have reached the stage of clinical trials have shown significant toxicity and as a result, have not been approved for marketing – points out Prof. Poręba. – In our project, we aim to develop a new generation of highly selective antibody-drug conjugates to be activated exclusively by tumour-associated proteases. To put it simply: the antibody will only recognise the proteins that are on the surface of the cancer cell, and the conjugate will reach it and destroy it – and only it – by releasing the drug. In this way, their systemic toxicity will be significantly reduced.

To achieve this, the researchers need to create a highly selective peptide linker that will bind the antibody to the drug. And this is where detailed knowledge of enzyme activity in cancer cells will come in handy, as what they want to achieve is to create a linker that is sure to be recognised by proteases characterised by increased activity.

The main function of these enzymes is to cut through peptide bonds in the cell. So, when they cut through such a “linker” in the antibody-drug conjugate, they will release the drug, which will kill the cancer cell.

– If such a prodrug reaches a healthy cell, there will be no enzyme in the cell that can cut through this "linker" and thus release the drug. Such a cell will therefore be safe – explains the project leader.

The third phase of the research will be carried out by researchers from Slovenia – partners in this project, who have received a grant from a Slovenian science agency (almost 1.5 million PLN). Their responsibility will be to implant tumours into mice and observe disease progression using TOF-type markers and magnetic resonance imaging.

The researcher stresses that a more detailed analysis of cancer biomarkers to better understand their role in the disease is crucial in combating cancer. Research in this area is all the more important as the incidence of malignant tumours is increasing with every decade. According to WHO data, breast cancer is currently the most common cancer in the world. It is estimated that 1.7 million women are diagnosed with the disease each year worldwide.

The recovery process after cancer depends on several factors – including early diagnosis, accurate cancer type classification, or the choice of personalised treatment. Greater knowledge of cancer biomarkers can help tackle these challenges.