User Story: Dr Marcin Grzybowski and Dr Zbigniew Zasłona, MOLECURE S.A., Warsaw

User:

Dr Marcin Grzybowski and Dr Zbigniew Zasłona, MOLECURE S.A., Warsaw, Poland

EU-OPENSCREEN-DRIVE MSI site:

Prof. Dr Carsten Hopf, Center for Mass Spectrometry and Optical Spectroscopy (CeMOS), Mannheim University of Applied Sciences, Mannheim, Germany

The Polish biopharmaceutical company Molecure has been investigating arginase inhibitors over the past eight years. Their extensive work led to the discovery and development of a unique molecule, OATD-02, as a clinical candidate. OATD-02 targets arginases, which are now validated as significant players in cancer immunotherapy due to their impacts on antitumour responses and immune evasion.

Research from the group of Dr Zbigniew Zasłona, Molecure S.A., Warsaw, Poland, alongside findings from other scientific groups, has indicated that the effectiveness of an arginase inhibitor in cancer is critically dependent on its intracellular activity, especially targeting mitochondrial ARG2. The scaffold of OATD-02 was uniquely designed to penetrate cells, allowing it to specifically target mitochondrial ARG2. With demonstrated efficacy in various animal models, OATD-02 showed promising results both as a monotherapy and in combination with immune checkpoint inhibitors.

In March 2023, Zbigniew’s group initiated a Phase 1 clinical trial for OATD-02 in cancer patients. Recognising the need for a deeper understanding of OATD-02's mechanism of action, however, they sought facilities for MALDI-MSI to visualise the compound’s effects in vivo, a step which was considered valuable for its further clinical development.
To do so, Dr Marcin Grzybowski, a senior scientist in Zbigniew’s research group, ran an EC-funded EU-OPENSCREEN-DRIVE collaboration project with Prof. Dr Carsten Hopf and Dr Yasemin Ucal of the MSI site CeMOS to better understand the metabolic changes following OATD-02 administration, with a focus on the tumour microenvironment and the specific locations of these changes. Together, they conducted a study using the syngeneic CT26 tumour model, and biological samples were collected after OATD-02 administration. These samples, including CT26 tumours and selected organs, were sent to CeMOS for a comprehensive metabolic analysis.

By leveraging EU-OPENSCREEN services, Marcin was able to utilise advanced MALDI-MSI technology to visualise the metabolic alterations induced by OATD-02, particularly noting an increase in arginine levels and a decrease in polyamine levels in tumours. Notably, the dysregulation of polyamines in cancer contributes to the survival and progression of neoplastic cells, implicating a potential clinical use of OATD-02 in cancer types that utilise ARG2 to boost tumour metabolism.

According to Marcin, access to the EU-OPENSCREEN research infrastructure and this collaboration with CeMOS enabled experiments using advanced molecular techniques that were previously inaccessible to them. Marcin particularly highlighted the ability to empirically validate their scientific hypotheses about the mechanism of action of the arginase inhibitor OATD-02, which was an important milestone in the project.

The next phase of this project will involve the dissemination of the scientific findings achieved throughout the collaboration. Commenting on the future of the project, Marcin says that “we are eager to compile and publish our results in a peer-reviewed paper, aiming to contribute valuable insights to the broader scientific community and potentially impact future research and applications in the field.”