The main goal of this research programme of the NICR is to discover the molecular mechanisms of cancers and to identify prognostic, stratification, and therapeutic targets using the methods of molecular genetics, multiomics, imaging methods, and advanced techniques of cell biology including CRISPR/Cas-9 gene editing. These are, in brief, the main targets of another of NICR’s research programmes and Jan Trka, its main leader, is presenting them jointly with Aleksi Šedo.
Research programme 1 (RP1) focuses on discovering the molecular mechanisms of cancers. Its aim is to identify prognostic, stratification, and therapeutic targets, eventually also to validate these targets in cell or animal models. This research uses modern methods of molecular genetics, multiomic approaches, imaging methods, and advanced techniques of cell biology including CRISPR/Cas-9 gene editing.
RP1 brings together a number of research groups from several outstanding institutions that engage in cancer research. Their work focuses mainly on highly prevalent tumours (breast cancer, ovarian cancer, osteosarcoma), tumours that tend to have highly unfavourable prognosis (glioblastomas, liver cancer), and cancers characteristic for a particular life stage (paediatric acute leukaemia).
Some of the most interesting outputs of RP1
Martin Gregor’s team from the Institute of Molecular Genetics of the CAS (IMG CAS) has identified plectin as a new marker and potential treatment target of hepatocellular liver carcinoma that would use plecstatin as a selective inhibitor.
Researchers from the Laboratory of genome integrity (at IMG CAS) led by Zdeněk Hodný developed a new thiol-reactive substance (K2071) with anti-tumour and senotherapeutic effects and published their results. Thiol-reactive substances currently account for 30 percent of clinically used anti-tumour drugs. Their advantage is a much lower level of therapeutic resistance of tumour cells compared to non-covalent modifiers.
An international team led by Czech scientists, in particular Zdeněk Kleibl’s team from the First Faculty of Medicine of the CU, had deciphered the meaning of hundreds of hereditary variants of the CHEK2 gene, which is linked to an increased risk of breast cancer. The research included an analysis of over 80,000 patients from 12 countries. It demonstrated that the newly described risk-associated variants of CHEK2 gene are present in approximately 0.5% of all women suffering from breast cancer. A key part of this work was a modelling of the effects of CHEK2 variants in collaboration with Libor Macůrek’s team from the IMG CAS.
Meri Alberich Jordà’s team from the IMG CAS had discovered a new mechanism that contributes to the development of acute myeloid leukaemia. They identified new mutations of the PPM1D gene, whose effect suppresses the physiological function of TP53 protein, a key guardian of the genome. These mutations can lead to the survival of damaged cells and the development of leukaemia. This team also investigates the effects of chronic inflammations on the emergence and development of cancers. Using a mouse model of chronic bone inflammation, the researchers have demonstrated the development of a tumour influenced by this chronic state.
Researchers from the Brno node of NICR, in particular the team of Marek Mráz at the CEITEC MU, have developed a co-cultivation model, which induces cell proliferation in about 50% of chronic lymphocytic leukaemia (CLL) in vitro. It is a truly unique model that enables the creation of individual ‘avatars’ of patient’s leukaemia in an environment simulating a lymph node. This model had enabled the identification of pan-RAF inhibitors and FOXO1 inhibitors as substances that block the proliferation of chronic lymphocytic leukaemia. Further, Mráz‘s team developed a GAB1 inhibitor that can block the compensatory activation of AKT that accompanies adaptation to BCR inhibitors.
Petr Beneš’s team from the Faculty of Science of MU has identified genes which influence the metastatic activity of cells of the most prevalent bone tumour (osteosarcoma) and described the mechanism of their action. They found that elevated expression of MYB transcription factor supports the formation of metastases, while the TPM2 protein suppresses it.
Researchers from Šárka Pospíšilová’s team from the Faculty of Medicine of MU and CEITEC MU became the main authors of international guidelines for testing the TP53 gene in chronic lymphocytic leukaemia. This work included the identification of defects in TP53, a study of the behaviour of cells with a damaged gene, and an analysis of the effect of TP53 damage on patient survival. This team is a long-term leader in research of chronic lymphocytic leukaemia in Europe.
A study by a Prague-based team of Aleksi Šedo from the First Faculty of Medicine of CU had proven that protease-activated NIR (near-infra-red) probes have the potential to become a targeted instrument for per-operative detection of tumour tissue in glioblastoma. This team had also discovered that fibroblastoma activation protein (FAB) is significantly expressed in brain metastases, which makes it a potential target of new diagnostic and therapeutic approaches.
Vítězslav Bryja a Vendula Hlaváčková Pospíchalová from the Faculty of Science of MU with their team published a breakthrough study that offers a new perspective on how extracellular vesicles (exosomes) can influence the tumour microenvironment and serve as biomarkers for prediction of survival of patients with ovarian cancer. Another study of the same team (but led by Karel Souček) had shown that the unique ‘imprint’ of surface antigens of prostate carcinoma cells, which are inherently resistant to docetaxel, is significantly reflected on the surface of extracellular vesicles. This finding is the first step to a future development of non-invasive predictive markers of docetaxel resistance.
Jan Zuna and his team from the Second Faculty of Medicine of CU described a new kind of acute leukaemia with transcript BCR::ABL1, which in virtue of its less mature cell of origin resembles rather the chronic myeloid leukaemia (CML). This new subtype has already been included in the official classification of leukaemias. Jan Trka’s group from the same institute described the genomic characteristics of paediatric acute myeloid leukaemias. Based on this description, the team had completed a hierarchical algorithm which now helps with the diagnosis, stratification, and treatment monitoring of all children with acute leukaemias in the Czech Republic and Slovakia.
For better results in cancer patients
In conclusion, it can be stated that research teams of RP1 had achieved significant progress in various areas of cancer research. From molecular biology through genetics and all the way to the development of new therapeutic approaches they contribute to a better understanding of cancer and to the development of more efficient diagnostic and treatment methods. It should be stressed that many of these successfully running projects use the complementarity of expertise and technology among the groups that participate in RP1. Their results have the potential of improving the care for cancer patients not only in the Czech Republic but worldwide.