Molecular changes associated with malignant transformation (including driver mutations and mechanisms of metastasis),tumour microenvironment, and detailed molecular characterisation of cancer aimed at finding personalised therapeutic plans for precision oncology are the three key areas of research presented by the programme’s main leaders Karel Smetana and Ondřej Slabý.
The incidence of malignant diseases is increasing worldwide. It is a phenomenon that seems to be associated with population ageing. Sophisticated therapies based on the progress of cancer research have improved the prognosis of cancer patients, many of whom are able to return to normal life. In this effort, time is an important factor and early diagnosis is of a great importance. It is therefore important to identify new biomarkers that enable early diagnosis, prediction of therapeutic response, and monitoring of the disease. Moreover, these biomarkers could be potential targets of anticancer therapy. Due to the complexity of research, collaboration with other research programmes of the National Institute for Cancer Research (NICR) and large hospitals is of great importance. We investigate new biomarkers of cancer diseases and their use especially in colorectal cancer, ductal adenocarcinoma of the pancreas, malignant melanoma, squamous cell carcinoma of the skin and mucosa, breast and prostate cancer, and glioblastoma. Researchers from the RP3 focus in their research on three main directions of new diagnostic approaches:
Early detection of cancer and evaluation of treatment effectiveness
The first direction emphasises research of the molecular changes associated with malignant transformation of cancer cells, including driver mutations and dysregulation of the control of differentiation, proliferation, and migration of cancer cells, including the mechanisms of metastasis formation. Noncoding RNAs, especially miRNAs, seem promising in terms of detecting the initiation of carcinogenesis and for monitoring cancer progression, including an evaluation of success of anticancer therapy. A good example of this is the technology for detecting faecal miRNA to detect early-stage colorectal carcinoma. Being a non-invasive diagnostic procedure, it seems extremely well-suited to a clinical application. Molecules such as miR-149-3p, miR-607-5p, miR-1246, miR-4488, and miR-6777-5p are good candidates for employment in clinical practice some time soon. Similarly, detection of the mucin MUC13-miRNA-4647 axis can be a good prognostic factor for the survival of patients who have colorectal cancer. Long non-coding RNAs also seem to be promising diagnostic and prognostic cancer biomarkers. In renal cell carcinoma, a model based on the expression levels of COLCA1, RMST, SNHG3, and ZNF667-AS1 enable the prediction of early relapse after nephrectomy with high sensitivity and specificity. Scientists from the CEITEC MU have moreover identified specific lncRNA profiles in a population of extracellular vesicles from low-volume blood serum specimens of colorectal cancer patients, thus highlighting the value of innovative techniques in biomolecular research, particularly for detection and analysis of low-abundance biomolecules in clinical samples.
The cancer ecosystem: Research with a therapeutic potential
The second research direction focuses on the cancer microenvironment. For example, cancer-associated fibroblasts (CAFs) are an important member of the cancer ecosystem. The activity of three genes (IL6, VEGFA, MFGE8) was discovered as a molecular signature of CAFs regardless of cancer origin, which is something that could be used for a more precise detection of CAFs in clinical materials. As attested by the following examples, this research has both clinical relevance and therapeutic potential:
- Detection of IL-6 predicts complications after resection of colorectal cancer.
Scientists from the First Faculty of Medicine (Charles University in Prague), and the Department of Surgery of the Faculty of Medicine (Masaryk University) and the University Hospital Brno have discovered that elevated serum levels of cytokine IL-6 immediately after resection of colorectal cancer function as an excellent predictor of severe surgical complications. These might be prevented with more extensive care for the at-risk patients, which would be clearly beneficial. Detection of IL-6 is simple, cheap, and since it might lead to a shorter stay in the ICU, shorter overall hospitalisation, and less antibiotic use, it is also cost-effective.
- Development of small-molecule protein inhibitors of the IL-6 receptor.
A systematic collaborative research of people from the First Faculty of Medicine and the Institute of Biotechnology (Czech Academy of Sciences) in Prague has led to the development of small-molecule new protein inhibitors of the α subunit of IL-6 receptor, which negatively affect the proliferation and migration of cancer cells and can be used to detect IL-6 receptors in cancer cells. These results have been published as a scientific report and we have submitted a patent application.
Molecular characterisation for precision oncology
The third important area is a detailed molecular characterisation of cancer for the purpose of creating personalised therapeutic plans, in other words, research and development in the area of precision oncology. A research team from the Masaryk University has developed a unique web tool called PredictONCO 1.0 which analyses the effects of mutations on proteins frequently altered in various types of cancer. The server can assess the impact of mutations on the protein’s sequential and structural properties and subsequently conduct a virtual screening to identify potential inhibitors that could be used in a highly personalised therapeutic approach, possibly based on drug repurposing. Another success in the field of precision oncology has been achieved very recently. In a collaboration between two teams from Masaryk University and the Centre for Precision Medicine at the University Hospital Brno, scientists and oncologists have shown how a precision immuno-oncology approach can be used to successfully treat siblings with constitutional mismatch repair deficiency syndrome.
All results were obtained thanks to intensive networking both inside the NICR and outside it, in several EU countries (especially Finland, Germany, Slovakia) and in the United States. Collaboration within the NICR and with institutions abroad is essential because we need to share the costly and oftentimes unique equipment. The main advantage of the NICR is that it offers a wide collaborative network of leading scientists in this country: that aids progress in cancer research. A particular advantage is the collaboration with large university hospitals in Prague (4), Pilsen (1), Brno (3), and Olomouc (1), which guarantees a rapid transfer of research results into clinical practice.
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