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Molecular Oncology II – Solid Cancer

THEMATIC RESEARCH FOCUS

RESEARCH AREAS

  • Biology of non-coding RNAs (ncRNAs, microRNA, T-UCR, LncRNA, pyknons, etc.) and their involvement in carcinogenesis
  • Significance of ncRNAs in solid cancer pathogenesis and identification of new therapeutic targets
  • Application of ncRNAs in solid cancer diagnostics and individualisation of therapy in cancer patients

MAIN OBJECTIVES

  • Introduction of high-throughput analyses (whole genome sequencing and transcriptome profiling) of human genome mainly focused on ncRNAs. Utilisation of these technologies in medicine and development of diagnostic tests based on high-throughput methods.
  • Comprehensive analyses of ncRNAs (expression, SNPs, methylation profiles) in solid cancer (mainly colorectal cancer, esophageal cancer, renal cell carcinoma, breast cancer, lung cancer and glioblastoma multiforme). Integration of experimental data with clinico-pathological characteristics of patients aiming at identification of potential suspectibility, diagnostic, prognostic, and predictive biomarkers, as well as new therapeutic targets in tumour tissue or patient’s body fluids. Design and coordination of large multi-centric validation studies.
  • Detailed phenotypic characterisation (e.g. validation of predicted targets of miRNAs and their integration into signalling pathways) and functional evaluation (proliferation, cell cycle, apoptosis, invasiveness, etc.) of ncRNAs suspected to be involved in carcinogenesis or cancer outcome in vitro in a relevant cell line models. Studies examining oncogenic or tumour-suppressive function of particular ncRNA in vivo with subsequent pharmacological analyses evaluating usage of this RNA as a therapeutic target.
  • Formulation and design of recommendations for potential implementation of novel biomarkers to clinical management of solid cancer patients leading to a higher level of individualisation and better therapeutic outcomes. Development and technological transfer of new targeted therapeutic strategies in solid cancer.

CONTENT OF RESEARCH

Significance of microRNA in pathogenesis, diagnosis and therapy of colorectal and renal carcinomas and glioblastoma multiforme

Colorectal cancer – significance of microRNA in pathogenesis, diagnosis and therapy

The work package is focused on microRNA significance in colorectal cancer (CRC), which is one of the leading types of cancer in the Czech Republic. Prognosis of the patients depends on the progression of disease and possibility of curative surgical intervention, which is feasible only for patients with disease limited to a primary tumour and regional lymph nodes. The goal of this work package is molecular characterisation of CRC tissues by modern and progressive approach based on the microRNA expression profiles analyses. MicroRNAs are short noncoding RNAs, 18-25 nucleotides in length that post-transcriptionally regulate gene expression. According to the extent of complementarity with target mRNA, miRNAs act by two mechanisms of post-transcriptional regulation of gene expression, which lead to target mRNA degradation or repression of its translation and conseqeunt decrease of particular protein levels. Bioinformatics have predicted that the capacity of miRNAs is to regulate up to half of the mammalian genes, among them there is also a significant number of important oncogenes, tumour suppressor genes and genes connected with invasion, dissemination and chemoresistance of tumours. MicroRNAs were studied in the connection with broad spectrum of solid cancers. It has been supposed that microRNAs or proteins, which are under microRNAs control, are potential new predictive markers of disease progression enabling higher level of individualisation of treatment and follow-up of CRC patients.

Renal cell carcinoma – significance of microRNA in pathogenesis, diagnosis and therapy

MicroRNAs were studied in the connection with broad spectrum of oncologic diseases, including renal cell carcinoma (RCC) which accounts for ~3% of cancers in adults. The incidence rate in the Czech Republic is about 22 per 100 000 people. This research field proposes comparative analysis of microRNA expression profiles of RCC tissue and adjacent non-tumourous tissue, but particularly it is focused on microRNAs with significance in disease-specific survival, as potential prognostic markers in the RCC patients. It is supposed, that identified microRNAs with prognostic information in RCC patients or their targets on the protein level, might improve present nomograms and algorithms for prediction of relapse-free and overall survival, and become additional predictive factors for the indication of targeted therapy (bevacizumab, sunitinib, sorafenib, temsirolimus), immunotherapy and enable physicians to use a more individualised approach to the therapy of RCC patients.

Glioblastoma multiforme – significance of microRNA in pathogenesis, diagnosis and therapy

Glioblastoma (GBM) is the most common primary tumour of the central nervous system. GBM is also one of the most lethal tumours, with infaust prognosis, and a median survival after diagnosis of only 12-15 months, in spite of the surgery and cytostatictherapy. GBM is highly aggressive and invasive tumour, locally but in diffuse manner invading surrounding brain tissue. Although a several genetic and molecular alterations were described in association with progression and chemo- and immuno-resistance of GBM (MGMT, TGFbeta signalling, selected extracelullar matrix molecules and adhesive molecules, etc.), the recent knowledge is not sufficient for a deeper understanding of molecular nature of this tumour and for GBM´s targeted therapy. Very recently, differences in microRNA expression profiles in GBM and non-tumoural adjacent brain tissue were noticed. Deregulation of various microRNA expression is one of the causal events in carcinogenesis and invasiveness of GBM. MicroRNAs are therefore potential markers of chemo- and radioresistance of GBM. This project supposes that predictive microRNAs or their targets on protein level, will be suitable for routine use in the prediction of GBM response to the new alkylating agent temozolomide or immunotherapy, and will enable a higher level of individualisation in GBM therapy. MicroRNAs were described also as key players in molecular pathology of glioblastoma stem (intiating) cells and present a novel class of GBM therapeutic targets. These topics are another of the important aims of our glioblastoma project.

Technologies used: massive parallel DNA sequencing (next-generation high-throughput sequencing), SNP mapping (high resolution SNP microarrays), gene expression profiling (microarrays, QRT-PCR), FACS, bioinformatic processing.

KEY RESEARCH EQUIPMENT

PLANNED RESEARCH INFRASTRUCTURE

Technology Units

Molecular oncology

MAIN PROJECTS

  • Identification of new prognostic markers and update on staging of locally advanced renal cell carcinoma by microRNA expression profiles analysis (NS10361), Ministry of Health, 2009-2011, Ondrej Slabý, Masaryk Memorial Cancer Institute.
  • Epidemiological, genetic, histological and clinical aspects of „triple-negative“ (ER-alfa, PR, c-ErB2 negative) breast cancer in population of Czech women (NS10357), Ministry of Health, 2009-2011, Marek Svoboda, Masaryk Memorial Cancer Institute.
  • MicroRNAs significance in chemoprotective effects of phytochemicals contained in Brassica vegetables and association of their binding sites polymorphisms with risk of colorectal cancer (NS10352), Ministry of Health, 2009-2011, Ondrej Slabý, Masaryk Memorial Cancer Institute.
  • Identification and functional characterization of microRNAs with predictive significance in patients with glioblastoma (NT11214), Ministry of Health, 2010-2013, Ondrej Slabý, Masaryk Memorial Cancer Institute.
  • Identification and functional studies of microRNAs with predictive and prognostic significance in patients with colorectal cancer (NS9814), Ministry of Health, 2009-2011, Ondrej Slabý, Masaryk Memorial Cancer Institute.

SELECTED PUBLICATIONS

  • SLABY, O. (Ed.). MicroRNAs in Solid Cancer: From Biomarkers to Therapeutic Targets. New York: Nova Science Publishers, 2011.
  • SLABY, O., JANCOVICOVA, J., LAKOMY, R., SVOBODA, M., POPRACH, A., FABIAN, P., KREN, L., MICHALEK, J., VYZULA, R. Expression of miRNA-106b in conventional renal cell carcinoma is a potential marker for prediction of early metastasis after nephrectomy. J. Exp. Clin. Cancer Res. 2010, 29, p. 90.
  • SANA, J., HAJDUCH, M., MICHALEK, J., VYZULA, R., SLABY, O. MicroRNAs and glioblastoma: roles in core signalling pathways and potential clinical implications. J. Cell. Mol. Med. 2011, 15(8), p. 1636-44.
  • SLABY, O., SVOBODA, O., MICHALEK, J., VYZULA, R. MicroRNAs in colorectal cancer: translation of molecular biology into clinical application. Molecular Cancer. 2009, 8, p. 102.
  • SLABY, O., SVOBODA, M., FABIAN, P, SMERDOVA, T., KNOFLICKOVA, D., BEDNARIKOVA, M., NENUTIL, R., VYZULA, R. Altered expression of miR-21, miR-31, miR-143 and miR-145 is related to clinicopathologic features of colorectal cancer. Oncology. 2008, 72(5-6), p. 397-402.
 

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