josmart 05.06.2017

Research

Institute of Biochemistry and Experimental Oncology (IBEO) is the teaching and research institute of the First Faculty of Medicine, Charles University in Prague The Institute teaches undergraduate medical students in Medical Chemistry and Biochemistry, a compulsory, theoretical, two semestral subject covering basic medical chemistry, biochemistry, inter-organ biochemistry, and molecular biology. The classes are taught in Czech and English languages. The institute teaches cancer pathobiochemistry at 5th semester and it also takes part in the tuition of Biochemistry for bachelors' students.

In the graduate education, the Institute offers programs in biochemistry or genetics for PhD students according to the specialization of research teams.

Research laboratories:

Laboratory of cancer cell biology (head: Aleksi Šedo)

Laboratory of oncogenetics (head: Zdeněk Kleibl)

 

LABORATORY OF CANCER CELL BIOLOGY

Head: Aleksi Sedo

Research activities: The laboratory of cancer cell biology (LCCB) was established by Aleksi Šedo, M.D., PhD. in 1997 at the Institute of Medical Chemistry and Biochemistry as a joint laboratory of the 1st Faculty of Medicine, Charles University in Prague and the Institute of Physiology of The Czech Academy of Sciences. In 2002, LCCB joined the Institute of Biochemistry and Experimental Oncology and became its integral part. LCCB focuses on the role of membrane-bound serine proteases in various pathophysiological processes with a special focus on the pathogenesis of cancer and autoimmune disorders. Our results contributed to the definition of the group of “Dipeptidyl peptidase-IV structure and/or activity homologues” (DASH) and to the description of the expression pattern of DASH molecules in autoimmune rheumatoid diseases and in gliomas (CIT).

Currently, the main research interest is the role of the membrane bound proteases dipeptidyl peptidase-IV (DPP-IV) and fibroblast activation protein (FAP) in gliomagenesis. Gliomas are the most frequent primary intracranial tumors. The prognosis for the most common grade IV tumors (glioblastoma multiforme) remains dismal with a median survival of 14 months despite surgical resection and postoperative radiotherapy and chemotherapy. The identification and validation of qualitatively new therapeutic targets and approaches is therefore imperative to improve the limited therapeutic options. Analysis of the bioptic material, functional in-vitro assays as well as in vivo animal models including knock-out mice are being utilized to determine the role of DPP-IV and FAP within the tumor microenvironment and the interactions between malignant glial cells and the stroma with the aim of designing and testing inhibitors or inhibitor based targeting compounds as potential therapeutics.

LCCB closely cooperates with the neurosurgical departments of the Na Homolce Hospital and with the Military University Hospital and the Institute of Organic Chemistry and Biochemistry AS CR, v.v.i. LCCB is the founding member of the Neurooncological section of the Czech Oncological Society of the Czech Medical Association of J.E. Purkyně. The section should facilitate the national and international cooperation between clinical and biomedical disciplines that participate on the diagnostics, treatment and research of malignancies affecting the central nervous system. In addition to the neurooncology field, LCCB participates on the projects exploring the role of DPP-IV and FAP in the pathogenesis of pancreatic adenocarcinoma and possible effects of DPP-IV inhibitors on the immune system in patients with diabetes mellitus.

Publication list: see in PubMed

Our team and research interests:

  • Aleksi Šedo, M.D., Ph.D. (head) – role of proteases in cancer pathogenesis, gliomagenetic processess
  • Petr Bušek, M.D., Ph.D. – glioma cell invasion, proliferation, glioma stem-cells, targeting of FAP as a potential therapeutic approach
  • Eva Balážiová, M.D., Ph.D. – role of DASH molecules in glioma angiogenesis and microenvironmental interactions
  • Zdislava Vaníčková, M.D. – role of DASH molecules in pancreatic cancer and pancreatic cancer associated diabetes mellitus
  • Evžen Křepela, M.D., Ph.D. – proteases and protease inhibitors as regulators in cancer cell biology, enzymology of cancer cell apoptosis, role of proton dynamics in cancer cells.
  • Lucie Stollinová Šromová, Ph.D. - glioma stem-cells, flow cytometry

Current grant projects:

  • The diagnostic and therapeutic potential of fibroblast activation protein (FAP) in human astrocytic tumors. (2011-2015, Internal Grant Agency of the Ministry of Health of the Czech Republic, project NT12237-5)
  • Complex oncological program. (2012-2016, Charles University Research Development Schemes, project P27/LF1/1)
  • Molecular heterogeneity of dipeptidyl peptidase-IV (DPP-IV) and fibroblast activation protein alpha (FAP) and its association with WHO grade of human astrocytic tumors. (2012-2014 Charles University Grant Agency, project 671612)
  • Novel concepts for the therapeutic targeting of tumor microenvironment in human glioblastomas. (2015-18; Agency for Medical Research of the Ministry of Health of the Czech Republic, project …)
  • Early Diagnosis of Pancreatic Adenocarcinoma: Surface Proteases and Specific Biomarkers. (2013-2015, Internal Grant Agency of the Ministry of Health of the Czech Republic, project NT14254-3)
  • Mechanisms of reprogramming of complex cellular processes. (2012-2017, University Research Centers, project UNCE 204013)
  • The importance of the tumor microenvironment in gliomagenesis. (2014-2016, Charles University Grant Agency, project 44214)

Our current Ph.D. students:

  • Marek Hilšer (2007)
  • Edita Fejfarová (2012)
  • Lenka Kotačková (2014)
  • Ivana Matrasová (2010, currently at maternal leave)
  • Jana Trylčová (2009, currently at maternal leave)

Our current undergraduate students:

  • Michal Zubáľ (2014)
  • Petr Výmola (2015)
  • Lukáš Ryba (2015)

Our finished Ph.D. students:

  • Radek Malík, M.D., Ph.D. (1999-2003; currently at The Czech Academy of Science)
  • Petr Bušek, M.D., Ph.D. (2004-2009; currently at our lab) ·
  • Jarmila Stremeňová, Ph.D. (2004-2009; Laboratory of Cell Signalling and Apoptotis, Institute of Molecular Genetics AS CR 2010-2014, currently at the Institute of Cellular Medicine, Newcastle University)
  • Eva Balážiová, M.D., Ph.D. (2006-2012; currently at the Dept. of Neurology and at our lab)
  • Lucie Šromová, Ph.D. (2006-2015; currently at our lab)

 

LABORATORY OF ONCOGENETICS

Head: Zdenek Kleibl

Research activities: The laboratory has been established by Petr Pohlreich, M.D., PhD. in 1997. It investigates factors contributing to the development of hereditary cancer syndromes with the main focus on hereditary breast and/or ovarian cancer in the Czech population.

Breast cancer (BC) is the most frequent malignant cancer diagnosis affecting Czech female population. It has been estimated that ~5-10% BC cases arise in patients carrying pathogenic alteration BC susceptibility genes; however, the proportion of breast cancer cases influenced by genetic factors is probably much larger. The most frequent BC-susceptibility alterations are found in the two major breast cancer predisposition genes BRCA1 and BRCA2 that code for the large phosphoproteins involved in the dsDNA break repair.

Since foundation of the lab, we identified more than 550 carriers of pathogenic variants in BRCA1 or BRCA2 from 350 families. Our results show that BRCA1 represents the most frequently altered BC susceptibility gene in our population, while mutation in BRCA2 and other tested genes (including CHEK2, ATM, PALB2, p53, NBS1, RAD51C, RAD51D, PPM1D/Wip1, or STK11) participate to BC susceptibility in smaller proportion of high-risk patients (less than 40% of patients with identified pathogenic variant).

Except genetic analyses in the large population series of high risk and unselected cancer patients using classical genotyping as well as high-throughput next-gen sequencing approaches, the laboratory is also involved in functional in vitro analyses of identified variants. Our studies are focused on the analyses of DNA repair capacity following genotoxic insults in modified cells expressing altered genes that code for DNA repair proteins.

We were also involved in pharmacogenomic studies focused on analyses of hereditary variants in genes that code for proteins involved in fluoropyrimidines catabolic pathway. We described variants in these genes that may contribute to the development of serious and body site-specific toxicities in fluoropyrimidine-treated cancer patients.

Publication list: see in PubMed

Our team and research interests:

  • Zdeněk Kleibl, M.D., Ph.D. (head) – characterization of cancer susceptibility genes using NGS, analyses of BRCA1 alternative splicing mRNA variants, pharmacogenomic studies in 5-FU toxicity.
  • Markéta Janatová, Ph.D. - analyses of PALB2, RAD51C and RAD51D in hereditary breast, ovarian, and pancreatic cancer patients, and analyses of promoter methylations/intragenic rearrangements of BC-susceptibility genes.
  • Petra Kleiblová, M.D., Ph.D. – identification of the tissue/disease-specific alternative splicing mRNA variants of the BC-susceptibility genes, analysis of the moderate penetrance genes (especially CHEK2, CHEK1 and PPM1D), qPCR /HRM analyses, and the clinical interpretation of genomic data.
  • Jana Stříbrná, MD, Ph.D. – laboratory procedures in the mutation analyses of the BRCA1 and BRCA2 genes.
  • Jana Soukupová, Ph.D. – NGS sequencing optimization, NGS analyses for the identification of pathogenic variants in cancer susceptibility genes, analyses of selected rare genetic disorders (Sotos sy, ataxia telangiectasia).
  • Jan Ševčík, Ph.D. – functional in vitro studies of the DNA repair mechanics, characterization of sequence variants in cancer susceptibility genes.

Current grant projects:

  • Contribution of newly characterized intermediate-risk susceptibility genes to familial breast and ovarian cancer (2012-15; Internal Grant Agency of the Ministry of Health of the Czech Republic, project NT13343) - detail
  • Targeted NEXT-GEN sequencing as a tool for identification of the new breast cancer susceptibility genes in high-risk patient (2013-15; Internal Grant Agency of the Ministry of Health of the Czech Republic, project NT14054) - detail
  • A role of hereditary mutations of the PALB2 gene in breast, ovarian and pancreatic cancer development in the Czech Republic (2013-15; Internal Grant Agency of the Ministry of Health of the Czech Republic, project NT14006 - detail
  • Functional analysis of the BRCA1 alternative splicing variants in vitro and their relationship to the mammary carcinogenesis (2012-15; Czech Science Foundation project GAP301/12/1850) - detail
  • Characterization of genetic predisposition to ovarian cancer using Next Gene Sequencing analysis (2015-18; Agency for Medical Research of the Ministry of Health of the Czech Republic, project 15-27695A) – detail
  • Identification of genetic factors contributing to hereditary breast cancer development and prognosis (2015-18; Agency for Medical Research of the Ministry of Health of the Czech Republic, project 15-28830A) – detail

Our current Ph.D. students:

  • Marianna Borecká (2013)
  • Petra Zemánková (Boudová) (2013)
  • Jan Hojný (2012)
  • Filip Lhota (2010)
  • Lenka Stolařová (2015)
  • Klára Zdařilová (2015)

Our current undergraduate students:

  • Žaneta Chmelařová (2014)
  • Kristýna Judasová (2014)

Our finished Ph.D. students:

  • Martin Matějů, M.D., Ph.D. (2005-2014; Dept. of Oncology)
  • Jan Ševčík, Ph.D. (2004-2012; Brisbane University, Australia; currently at our lab)
  • Ondřej Havránek, M.D., Ph.D. (2008-2011; currently at MD Anderson, Houston, USA)
  • Ivana Tichá, Ph.D. (2008-2011; Linköping University, Sweden (2011-2014); currently at Dept. of Pathology)
  • Jana Soukupová (Prokopcová), Ph.D. (2004-2008; currently at our lab)
  • Markéta Prchalová (Brožová), Ph.D. (2004-2008; currently at maternal leave)
  • Eva Scholzová (Vondrušková), Ph.D. (2004-2008)
  • Markéta Janatová, Ph.D. (2001-2005; currently at our lab)
  • Michal Zikán, M.D., Ph.D. (2000-2004; currently at the Dept. of Gynecology and Obstetrics)

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