INSTITUTE OF CHEMICAL BIOLOGY
 
  Drug Discovery
  Molecular Analysis
  Organic and Organometallic Chemistry
  Medicinal Chemistry
  Synthetic and Medicinal Chemistry
  Synthetic Medicinal Chemistry and Chemical Biology
  Identification & validation of novel therapeutic targets - Biological evaluation of bioactive small molecules and drugs
  Structural Biology & Chemistry
  Cryogenic electronic microscopy (Cryo-EM) with emphasis on study of proteins, of their interactions and of subcellular particles
  Molecular Endocrinology
  Signal Mediated Gene Expression
  Molecular & Cellular Ageing
  Biomedical Applications
  Holistic Approaches in Health
  Environment and Health
  Metabolic Engineering-Bioinformatics
  Biomarker Discovery & Translational Research
  Bioinformatics focusing on the development of new methodologies and tools
  Biotechnology
  Enzyme and Synthetic Biotechnology
  Biomimetics & Nanobiotechnology
  Conjugated Polymers for Healthcare, Bioelectronics and Bioimaging

 

Signal Mediated Gene Expression
Dr. Alexander Pintzas | Research Director, Group Leader

 

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The Signal Mediated Gene Expression Group focuses on the biology of cancer and interplay with cancer cell death.  The validation of cancer targets, the development and evaluation of new targeted therapeutic anticancer agents, by collaborating with ICB chemists, structural biologists, in silico drug designers, is another aim of the Group. Rational combinatorial treatments of targeted anticancer agents to overcome resistance have also been proposed. The evaluation of predictive cancer variants by NGS for precision oncology is being performed in collaboration with clinical scientists.

ICB has a research platform on Drug and Biomarker Discovery. Signal Mediated Gene Expression Group (SMGEG) has a role in linking the targeted Drug Discovery towards Precision Oncology line. SMGEG in collaboration with clinical groups performs NGS gene analysis, for target and biomarker discovery. Moreover, the Group contributes in the biological evaluation of targeted bioactive molecules-candidate drugs in relevant preclinical cancer models. For this aim, very active collaboration is under way with ICB researchers on structural biology, in silico design, chemical synthesis, bioinformatics, nano-biotechnology. In brief, SMGEG serves the strategic aim of ICB: Targeted Drug Discovery and Precision Oncology, two sides of the same coin.

 

Main Research Directions / Ongoing Research Activities

 

Sensitization of cancer cells in targeted anti-cancer molecules and their synergistic rational combinations, focusing on inhibitors of kinases and apoptotic factors

a) Development of novel BRAF inhibitors (ICB activity)

Biological evaluation is performed of novel putative BRAF pathway inhibitors, designed and synthesized by ICB groups (Goulielmaki et al., 2019). Hit-to-lead optimization. New protocols of drug delivery (Theochari et al., 2017).

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In collaboration with ICB groups for In silico Drug Design, Structural Biology, Synthetic Chemistry, Nanotechnology Goulielmaki M, et al. Transl Oncol. 2019 Jul;12(7):932-950.

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b) Establishment of efficient rational combinations of BRAF/PI3K kinase inhibitors with apoptosis/autophagy modulators to overcome drug resistance in mtBRAF CRC tumours

Following the studies on protocols regarding specific BRAF kinase inhibitors with autophagy inhibitors (Goulielmaki et al., 2016); SMAC mimetics with either BRAF/TRAIL/BCl-2 inhibitors (Perimenis et al., 2016):

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Genomic and bioinformatic analysis revealed the interest for combinatorial treatments of BRAFi with Mcl-1 and Notch modulators show a better effect than the corresponding mono-treatments (Koumaki et al., 2021). This promising combinatorial protocol is further exploited (in preparation, 2022).

Koumaki K, et al. BRAF paradox breakers PLX8394, PLX7904 are more effective against BRAFV600Ε CRC cells compared with the BRAF inhibitor PLX4720 and shown by detailed pathway analysis. Biochim Biophys Acta Mol Basis Dis. 2021 Apr 1;1867(4):166061.
doi: 10.1016/j.bbadis.2020.166061

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 Supported by the following research grants:      
 “STHENOS-b”: Targeted therapeutic approaches against degenerative diseases with special focus on cancer and ageing-optimisation of the targeted bioactive molecules” (2017-2021, funding for NHRF/ICB 790kEuros) (co-ordinator); “EATRIS-GR”: Infrastructure for Preclinical and early-Phase Clinical Development of Drugs, Therapeutics and Biomedical Devices (EATRIS-GR) (2019-2022)

Prognostic biomarkers of disease and predictive biomarkers for drug response in the era of precision oncology

a) Apoptosis pathway components as novel tumour biomarkers

The expression of Noxa, as well as the Noxa/Mcl1 expression ratio have been proposed as exploitable tumour markers (Kosmidou, et al., 2021), following previous studies on 5-gene apoptotic signature (Devetzi et al., 2016). In collaboration with Pathology Dept. and 3rd Surgical Clinic, General Hosp. Athens, G. Gennimatas.
Kosmidou V, et al. Noxa upregulation and 5-gene apoptotic biomarker panel in colorectal cancer. Eur J Clin Invest. 2021 Jan;51(1):e13353. doi: 10.1111/eci.13353.

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b) Intra-tumour heterogeneity as a drug-resistance mechanism

Following previous activities on CRC: Transcriptomic and PET data feature sets, were evaluated for their discrimination performance between colorectal adenocarcinomas and adjacent normal mucosa (Vlachavas et al., 2019). A signature was derived, pertaining 12 features: 7 genes and 5 PET variables.
Vlachavas EI, et al. Radiogenomic Analysis of F-18-Fluorodeoxyglucose Positron Emission Tomography and Gene Expression Data Elucidates the Epidemiological Complexity of Colorectal Cancer Landscape. Comput Struct Biotechnol J. 2019 Jan 25;17:177-185.
doi: 10.1016/j.csbj.2019.01.007

c) Molecular analysis (next-generation DNA sequencing) of cancer variants for targeted therapies for Precision Oncology

NHRF/ICB is involved in Hellenic Network of Precision Medicine (HNPM), which aims to make accessible to citizens the applications of Personalized Medicine. Giopanou I, Pintzas A. RAS and BRAF in the foreground for non-small cell lung cancer and colorectal cancer: Similarities and main differences for prognosis and therapies. Crit Rev Oncol Hematol. 2020 146:102859.

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NHRF/ICB is one of the eleven important research and academic organizations being involved in HNPM.  Giopanou I, Pintzas A. Crit Rev Oncol Hematol. 2020 Feb;146:102859.

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Supported by the following selected research grants:
“Hellenic Network of Precision Medicine on Cancer (HPMN)” (2018-2021, Funding for NHRF/ICB, 250kEuros) URL: www.oncopmnet.gr; Athens Comprehensive Cancer Center (ACCC) in collaboration with the DKFZ German Cancer Research Center. Helmholtz European Partnering Program. (2018-2022, funding 1.5 MEuros). Role: Partner

 

Group Structure and Personnel

Members of the team from 2018 to present

Dr. Alex Pintzas, PhD, Research Director (Group Leader)
Vivian Kosmidou, MSc (Scientific Technical Personnel)

Ioanna Giopanou, PhD (Postdoctoral Researcher) (1/3/2019- 15/10/2020)
Recruited in the frame of the Hellenic Network of Precision Medicine on Cancer (HPMN)

Marianna Kalioraki, MSc (Scientific Personnel) (1/7/2020-31/12/2021)
Recruited in the frame of the Hellenic Network of Precision Medicine on Cancer (HPMN)
Salomi Skarmalioraki, MSc (Scientific Personnel) (20/10/2020-30/6/2021)
Recruited in the frame of STHENOS-b
Kassandra Koumaki, MSc (PhD student)    (1/3/2018-15/5/2020)
Recruited in the frame of STHENOS-b

Eirini Kalogerakou (undergraduate student) (1/11/2017-30/4/2018)
Salomi Skarmalioraki (undergraduate-MSc student) (1/10/2018-30/9/2019)
Fani Pahitsa, BSc (MSc student) (9/9/2019-5/9/2020)
Camelia Sidahmet, BSc (MSc student) (5/10/2020-31/12/2021)

Eleni Poulou, MSc, selected in 2021 for 10/1/2022, Recruited in the frame of EATRIS-GR

 

Collaborations

Internal (NHRF)
Dr Vassilis Gregoriou

Institute of Chemical Biology, National Hellenic Research Foundation
Dr Maria Zervou
Dr Ioannis Kostas
Dr Dimitris Papahatjis
Dr Vasilis Souliotis
Dr Vasilis Zoumpourlis
Dr Olga Papadodima
Dr Aristotelis Chatziioannou
Dr Aris Xenakis
Dr Vasiliki Papadimitriou

Institute of Theoretical and Physical Chemistry, National Hellenic Research Foundation
Dr Nikos Tagmatarchis
Dr Stergios Pispas

National
Dr George Zografos, 3rd Department of Surgery, General Hospital of Athens G. Gennimatas, Athens, Greece
Dr Pantelis Hatzis, Biomedical Sciences Research Center Alexander Fleming, Vari, Greece
Prof Leonidas Alexopoulos, National Technical University of Athens
Prof Rafail Sandaltzopoulos, Demokritus University of Thrace, Greece
Dr Lesley Probert, Hellenic Pasteur Institute, Athens, Greece

International
Dr Ladislav Andera, Czech Academy of Sciences, Prague, Czech Republic
Prof Enzo Medico, Candiolo Cancer Institute, Candiolo, Italy
Dr Τakehiko Sasazuki, Institute for Advanced Study, Kyushu University, Fukuoka, Japan
Dr Senji Shirasawa, Faculty of Medicine, Fukuoka University, Fukuoka, Japan
Dr Rivka Dikstein, Department of Biomolecular Sciences, The Weizmann Institute of Science, Rehovot, Israel
Prof Imre Boros, Faculty of Science and Informatics, University of Szeged, Szeged, Hungary
Dr Laszlo Tora, and Dr Irwin Davidson, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Centre National de la Recherche Scientifique, CNRS, INSERM, Illkirch, France
Prof Allan Balmain, UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, USA
Dr Peter Angel, Division of Signal Transduction and Growth Control, DKFZ/ZMBH Alliance, Heidelberg, Germany

 

 

Funding

EU, national external research funding (-2022), total lab budget >4,000 kEuros, selected grants

  1. 2018-2021: “EDIAO”, Hellenic Network for Precision Medicine in Oncology: Funding for the Institute: 250 kEuros
  2. 2019-2022: “EATRIS-GR”, Infrastructure for Preclinical and early-Phase Clinical Development of Drugs, Therapeutics and Biomedical Devices
  3. 2022-2024: “JANE”, Joint Action on European Networks of Expertise, NHRF Funding 207 kEuros
  4. 2013-2015: “STHENOS”, National Strategic Reference Framework, Institute funding: 1500 kEuros (co-ordinator)
  5. 2012-2015: “THERACAN”,  Exploiting molecular pathways of apoptotic cell death for the rational design of therapeutic strategies for colon cancer. National Strategic Reference Framework, Lab funding: 200 kEuros
  6. 2009-2012: “EpiDiaCan”, Development of sensitive methodologies for exploitation of early epigenetic marker diagnosis in major types of cancer. 7FP EU- Cooperation”  Theme "Health”. Total funding 2.843 kEuros, for lab 504 kEuro (co-ordinator)
  7. 2010-2014: “POM”, PIK3CA Oncogenic Mutations in Breast and Colon Cancers: Development of Targeted Anticancer Drugs and Diagnostics. National  Strategic Reference Framework, Funding for the lab: 130 kEuros
  8. 2006-2010 : “ONCODEATH”, Resistant determinants and sensitisation of solid tumor cells to death receptor related therapies: combination of TRAIL with other therapeutic molecules. EU- Combating Cancer Programme. Total funding 2.345 kEuros , for the lab: 589 kEuros (co-ordinator)
  9. 2006-2009: Functional oncogenomics: a powerful tool towards diagnosis and treatment of human colorectal cancer. Greek Research Network PENED. Funding 235 kEuros (co-ordinator)
  10. 2004-2008: “TAF-Chromatin” EU Research Training Network (RTN) Programme. Lab funding : 370 kEuros
  11. 2004-2007: “Transcription complex dynamics controlling specific gene expression programs” EU- Fundamental Genomics Programme. Lab funding : 450 kEuros

 

Participation in additional funded competitive grants
“Strategic Partnership between the DKFZ/NCT Heidelberg and the Athens Comprehensive Cancer Center ACCC in Athens, Greece for Individualized Cancer Medicine”: Funded by Helmholtz Association, 1,5 MEuros, duration: 1/1/2018-31/12/2022

 

Publications

Selected peer-reviewed publications

  1. Koumaki K., Kontogianni, G., Kosmidou, V., Pachitsa, F., Kritsi, E., Zervou, M., Chatziioannou, A., Souliotis, V. L., Papadodima, O. and Pintzas, A. (2021). BRAF paradox breakers PLX8394, PLX7904 are more effective against BRAFV600Ε CRC cells compared with the BRAF inhibitor PLX4720 and shown by detailed pathway analysis. BBA Molecular Basis of Disease 1867, 166061.
  2. Giopanou, I., Pintzas, A. (2020). RAS and BRAF in the foreground for Non-Small Cell Lung Cancer and Colorectal Cancer: similarities and main differences for prognosis and therapies. Critical Reviews in Oncology / Hematology, 146, 102859.
  3. Vlachavas, E., Pilalis, E., Papadodima, O., Koczan, D., Willis, S., Klippel, S., Cheng, C., Pan, L., Sachpekidis, C., Pintzas, A., Gregoriou, V., Dimitrakopoulou-Strauss, A., and Chatziioannou, A. (2019). Radiogenomic analysis of F-18-Fluorodeoxyglucose Positron Emission Tomography and gene expression data elucidates the epidemiological complexity of colorectal cancer landscape. Computational and Structural Biotechnology Journal.17:177-185.
  4. Theochari, I., Goulielmaki, M., Danino, D., Papadimitriou, V., Pintzas, A. and Xenakis, A. (2017). Drug nanocarriers for cancer chemotherapy based on microemulsions: the case of Vemurafenib analog PLX4720. Colloids and Surfaces B. 154, 350–356.
  5. Goulielmaki, M., Koustas, E. Moisidou, E., Vlassi, M., Sasazuki, T., Shirasawa, S., Zografos, G., Oikonomou, E., and Pintzas A. (2016). BRAF associated autophagy exploitation: BRAF and autophagy inhibitors synergise to efficiently overcome resistance of BRAF mutant colorectal cancer cells. Oncotarget. 7, 9188-9221.
  6. Devetzi, M., Kosmidou, V., Vlassi, M., Perysinakis, I., Aggeli, C., Zografos G.N., and Pintzas A. (2016). Death receptor 5 (DR5) and a 5-gene apoptotic biomarker panel with significant differential diagnostic potential in colorectal cancer. Sci. Rep. 6:36532
  7. Kosmidou, V., Oikonomou, E., Vlassi, M., Avlonitis, S., Katseli, A., Tsipras, I., Mourtzoukou, D., Kontogeorgos, G., Zografos, G. and Pintzas, A. (2014). Tumor heterogeneity revealed by KRAS, BRAF and PIK3CA pyrosequencing:  KRAS and PIK3CA intratumor mutation profile differences and their therapeutic implications. Human Mutation 35, 329-340.
  8. Ferraro, A., Kontos, C., Boni, T., Bantounas, I., Siakouli, D., Kosmidou, V., Vlassi, M., Spyridakis, Y., Tsipras, I., Zografos, G., and Pintzas, A. (2014). Epigenetic regulation of miR-21 in colorectal cancer: ITGB4 as a novel miR-21 target and a three-gene network (miR-21-ITGB4-PCDC4) as predictor of metastatic tumor potential. Epigenetics 9, 129-141.
  9. Ferraro, A., Mourtzoukou, D., Kosmidou, V., Avlonitis, S., Kontogeorgos, G., Zografos, G., and Pintzas, A. (2013). EZH2 is regulated by ERK/AKT and targets Integrin α2 gene to control Epithelial-Mesenchymal Transition and anoikis in colon cancer cells. Int J Biochem Cell Biol, 45, 243-254.
  10. Pintzas, A., Zhivotovsky, B., Workman, P., Clarke, P.A., Linardopoulos, S., Martinou, J-C., Lacal, JC, Robine, S., Nasioulas, G. and Andera, L. (2012). Sensitisation of (colon) cancer cells to death receptor related therapies: a report from the FP6-ONCODEATH research consortium. Cancer Biology and Therapy 13, 507 – 515.
  11. Makrodouli, E., Oikonomou, E., Koc, M., Andera, L., Sasazuki, T., Shirasawa, S., and Pintzas, A.* (2011). BRAF and RAS oncogenes regulate Rho GTPase pathways to induce migration and invasion properties in human colon cancer cells: a comparative study. Mol. Cancer 10, 118.
  12. Oikonomou E., Koc M., Sourkova, V., Andera, L., and Pintzas A. (2011). Selective BRAFV600 inhibitor PLX4720, requires TRAIL assistance to overcome oncogenic PIK3CA resistance. PLoS ONE. 6, e21632.
  13. Voulgari A. and Pintzas A. (2009). Epithelial-Mesenchymal Transition in cancer metastasis: mechanisms, markers and  strategies to overcome drug resistance in the clinic. BBA Reviews on Cancer 1796, 75-90.
  14. Oikonomou, E., Kosmidou, V., Katseli, A., Kothonidis, K., Mourtzoukou, D.,   Kontogeorgos, G., Andera, L., Zografos, G., and Pintzas, A. (2009). TRAIL Receptor Upregulation Correlates to KRAS/ BRAF Mutations in Human Colon Cancer Tumours and Respective Normal Tissue. Int. J. Cancer 125, 2127-2135.
  15. Psahoulia, F. H., Drosopoulos K. G., Doubravska, L., Andera, L.  and Pintzas, A. (2007). Quercetin enhances TRAIL-mediated apoptosis in colon cancer cells by inducing the accumulation of death receptors in lipid rafts. Mol. Cancer. Ther  6, 2591-2599
  16. Roberts, M., Drosopoulos, K., Vasileiou, G., Stricker, M., Taoufik E., Maercker, C., Guialis, A., Alexis, MN. and Pintzas, A. (2006). Microarray analysis of the differential transformation mediated by kirsten and harvey ras oncogenes in a human colon adenocarcinoma cell line. Int. J. Cancer 118, 616–627. 
  17. Zoumpourlis, V., Papassava, P., Linardopoulos, S., Gillespie, D., Balmain, A. and Pintzas, A. (2000). High levels of phosphorylated c-Jun, Fra-1, Fra-2 and ATF-2 proteins correlate with malignant phenotypes in the multistage mouse skin carcinogenesis model. Oncogene 19, 4011-4021
  18. Giovane, A., Pintzas, A., Maira, M., Sobieszczuk, P. and Wasylyk, B. (1994). Net, a negative ets transcription factor that is activated by Ras. Genes and Development 8, 1502- 1513.
  19. Oehler, T., Pintzas, A., Stumm, S., Darling, A., Gillespie, D. and Angel, P. (1993). Mutation of a phosphorylation site in the DNA binding domain is required for redox-independent transactivation of AP-1 dependent genes by vJun. Oncogene, 8, 1141-114727.
  20. Frame, M., Wilkie, N.M., Darling, A. J., Chudleigh, A., Pintzas, A., Lang, J.C. and Gillespie, D.A.F. (1991). Regulation of AP-1/DNA complex formation in vitro. Oncogene, 6, 205-209.  Oncogene, 6, 205-209.

 

 

 

 

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