NKUA-CRG (Working groups)

NKUA-CRG is a multidisciplinary entity composed of working groups from five NKUA Departments with strong educational, managerial and scientific links. Participating Departments: Histology & Embryology (DHE, Faculty of Medicine - School of Health); Cell Biology & Biophysics (DCBB, Faculty of Biology - School of Sciences); Biochemistry & Molecular Biology (DBMB, Faculty of Biology - School of Sciences); Animal & Human Physiology (DAHP, Faculty of Biology - School of Sciences); Pharmacy (DPH, School of Health).

Some of the major achievements and the demonstrated scientific excellence of the NKUA-CRG senior and recently recruited new academic members in the three main axes of interest are as follows:

a. Tumour promoting factors and anti-tumour barriers.

NKUA-CRG members have shown that among the main causes of tumorigenesis are the DNA double-strand breaks which can be also formed through the activation of oncogenes which induce a state of abnormal proliferation resulting in a condition termed replication stress. These studies on pre-cancerous lesions and cancers have led to the proposal of a model for cancer development where the common features observed in most tumours have been integrated. Also, the significance of the Epithelial to Mesenchymal Transition (EMT) for carcinogenesis and tumour metastasis has been extensively investigated. Considering that uncontrolled cell growth or loss of a cell's ability to undergo cell death are among the major pathways being compromised during tumorigenesis several members of NKUA-CRG study the implication of certain cancer-related genes [e.g. Clusterin/Apolipoprotein J (CLU); an antisense target in phase II clinical trials for tumour therapy in the regulation of cell cycle and death, as well as autophagy regulation in higher eukaryotes. b. Identification and functional analysis of tumour biomarkers. Polyadenylate polymerase enzymatic activity has been proposed by NKUA-CRG members to represent a new independent prognostic marker in primary breast cancer, while several cancer related genes have been discovered and cloned. The expression of these genes was found to be related to development, progression and discrimination of various types of cancer (e.g. BCL2L12, CEAL1, DDC, Kallikreins) or to chemoresistance acquisition of human cancer cells (e.g. CLU, BCL2L12).

c. Cancer immunotherapy / Drug targeting of cancer-related signalling networks.

Studies by NKUA-CRG academic members have revealed that the immunoregulatory polypeptide prothymosin alpha (proTα) induces, both in animal tumour models and in humans, a significant anticancer cell-mediated response and have functionally characterized the various protein domains of the molecule. Moreover, via proteomic analysis it has been shown that proTα’s immune effect is exerted via toll-like receptor signaling. Also, dendritic cells which matured in the presence of the proTα-immunoactive peptide could efficiently stimulate antigen-specific T cell mediated immune responses in cancer bearing animals in vivo and in human lymphocytes in vitro. Towards the translation of NKUA-CRG’s basic research for patient benefit, members of NKUA-CRG, in collaboration with foreign research institutes, have exploited the small interference RNA technology for the targeting of cancer-related cytoprotective proteins (e.g. CLU); studied the anti-leukemic activity of novel compounds (e.g. 2,5-Dihydroxybenzoate Molybdenum-VI) and the immuno-modulating characteristics of labdabe diterpenes; characterized human HER-2/neu-derived peptide epitopes that can be recognized by cytotoxic NK-T lymphocytes and analyzed the immunomodulatory effects of phenoxodiol in vitro and in vivo. Also, fused xanthone derivatives have been studied as anti-proliferative anticancer agents, while the usage of extracts from the endemic plants of the Greek flora led to the isolation of natural compounds that could be used as nuclear receptor (ERα, ERβ, and PPAR) modulators. An important experience has been gained through the systematic study of different molecular scaffolds concerning their interaction with a variety of protein targets using molecular modelling calculations. Finally, a major achievement in the area of medicinal chemistry and natural compounds, was the discovery of a new natural compound (6-bromo indirubin) with strong and specific activity as an inhibitor of several kinases (e.g. Glucogen synthase kinase-3, aurora kinases B and C or cyclin-dependent kinases) involved in cancer-controlling signalling pathways; more than 200 chemically optimized derivatives have been developed from the original natural structure and four of these have been commercialized as pharmacological tools (by Merck, Calbiochem and Alexis).