A multidisciplinary approach to discover selective drugs targeting cancer stem cells: The role of potassium transport - MultiCaST
Targeting cancer stem cells (CSC), rather than cancer cells in general, is a novel and highly promising strategy for cancer treatment. The defining characteristics of CSC are self-renewal, propagation into heterogeneous lineages of cancer cells, and increased resistance to chemotherapy, thus, attacking the CSC should abolish a tumor's ability to recur or metastasize.
Recently, a natural potassium ionophore salinomycin was identified as one of a few available CSC-selective substances, but the precise mechanism of its selectivity remains elusive. Based on hypothesis that the potassium transport is an important process of CSC biology, the objective of the proposed research is to understand fundamental processes of CSC-resistance to therapy and to discover novel compounds with ion homeostasis-modulating properties to selectively target CSC.
Project methodology orchestrates research in three principle areas and their close interactions, covering synthesis and characterization of molecules (chemistry), assessment of their activity in biological models (biology, medicine) and computer-aided drug design (computational sciences). We will focus on salinomycin and a series of proprietary crown ether compounds, which will be optimized and developed.
Their efficacy/selectivity and influence on drug transporters P-gp- and/or ABCG2-mediated efflux of chemoterapeutics will be assessed, as well as the toxicity and in vivoactivity of the most promising compound. Deploying cutting-edge techniques in cell and molecular biology, bioimaging, molecular electrophysiology and transgenic cell lines (e.g. a unique CSC model – HMLEshEcad cells) we will strive to recognize novel biomarkers for identification and enrichment of CSC, related to abnormal potassium transport regulation that promote acquisition of CSC phenotype and/or influence their proliferation, death and migratory potential.
The ultimate aim is to translate this knowledge into innovative mechanism-based therapeutic approaches.
This project is a direct continuation of a fruitful collaboration between three RBI research groups covering three disciplines: biology/biomedicine, chemistry and computational sciences.
The main part of the experimental work on the project, covering compounds screening, mechanisms of compounds activity elucidation and signalling/biomarkers investigation will be performed in the Laboratory for Experimental Therapy, Division of Molecular Medicine (LET; DMM). LET has been studying the basic mechanisms underlying the tumor cell response to therapy (primarily the role of p21 protein in these processes), and, in collaboration with Computational Biology and Bioinformatics Group is continually developing an integrated platform of computational models aimed at screening and characterization of antitumor compounds in order to engender new leads of potential anticancer drugs. The members of LET involved in MultiCaST project:
LET has a long-lasting collaboration with the Laboratory for Synthetic Organic Chemistry (LSOC) at the Division of Organic Chemistry and Biochemistry (DOCB). We have been involved in study on the antitumor ability of crown ether compounds including computational structure activity relationships (QSAR), cell cycle disturbances and cell death studies. The following members of LSOC will be involved in synthesis and characterization of novel molecules and cation binding abilities of prepared compounds:
Computational Biology and Bioinformatics Group (CBBG, Division of Electronics, DE), will be involved in computational activities oriented towards acquiring all relevant publicly available data for the project and orchestrating/assembling them with experimental (in vitro) data of the project. Data will also be utilized to build insightful models (clustering, PCA, SOM techniques) for the discovery and confirmation of important mechanisms related to CSC-phenotype and QSAR models developed to predict crown ether anti-CSC activity and/or synergy with existing therapeutics. The CBBG mambers are: