Repositioning chloroquine and metformin to eliminate cancer stem cell traits in pre-malignant lesions |
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Authors: | Alejandro Vazquez-Martin Eugeni López-Bonetc Sílvia Cufí Cristina Oliveras-Ferraros Sonia Del Barco Begoña Martin-Castillo Javier A. Menendez |
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Affiliation: | 1. Unit of Translational Research, Catalan Institute of Oncology-Girona (ICO-Girona), Avenida de Francia s/n, E-17007 Girona, Catalonia, Spain;2. Girona Biomedical Research Institute (IdIBGi), Avenida de Francia s/n, E-17007 Girona, Catalonia, Spain;3. Department of Anatomical Pathology, Dr. Josep Trueta University Hospital, Avenida de Francia s/n, E-17007 Girona, Catalonia, Spain;4. Medical Oncology, Catalan Institute of Oncology-Girona (ICO-Girona), Avenida de Francia s/n, E-17007 Girona, Catalonia, Spain;5. Unit of Clinical Research, Catalan Institute of Oncology-Girona (ICO-Girona), Avenida de Francia s/n, E-17007 Girona, Catalonia, Spain |
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Abstract: | Ideal oncology drugs would be curative after a short treatment course if they could eliminate epithelium-originated carcinomas at their non-invasive, pre-malignant stages. Such ideal molecules, which are expected to molecularly abrogate all the instrumental mechanisms acquired by migrating cancer stem cells (CSCs) to by-pass tumour suppressor barriers, might already exist. We here illustrate how system biology strategies for repositioning existing FDA-approved drugs may accelerate our therapeutic capacity to eliminate CSC traits in pre-invasive intraepithelial neoplasias. First, we describe a signalling network signature that overrides bioenergetics stress- and oncogene-induced senescence (OIS) phenomena in CSCs residing at pre-invasive lesions. Second, we functionally map the anti-malarial chloroquine and the anti-diabetic metformin (“old drugs”) to their recently recognized CSC targets (“new uses”) within the network. By discussing the preclinical efficacy of chloroquine and metformin to inhibiting the genesis and self-renewal of CSCs we finally underscore the expected translational impact of the “old drugs–new uses” repurposing strategy to open a new CSC-targeted chemoprevention era. |
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