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Altered oncogene expression in cancer cells causes loss of redox homeostasis resulting in oxidative DNA damage, e.g. 8-oxoguanine (8-oxoG), repaired by base excision repair (BER). PARP1 coordinates BER and relies on the upstream 8-oxoguanine-DNA glycosylase (OGG1) to recognise and excise 8-oxoG. Here we hypothesize that OGG1 may represent an attractive target to exploit reactive oxygen species (ROS) elevation in cancer. Although OGG1 depletion is well tolerated in non-transformed cells, we report here that OGG1 depletion obstructs A3 T-cell lymphoblastic acute leukemia growth in vitro and in vivo, validating OGG1 as a potential anti-cancer target. In line with this hypothesis, we show that OGG1 inhibitors (OGG1i) target a wide range of cancer cells, with a favourable therapeutic index compared to non-transformed cells. Mechanistically, OGG1i and shRNA depletion cause S-phase DNA damage, replication stress and proliferation arrest or cell death, representing a novel mechanistic approach to target cancer. This study adds OGG1 to the list of BER factors, e.g. PARP1, as potential targets for cancer treatment. ; S.R.P.'s laboratory is partially funded by funds from the Spanish National Research and Development Plan, Instituto de Salud Carlos III and FEDER [PI17/02303 to S.R.P]; R.T.R. is supported by a fellowship from the AECC scientific foundation; J.M.B. is supported by Spanish Ministry of Education, Culture and Sport [FPU15/01978]; J.B.'s laboratory is partially funded by FEDER funds, H2020 BRIDGES project and the Spanish Network on Rare Diseases (CIBERER) [FIS PI16/00440]; Faculty of Medicine at the Norwegian University of Science and Technology and the Central Norway Regional Health Authority supports [46056921 to A.S. and H.E.K.]; Svanhild and Arne Must's Fund for Medical Research (to A.S. and H.E.K.); Norwegian Research Council (to T.V.); SIN-TEF SEP project 102020885 (to T.V.); Vinnova (to A.C.K and P.S.); the Torsten and Ragnar Soderberg Foundation (to T.H.) and the Helleday Foundation (to C.B.). Funding for open access charge and project support: European Union's Horizon 2020 research and innovation programunder the Marie Sklodowska-Curie grant agreement [722729 to A.P., B.M.F.H., T.H.]; European Research Council [ERC TAROX-695376 to T.H.]; Swedish Research Council (to T.H. and P.S.); Swedish Cancer Society (to T.H. and P.S.); Swedish Children's Cancer Foundation (to T.H.); Swedish Pain Relief Foundation (to T.H.). ; Sí

xtracellular vesicles (EVs), such as exosomes and microvesicles, are released by different cell types and participate in physiological and pathophysiological processes. EVs mediate intercellular communication as cell-derived extracellular signalling organelles that transmit specific information from their cell of origin to their target cells. As a result of these properties, EVs of defined cell types may serve as novel tools for various therapeutic approaches, including (a) anti-tumour therapy, (b) pathogen vaccination, (c) immune-modulatory and regenerative therapies and (d) drug delivery. The translation of EVs into clinical therapies requires the categorization of EV-based therapeutics in compliance with existing regulatory frameworks. As the classification defines subsequent requirements for manufacturing, quality control and clinical investigation, it is of major importance to define whether EVs are considered the active drug components or primarily serve as drug delivery vehicles. For an effective and particularly safe translation of EV-based therapies into clinical practice, a high level of cooperation between researchers, clinicians and competent authorities is essential. In this position statement, basic and clinical scientists, as members of the International Society for Extracellular Vesicles (ISEV) and of the European Cooperation in Science and Technology (COST) program of the European Union, namely European Network on Microvesicles and Exosomes in Health and Disease (ME-HaD), summarize recent developments and the current knowledge of EV-based therapies. Aspects of safety and regulatory requirements that must be considered for pharmaceutical manufacturing and clinical application are highlighted. Production and quality control processes are discussed. Strategies to promote the therapeutic application of EVs in future clinical studies are addressed. ; The authors have not received any funding or benefits from industry to conduct this study. The authors acknowledge the european COST action for supporting the European Network on Microvesicles and Exosomes in Health and Disease (ME-HaD, BM1202, www.cost.eu/COST_Actions/BMBS/ Actions/BM1202) who funded publication of this work.