Please cite this article in press as: Bizzarri, M. et al. Drug Discovery Today  Volume 00, Number 00  February 2020 REVIEWS Redifferentiation therapeutic strategies in cancer Mariano Bizzarri Q2 1 ,2 , Alessandro Giuliani 3 , Alessandra Cucina 4,5 and Mirko Minini 1,4 1 Department of Experimental Medicine, Sapienza University of Rome, 00161 Rome, Italy Q3 2 Systems Biology Group Lab, Sapienza University, Rome, Italy 3 Istituto Superiore di Sanità, 00161 Rome, Italy 4 Department of Surgery ‘Pietro Valdoni’ , Sapienza University of Rome, 00161 Rome, Italy 5 Azienda Policlinico Umberto I, 00161 Rome, Italy The widely recognized problems of pharmacological strategies based on killing cancer cells demand a rethink of therapeutic approaches. Tumor reversion strategies that aim to shift cancer cells to a healthy differentiated state are a promising alternative. Although many studies have firmly demonstrated the possibility of reverting cancer to a normal differentiated state, we are still unable (with the exception of retinoic acid in a form of leukemia) to revert cancer cells to a stable differentiated healthy state. Here, we review the main biological bases of redifferentiation strategies and provide a description of the most promising research avenues. Introduction: crucial issues of anticancer treatments Concerns about the effica Q4 cy of solid cancer treatments are on the increase, given that the clinical benefits achieved over the past 30 years through pharmacological interventions, notwith- standing recent attempts to establish a ‘personalized’ target- based approach, are both limited and controversial [1]. Indeed, both industry and oncologists frequently overestimate the ben- efit of new treatments [2]. In principle, the current therapeutic strategy aims to promote cancer cell death through direct and indirect mechanisms, by launching an all-out attack against cancer cells, as exhorted by the National Cancer Institute’s War on Cancer in 1971. Yet, this approach suffers from intrinsic, insurmountable limits: (i) conventional treatments cannot selectively target cancer cells and spare normal cells, despite intensive research conducted to identify specific and selective targets; and (ii) tumors display an astonishing genomic heterogeneity, which is subject further to endless changes across time and is under pressure from external stimuli, thus preventing the identification of true, ‘causative’, genomic targets [3]. Therefore, we have to ask whether treatment models based mainly on cancer cell killing represent the only feasible approach. In other words, could other strategies be planned? Over the past few decades, an alternative approach aiming to manage cancer by promoting the differentiation of malignant, highly dedifferentiated tumor cells, thus provoking ‘tumor reversion’, has been gaining momentum [4]. Tumor reversion is an old concept, first suggested at the beginning of the 1960s [5]. The first report describing the phenomenon of tumor reversion can be traced back to 1907. This study referred to an ovary teratoma evolving spontaneously through differentiation toward a normal epithelial phenotype [6]. Similar findings have also been recorded in plants, fish, and other organisms. These studies demon- strated that, when tumor cells are placed within a ‘normal’ morpho- genetic milieu, they can not only be ‘reprogrammed’, thus acquiring de novo a healthy phenotype, but can also be incorporated into a complex organism, behaving like native cells. Further research in- vestigated the relation between tumor reversion and chromo- somal abnormalities, gene mutations, and gene alterations in their genetic regulatory networks (GNRs), confirming that the Reviews  GENE TO SCREEN Corresponding author: Bizzarri, M. (mariano.bizzarri@uniroma1.it) 1359-6446/ã 2020 Published by Elsevier Ltd. https://doi.org/10.1016/j.drudis.2020.01.021 www.drugdiscoverytoday.com 1