Undoubtedly, the development and implementation of novel therapeutic agents is one of the predominant factors behind the increase in life expectancy observed in patients with cancer. For example the use of immunotherapies that recently entered clinical practice has almost doubled the survival of patients with cancer compared to 40 years ago, and facilitated an increase in patient survival expectancy to >10 years from the point of diagnosis. Therefore, investing in drug discovery has clear benefits for patient treatment and outcomes. The review articles in the current thematic issue of Molecular Oncology on ‘Drug discovery for cancer therapy’ present guidelines for the development of cancer therapies and pave the way for future research on drug discovery.
For instance, Kirsten McAulay and colleagues highlight considerations to take into account when opting for fragment-based drug discovery (FBDD) such as candidate diversity and desirable lead properties for rapid development. Jordan Wilson and Joanna Loizou offer a panoply of approaches for the use of CRISPR-based genetic screens in order to elucidate novel gene-gene interactions that can be disrupted pharmacologically for the purpose of cancer treatment, with a focus on DNA repair inhibitors. Rudd and Helleday review inhibitors that target enzymes in dNTP metabolism, with a focus on the enzymes MTH1, MTHFD2 and SAMHD1. They also urge that additional research is needed to investigate the mechanism of action of each inhibitor in order to limit toxicity and resistance mechanisms. Lord et al. complement the previous article by outlining mechanisms that may lead to resistance to DNA repair inhibitors (such as PARP, ATR, PolΘ or WRN) and describe mutations which would render patients unresponsive to those.
Contrary to genotoxic chemotherapy, another route to cancer therapy aimed at eradicating senescent cells from the body employs the use of agents that promote senescence of rapidly replicating cells coupled with a second round of treatment with a senolytic drug, (‘one-two punch approach’). Laura Bousset and Jesus Gil summarise our current understanding of how senolytic drugs could complement anticancer therapies and how monitoring senescence in cancer patients can serve as a proxy for assessing the efficacy of the ‘one-two punch approach’. Giulio Donati and Bruno Amati condense efforts from the field to limit c-Myc activity by targeting c-Myc interaction with MAX or modulating c-Myc transcription via BRD inhibitors. In addition, authors discuss other approaches for targeting the downstream events induced by c-Myc activation such as interfering with DNA damage response dependencies or mitochondrial activity.
The development of bioinformatics tools used for drug discovery is constantly on the rise with new software emerging more rapidly than its integration in the clinic, thus highlighting the need for software standardisation. Fátima Al-Shahrour et al describe an array of bioinformatic tools that can facilitate phylogenetic reconstruction of cancer cells and their site of origin, inferring a drug’s mechanism of action or stratifying patients for precision oncology treatment.
A comprehensive summary of the Review articles included can be found in the Editorial written by Matilde Murga and Oscar Fernandez-Capetillo or to find the individual articles read the Thematic Issue in full: https://febs.onlinelibrary.wiley.com/toc/18780261/2022/16/21