Scientific background

Biomarkers that are predictive and/or diagnostic of the Multi-Drug Resistant (MDR) phenotype ex ante have only been identified for a few tumours (Guestini, 2015; Crawley, 2015; Nymoen, 2015; De Mattia, 2015; Mirzaei, 2016; Bourguignon, 2016; He, 2017). Moreover, all previous therapies for MDR tumours have failed because of their poor specificity and high toxicity (Dlugosz, 2016; Lorendeau, 2017). Indeed, despite the multiple MDR-reversing strategies proposed in the past (Li, 2016), all approaches have failed because they have been focused on targeting the cell surface ABC transporters, without considering other biomarkers of the MDR phenotype as suitable targets; there are currently no chemotherapeutic drugs that are specifically tailored for MDR-cell CS inducers and that are designed in a biomarker-driven way.

STRATAGEM is relevant as our topics include:

1) comprehensive analysis of MDR signatures in solid tumours by integrating high throughput bioinformatic, genomic/transcriptomic and proteomic tools to analyse the data-resources that are available for large clinical cohorts

2) identification of diagnostic biomarkers of MDR tumours beyond the presence of ATP binding cassette (ABC) transporters. The project performs in-depth analyses to retrieve new biomarkers that are shared by MDR tumours of a variety of origins, in order to:

– build the first predictive/diagnostic algorithm for MDR tumours

– identify new therapeutic targets for MDR tumours

3) production of new therapeutic tools against MDR tumours. The identification of new

therapeutic targets drive the correct selection of new MDR-reversing agents, including both natural products and synthetic chemotherapeutic drugs that are tailored to specific MDR-cell targets

4) identification of compounds that, besides being tailored to MDR tumours, also possess

satisfactory pharmacokinetic and toxicological features, as identified by ADMET processes

5) maintaining the first platform for the personalized treatment of MDR solid tumours

Around 6,400 papers on chemoresistance have been published over the last 10 years. However, only 63 clinical trials on those topics have been registered over the same timeframe, and these have reported mixed results. This indicates that the diagnostic and therapeutic approach for MDR tumours still need improvement. This goal can only be achieved by combining the skills and competences within a multidisciplinary network. Indeed, the identification of biomarkers and the development of natural and synthetic compounds, with the relevant information on efficacy and safety being freely available, is best done via collaboration between experts in specific area who cooperate to pool results and expertise, as is facilitated by this COST Action.

The ongoing frequent and close communication in the framework of the research network, created in the course of the COST Action and the COST Innovators Grant is an excellent way to tackle the aforementioned challenges, as it provides coordinated access to resources and knowledge that catalyses the identification of novel targets for therapeutic intervention against MDR tumours. Exposure to this breadth of information and expert discussion on a regular basis enables European early-stage researchers (ESRs), in particular, to grow scientifically, to be trained by experts in the field, and to start innovative interdisciplinary collaborations. This need is being addressed with the creation of PANDORA COST Innovators Grant.