Targeting SYNthetic lethal interactions for new cancer treatments TRAINing network

Informations projet

SYNTRAIN

N° de convention de subvention: 722729

DOI

10.3030/722729

Projet clôturé

Date de signature de la CE 10 Août 2016

Date de début 1 Septembre 2016

Date de fin 30 Novembre 2020

Financé au titre de

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Coût total

€ 3 990 269,16

Contribution de l’UE

€ 3 990 269,16

Coordonné par

KOBENHAVNS UNIVERSITET
Denmark

Periodic Reporting for period 2 - SYNTRAIN (Targeting SYNthetic lethal interactions for new cancer treatments TRAINing network)

Période du rapport: 2018-09-01 au 2020-11-30

Résumé du contexte et des objectifs généraux du projet

Breast and ovarian cancer constitute serious health challenges in the EU, they are among the leading causes of death among women. There is a clear need to identify new improved breast and ovarian cancer therapeutic approaches. SYNTRAIN aims to innovate breast and ovarian cancer therapeutic options through new concepts originating in basic science settings within the laboratories of beneficiaries. The new concept was a multi-facetted synthetic lethal approach, which takes advantage of the inherent genetic instability of cancer cells. Most mutations acquired by cancer cells do not cause lethality, but the very same mutations may cause cell death when a second gene in a redundant pathway is inactivated. Thus, targeting a gene that is synthetic lethal together with a cancer-specific mutation will kill only cancer cells while sparing normal cells. Synthetic lethal approaches have been clinically pioneered by members of our consortium, by combining cancer-promoting mutations (e.g. in BRCA2) with inactivating combinations of DNA repair genes. We have used this approach as the scientific frame for our ETN consisting of 9 academic and 1 SME beneficiary as well as 4 partners. We aimed to identify synthetic lethal interactions and exploit them to innovate future breast and ovarian cancer treatments through compound screening and development. SYNTRAIN consists of world leading researchers with complementary knowledge in genome maintenance and stress response pathways, and a critical mass of expertise for providing an excellent training in screening methodologies, mechanistic investigations, and drug discovery. We offered a structured training program that exceeds the capacities of each individual member. We have now educated a future generation of cancer researchers with a high innovative capacity and skills that enhance their career prospects in both academia and industry. We have trained 15 young researchers in a structured, internationalized and intersectorial programme: i) in techniques preparing for a career in cancer research, ii) in complementary skills relevant for work in academia and the pharma industry and iii) to become creative and entrepreneurial, capable of bridging the gap between basic and applied research.

SYNTRAIN offered and carried out a comprehensive cross-European training program for 15 ESRs, which included intersectoral involvement with secondments to academic laboratories and companies. In spite of COVID-19 challenges, all training events were executed and fellows advanced towards their PhD degrees. The project has also been highly successful at the scientific level. Multiple publications are published and many more are under preparation to disseminate the important findings. Briefly, SYNTRAIN research has led to the identification of new druggable targets and pathways. These targets have been carefully investigated to uncover their potential as drug targets. Furthermore, compound discovery and development has also been an important part of SYNTRAIN leading to patents and patent submissions to exploit our discoveries. We expect to harvest the fruits of the hard collaborative work in the coming years as the projects continue in the network laboratories.

Travail effectué depuis le début du projet jusqu’à la fin de la période considérée dans le rapport et principaux résultats atteints jusqu’à présent

The SYNTRAIN network officially started September 1st, 2016. 15 fellows have worked in beneficiary laboratories in order to carry out the individual projects. The kickoff meeting was held in April 2017 in Copenhagen, which marked the joint initiation of research projects, and the project came to an end in November 2020. During the execution of these projects, we identified new molecular cancer targets, obtained understanding of their mechanism and function, and, importantly, also developed compounds to achieve the aim. The research has been carried out by the highly selected group of 15 talented young researchers. 3 Summer schools have been held for advanced training, and fellows have participated in major international conference with several already presenting their exciting work. During the period, the consortium has contributed to the international scientific community environment by organizing a symposium on “DNA repair and synthetic lethality in cancer” and latest, an international online conference on “Genomic Instability in Cancer: from tumour evolution to novel cures”.

Our network progressed very well in the first period scientifically, and has now advanced further through the final period with excellent outcomes and results. The following section describes the three research work packages and their outcomes. The first focused on identification of novel synthetic lethal interactions with DNA replication stress to identify proteins with potential to be relevant targets for cancer therapy. 8 tasks were outlined in this work package, all tasks are well completed. The second research work package aimed to obtain mechanistic insights regarding the biological roles of genes involved in synthetic lethal interactions with homologous recombination repair deficiencies and/or DNA replication stress. This work package entailed 13 tasks, all have seen remarkable progress. Finally, the last research work package aimed at identifying and testing chemical compounds with activity against biological targets involved in synthetic lethal interactions with homologous recombination repair deficiencies and/or DNA replication stress. There were 8 tasks, and compound screens were carried out with promising leads being established, also for tasks connected with projects advancing from the second work package. At this stage 17 publications have been accepted and published on fellow projects, and additional manuscripts are in revision and expected to be published in 2021 and 2022. Furthermore the consortium members have so far submitted two patent applications, of which one has been granted.

Progrès au-delà de l’état des connaissances et impact potentiel prévu (y compris l’impact socio-économique et les conséquences sociétales plus larges du projet jusqu’à présent)

Our work has largely followed the SYNTRAIN project objectives as planned. An amendment process was carried out after the midterm evaluation to ensure optimal match between projects and deliverables. Accordingly, we succeeded well in reaching the outlined deliverables. This means that we managed to identify new targets for cancer therapy (WP1), understand their function (WP2), and to have chemical probes developed (WP3). The potential to advance into clinical trials exists for several projects. Given the involvement of Pharma in our project (Merck), we exploit an easy path at the level of fruitful discussions on commercialization as well as in terms of seeking partners for such development of the most promising chemical probes.

Syntrain Consortium at kick off in Copenhagen_april 2017