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Report

Teaser, summary, work performed and final results

Periodic Reporting for period 1 - SYNTRAIN (Targeting SYNthetic lethal interactions for new cancer treatments TRAINing network)

Teaser

Summary

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 identify new improved breast and ovarian cancer therapeutic approaches. To this end, we will pursue 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 will use this approach as the scientific frame for our ETN (SYNTRAIN) consisting of 9 academic and 1 SME beneficiary as well as 3 partners. We aim 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 will offer a structured training program that exceeds the capacities of each individual member. We will educate a future generation of cancer researchers with a high innovative capacity and skills that enhances their career prospects in both academia and industry. Our aims are to train young researchers: 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.

Work performed

The summary is part of the midterm report, which describes the work and progress within the SYNTRAIN network having officially started September 1st, 2016. 15 fellows are working in beneficiary laboratories in order to carry out the individual projects (see part B). The kickoff meeting was held in April 2017 in Copenhagen, which marked the joint initiation of research projects. 2 Summer schools have been held for advanced training, and fellows have participated in major international conference with several already presenting their exciting work. SYNTRAIN aims to innovate breast and ovarian cancer therapeutic options through new concepts originating in basic science settings within the laboratories of beneficiaries. With the execution of these projects we will identify new molecular cancer targets, obtain understanding of their mechanism and function, and importantly also develop compounds to achieve the aim. The research is carried out by the highly selected group that now consists of 15 talented young researchers. Our network has progressed very well through the first period scientifically. The following section describes the three research work packages:

WP1 - Identification of novel synthetic lethal interactions with DNA replication stress.
A major part of the network is to uncover 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 under way as will be further described in Part B section 1.2.

WP2 - Functional characterization of validated screen hits.
This work package aims 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 entails 13 tasks. Briefly, several projects are derived from either WP1, or, from more advanced projects already running in the host lab at SYNTRAIN start. The more advanced projects have seen remarkable progress. The more recently initiated WP1 associated tasks will -as expected- advance at more modest pace as lead targets need to be identified and validated first. Notably, the latter have also seen significant progress as will be further described in Part B section 1.2.

WP3 - Identification of chemical compounds targeting synthetic lethal interactions.
WP3 aims 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. WP3 consists of 8 tasks. This WP is a combination of advanced projects ready for compound screening (already advanced projects at network start in 2017), as well as projects advancing from WP1/WP2. Compound screens have already been carried out with promising leads being established, also for tasks connected with projects advancing from WP2. Thus, there is also good progress in this WP as will be further described in Part B section 1.2.

Final results

Our work follows the SYNTRAIN project objectives as planned. We thus expect to deliver at the level of the outlined deliverables. With the current level of progress, we expect 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.