ONCOgenic Receptor Network of Excellence and Training

Informazioni relative al progetto

ONCORNET

ID dell’accordo di sovvenzione: 641833

DOI

10.3030/641833

Progetto chiuso

Data della firma CE 16 Dicembre 2014

Data di avvio 1 Gennaio 2015

Data di completamento 31 Maggio 2019

Finanziato da

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Costo totale

€ 3 893 983,37

Contributo UE

€ 3 893 983,37

Coordinato da

STICHTING VU
Netherlands

Periodic Reporting for period 2 - ONCORNET (ONCOgenic Receptor Network of Excellence and Training)

Periodo di rendicontazione: 2017-01-01 al 2019-05-31

Sintesi del contesto e degli obiettivi generali del progetto

Cancer is a leading health concern. There is a need to fully understand the fundamental processes underlying development of cancer. There is increasing evidence that G protein-coupled receptors (GPCRs) and their associated signalling cascades are involved in both cancer progression and metastasis. As oncogenic GPCRs are likely to be amenable to manipulation via drugs they are ideal therapeutic targets. In ONCORNET (Oncogenic GPCR Network of Excellence and Training) we target two oncogenic GPCRs; the chemokine receptors CXCR4 and CXCR7. These are highly expressed in a range of tumours and yet their role in cancer progression is not well understood. Within ONCORNET we focus on unravelling how CXCR4 and CXCR7 are or can be modulated (small molecules, pepducins, nanobodies) and investigate the role of CXCR4 and CXCR7 in (oncogenic) signalling.

The key objective of this MSCA-ITN-ONCORNET initiative is to train 15 ESRs by offering an extensive multidisciplinary training programme to ensure that they can operate in today’s drug discovery programmes. This includes both research (e.g. drug discovery, proteomics, imaging, modelling) and transferable (e.g. entrepreneurship, writing, media training) skill sets – that is rarely offered at PhD level.

Lavoro eseguito dall’inizio del progetto fino alla fine del periodo coperto dalla relazione e principali risultati finora ottenuti

We have generated novel modulators targeting CXCR4 and CXCR7. A series of small molecules targeting CXCR4 have been generated, starting from virtual screening and a ligand-based design and pharmacophore model. For CXCR4 and CXCR7 synthesis strategies were devised to fluorescently or radiolabel CXCR4 and CXCR7 compounds. Differently formatted nanobodies targeting CXCR4 and CXCR7 were generated, which are currently being tested in various (oncogenic) signaling assays. Pepducins targeting CXCR4 were further characterized. To support and optimize the identification of selective CXCR4/CXCR7 modulators, binding modes of these compounds through molecular dynamic simulations and structure activity relationship models have been performed.

To unravel (onco)signalling by CXCR4 and CXCR7 different assays, sensors and cell lines were developed. To monitor expression and visualize trafficking of CXCR4 and CXCR7 distinct assays were set up using fluorescently labelled ligands and tagged and/or mutant receptors. BRET- or FRET-based sensors were generated to monitor G protein-(in)dependent signalling and ligand-induced conformational changes and to visualize homomers and heteromers. Novel and selective interaction partners for CXCR7 have been identified which are being further investigated.

Physiologically relevant cell systems were developed to study the CXCR4/CXCR7/CXCL12 axis in cancer. Different tumour cell lines were evaluated for expression of CXCR4/CXCR7 and effects of CXCL12, growth factors and GRK2. The CRISPR technology was used to generate CXCR4 or CXCR7 knock out cell lines to study their role in oncogenesis. Moreover, CXCR4 WHIM model systems to study its link with HPV infection and the role of CXCR4/CXCR7 in bone marrow microenvironments are under investigation.

Progressi oltre lo stato dell’arte e potenziale impatto previsto (incluso l’impatto socioeconomico e le implicazioni sociali più ampie del progetto fino ad ora)

Modulators developed in this consortium will be tested in the newly established in vitro signalling assays and potentially in the in vivo model systems. This will provide additional insight into a role of CXCR4 and/or CXCR7 in cancer. Impact of this network is expected in the last year of the network. Importantly, developed approaches within the ONCORNET programme can be extrapolated to other (oncogenic) GPCRs. With the training and courses to come students are able to personalise their career development plans based on their interests. Secondments planned will teach them if their interest is working with smaller or larger companies, start their own business and/or remain in research and development. Importantly, we are training ESRs to develop the next generation of multidisciplinary scientists with skills that are highly demanded by many of today’s employers in drug development industries.

ONCORNET Logo