Funding: European Commission

Program: CORBEL (Coordinated Research Infrastructures Building Enduring Life-science Services)

Start date - end date: 03/02/2017 – 31/08/2019

CORBEL (Coordinated Research Infrastructures Building Enduring Life-science Services) is an initiative of eleven new biological and medical research infrastructures (BMS RIs), which together will create a platform for harmonised user access to biological and medical technologies, biological samples and data services required by cutting-edge biomedical research. CORBEL will boost the efficiency, productivity and impact of European biomedical research.

Serrated adenocarcinoma (SAC) is a histological entity recently recognized by the WHO accounting for 7.5-8.7% of CRC which is characterized by its poor prognosis compared to conventional carcinoma (CC) and resistance to anti-EGFR treatment. The lack of a murine undisputed model for serrated carcinogenesis makes difficult the in vivo study of this tumor and the design of possible specific therapeutic agents. Similarly, CRC showing histological and molecular characteristics of microstatellite instability (hMSI-H), another end-point of the so-called serrated polyp pathway, apart from not showing benefit from 5-FU treatment, is generally resistant to anti-EGFR mAbs mainly because of its high frequency of BRAF mutation. Over the past eight years our group has been working in the clinical, histologic, immunohistologic, transcriptomic, methylomic and recenlty, microbiomic and miRNA characterization of SAC finding two interesting therapeutical targets (Fascin and FOXD2) Fascin is high expressed in SAC compared to CC and is involved in the actin cytoskeleton rearrangement that the tumoral cell needs to invade stroma, which can be evidenced at the invasive front by the development of tumor budding, a typical histological adverse prognostic factor. Moreover, fascin expression has been observed in breast and other carcinomas also associated with worse prognosis and migrastatin has showed inhibition effect on that protein. FOXD2 hypermethlation and lack of expression is associated with hMSI-H CRC and may function as a tumor suppresor gene in this subtype of CRC. Therefore, the objectives of this project are:

• Identify in silico probable fascin-inhibitors by compound library searching -In vitro screening of those chemical compounds selected from the previous objective
• To established the similarities of human SAC with a murine model for serrated carcinogenesis generated as described in previous reports
• Set up the in vivo conditions for future studies on drug testing in mouse that will required additional funding
• Characterize the effect of FOXD2 downregulation in the colorectal carcinoma murine models.

Area: Predictive systems pharmacology for safer drugs and chemical products

Web site: http://www.corbel-project.eu/1st-open-call.html (Cross Access Track)