banda transcan 2 2016ul

Title: Evolution of resistant clones to novel target-directed drugs in colorectal tumors. - A genetic and epigenetic study of intratumoral heterogeneity dynamics


Project Coordinator:
Josep TABERNERO CATURLA (Spain) Vall d'Hebron Institute of Oncology (VHIO), Barcelona


Project Partners:
Sabine TEJPAR (Belgium) Katholieke Universiteit Leuven. Leuven
Rene Bernards (Netherlands) The Netherlands Cancer Institute
Teresa TROIANI (Italy) Department of Experimental and Clinical Medicine and Surgery, Second University of Naples 
Andres CERVANTES (Spain) INCLIVA
Sabrina ARENA (Italy) Candiolo Cancer Institute IRCCS

Project Abstract:
The proposing research groups are part of the MoTriColor initiative recently funded by EU Commission (H2020). The central aim of such consortium is to evaluate the power of using distinctive gene expression subtypes to select patients to be treated with three different target-directed therapies: anti-PDL1 for MSI-like tumors, Vinorelbine for BRAFm-like tumors and TGFbeta inhibitors for Mesenchymal-like tumors. Samples at baseline and disease progression will be collected for all patients enrolled in each clinical trial. One of the major strengths of the present proposal is the access to all samples and clinical or molecular data from the prospective study structured in the MoTriColor initiative. Genetic evaluation of these paired samples will be a precious opportunity to identify the arising of resistant clones selected by each target therapy. Furthermore, a deep evaluation of the molecular heterogeneity present in the corresponding primary tumors will allow revealing how the resistance to specific targeted-therapies could already be codified in such original variegation and enriched along drug selection.
In addition, the generation of Patient-Derived Xenograft (PDX) models from selected patients at baseline and progression will allow testing the efficacy of new treatments to break the resistance driven by such arising clones.
Aims
1. Revealing the genetic and epigenetic nature of acquired resistance in advance CRC treated with target-directed drugs.
2. Describing the evolution of resistant clones with distinctive genetic alterations and gene expression profiles.
3. Testing the use of new single or combined treatments with drugs targeting those alterations present in arising resistant clones, in PDX models derived from patients that progressed to anti-PDL1, anti-BRAF or anti-TGFbeta drugs.
Hypotheses
1. Minor clones present in CRC tumors present mutations and a gene expression profile that confer resistance to particular target-directed drugs.
2. Describing the enrichment of such resistant clones will permit to define mechanisms of resistance acquired upon treatment.
3. The use of PDX derived from resistant tumors will allow evaluating the efficacy of novel drug combinations targeting those genetic and epigenetic alterations acquired along tumor evolution.
Impact:
The development of the proposed models thanks to our expertise in the field, together with the opportunity of using our patients’ samples will gives us an excellent chance to test novel drug combinations directed to target new molecular alterations responsible for drug resistance in colorectal cancer. As previously said, this will be the first time that the resistance to some therapies currently under development (with a great potential in the fight against colorectal cancer) will be tested in an academic ground. They will be evaluated directly in a clinical setting with the option of exploiting all the generated data in an academic setting. The outcomes may have an important impact.

(Project funded under JTC 2014)


TRANSCAN-2 News


Fourth Joint Transnational Call 2017 (JTC 2017)

on: Translational Research on Rare Cancers

12 projects selected for funding

visit the page

Newsletters

Newsletter 8, May 2019

Newsletter 7, October 2018
Newsletter 6, June 2108
Newsletter 5, March 2018
Newsletter 4, December 2017
Newsletter 3, September 2017
Newsletter 2, April 2017
Newsletter 1, December 2016

To subscribe to TRANSCAN-2 newsletter mailing list please send an email to: This email address is being protected from spambots. You need JavaScript enabled to view it.

eu flagship

This project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 643638.

Who's Online

We have 6 guests and no members online