Evolution of resistant clones to novel target-directed drugs in colorectal tumors. A genetic and epigenetic study of intratumoral heterogeneity dynamics
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.
INTRACOLOR is a genetic and epigenetic study of intratumoral heterogeneity dynamics in colorectal cancer (CRC). The research was run in parallel to Phase I/II MoTriColor trials (ID: 635342), which assessed a novel targeted strategy for mCRCm (MoTriColor study).
This framework was a unique opportunity to evaluate paired samples to identify molecular differences in primary vs metastatic samples and the acquisition of resistant clones. The study has allowed us to generate highly valuable preclinical models in mice (PDX– patient-derived xenografts) based on samples from patients treated in the MoTriColor study, based in immunotherapy plus antiangiogenic clinical combo therapy.
As a summary, 55 paired tissue samples were analysed and 13 PDX models were generated from samples directly obtained from these patients, which led us to the corresponding Clinical Trial Associated Xenograft (CTAX) models. After exhaustive analysis of evolutive disease outcomes, one of the main outputs was the discovery of new potentially targeted alterations for a molecular subpopulation of mCRC patients, including a fusion in NTRK oncogene, in addition to a hypermutant MSI genome profile.
The model showed response to NTRK inhibitors with mice presenting complete responses. Furthermore, the generated PDX/ CTAX models will be further used to identify new mechanisms of resistance and sensitivity to the proposed therapy in other prospective projects.
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This project has received funding from the European Union’s Horizon 2020 Research and Innovation Programme under grant agreement No. 964264.