Biomarkers and Combinatorial Drug Targets for a Personalized Therapy in Colorectal Cancer

Abstract

The hypothesis of the present thesis is that the presence or absence of some chromatin factors may facilitate or impair the action of chemotherapeutic drugs in colorectal cancer (CRC). Chromatin factors have been proven to modulate DNA structure; they can contribute to an open chromatin, more accessible, or favor chromatin compaction, thus, a more repressed state of DNA. For this reason, they might be playing a role on how chemotherapeutic agents, which in CRC are mainly DNA damaging agents, can access DNA. In this regard, facilitators could have synergistic effects with chemotherapy whereas “obstructors” could promote chemoresistance.

Therefore, the global aim of this thesis was to identify chromatin factors that could represent novel therapeutic targets for the treatment of advanced CRC by synergizing with chemotherapy, to prevent resistance to treatment, which is often the cause of deficient therapies.

To achieve this goal, the specific aims of this thesis were:

1. To perform a pool approach loss-of-function screen using an improved retroviral library of more than 7.300 shRNAs against 912 epigenetic and chromatin factors in the presence of two chemotherapeutic approaches given in the clinics for advanced CRC (FOLFOX and FOLFIRI).

2. To individually validate chromatin factors that could sensitize or impair chemotherapy action.

3. Study the mechanisms of action of selected genes in terms of chemotherapy synergistic or antagonistic effects by in vitro functional assays.

4. To explore the biomarker significance, in terms of predictive value for response to treatment, for top hit genes identified in the screen.