1. Mechanisms for the acquisition of the AR independent phenotype: We exploit our Genetically Engineered Mouse (GEM) prostate cancer models to identify mechanisms of progression and resistance to anti-AR therapies. Further, we have embarked ourselves in the ambitious endeavor of identifying synthetic lethal interactions with standard of care abiraterone and enzalutamide using genome-wide CRISPR/Cas9 screen. Also within this research topic we are invested in a basic research project aiming at elucidating the role of chromatin conformation change and epigenetic dysregulation in the acquisition of the lineage plasticity observed in patients that progress to androgen independent state with neuroendocrine features or squamous variants that no longer use AR signaling to sustain growth and differentiation.
2. Experimental therapeutics for high-risk prostate cancer. Predicting patients likely to respond to standard of care treatments as well as those inherently resistant is a major challenge in translational research and clinical oncology. Molecular profiling of drug-perturbed cancer models allows cross-species analysis to compare to human datasets in an attempt to identify molecular biomarkers of response and resistance as well as predict drugs that bet inhibit specific cancer drivers or vulnerabilities. Within our research line in experimental therapeutics we have initiated projects aiming at expanding this therapeutic use of such treatments in prostate patients even without evident homologous recombination or mismatch repair deficiencies. Hence we have on the one hand initiated a CRISPR/Cas9 screen for synthetic lethal interaction with Rucaparib, a novel PARP inhibitor, using in vivo and in vitro cancer models based on Pten;Kras or Pten:p53 alterations, and on the other hand, we are interest in investigating potential synergies between PARP inhibitors and drugs targeting master regulators of chromatin conformation.
3. Prostate cancer progression and metastasis. Following from the work developed during the postdoctoral stage of the Dr. Aytes, the group has since his establishment in IDIBELL in 2016, continued this research line, which aims at identifying functional drivers and dependencies in prostate cancer metastatic progression. We are particularly interested in the cross-talk between the regulatory program executed by this FOXM1-CENPF module and (i) the acquisition of the resistant phenotype to standard of care therapies, (ii) the emergence of increased cellular plasticity, neuroendocrine features and pluripotent characteristics, and (iiI) the potential actionability of this oncogenic program
