Vall d'Hebron Talks by VHIR 'Approaching Precision Medicine in Endometrial Cancer. Identification of Selective Dependencies in Endometrial Cancer by Genome-wide CRISPR Screens using Organoids in DepMap'

Speaker: Beatriz Villafranca Magdalena, Biomedical research in gynecology (VHIR)

Endometrial cancer (EC) is the most common gynecological cancer in developed countries. Mortality rates in patients with high-risk and recurrent EC are elevated due to limited treatment options and the high chemoresistance of the tumors. The Cancer Dependency Map (DepMap) initiative aims to dramatically accelerate precision cancer medicine by systematically identifying the landscape of cancer vulnerabilities across all tumors. In this study, our goal is to identify selective dependencies in EC by genome-wide CRISPR screens using high-risk patient-derived organoid models.  

For this, we selected five high-risk patient-derived endometrial cancer organoid models to perform genome-wide CRISPR viability screens. We develop methods to perform these screens using a Cas12a based library with 4 sgRNAs targeting the same genes with 2 sgRNA per construct for a total of ~20,000 genes. One of the four models screened, a uterine carcinosarcoma, was integrated with all the other screens in DepMap to identify selective dependencies. Among the identified dependencies, we selected two for which drugs are available in clinical trials, to perform drug sensitivity profiling in a larger panel of EC and non-EC organoid models.  The preliminary results of the target inhibitors tested in our model seem to be promising, validating the CRISPR screen and identifying a new potential therapeutic target.

Ultimately, thanks to the inclusion of additional endometrial cancer screens, we expect to identify additional selective hits in endometrial models and enrich the landscape of potential druggable targets for endometrial cancer, approaching precision medicine of this disease.

Host: Dr. Eva Colas Ortega, Head of group Biomedical Research in Gynaecology (VHIR)