#IDIBELLseminars: Functional Genomics for Cancer Drug Discovery and Modelling Therapy Response

We have an increasingly detailed understanding of the molecular alterations that occur across the diversity of human cancers. A challenging next step is to convert this wealth of descriptive information into new and better therapies for patients. My laboratory uses a range of functional genomics screening approaches and mechanistic studies to elucidate vulnerabilities operative in cancer cells that could be exploited therapeutically.

Combinations of anti-cancer drugs can overcome drug resistance and have potential to expand the range of treatments for patients. I will present large-scale screens in cancer cell lines to identify effective drug combinations. These studies are elucidating principles underpinning combinatorial drug activity and have identified specific drug combinations in defined molecular backgrounds. In addition, I will present studies to systematically investigate the genetic determinants of IFN-γ response in colorectal cancer cells using CRISPR-Cas9 screens and base editing mutagenesis. This reveals loss-of-function and gain-of-function mutations, including causal variants in hematological malignancies and mutations detected in patient’s refractory to immune checkpoint blockade. We functionally validate variants of uncertain significance in primary tumor organoids, where engineering missense mutations in JAK1 enhanced or reduced sensitivity to autologous tumor-reactive T cells. We identify more than 300 predicted missense mutations altering IFN-γ pathway activity, generating a valuable resource for interpreting gene variant function.

Hosted by Miguel Ángel Pujana – Breast Cancer Group

Mathew Garnett