Exploiting metabolic vulnerabilities in resilient tumors

LUCAS PONTEL

Barcelona

Exposición; Scientific seminar at Vall D?Hebron Institute of Oncology; 2022

Cancer cells originate from normal cells, which makes extremely challenging to find selective vulnerabilities that might be exploited in therapy. One long-established cancer-specific characteristic is metabolism, which is required to supply the energetic demands for uncontrolled growth. The same metabolic reactions that transform nutrients into energy and biomolecules can also produce surplus metabolites that could harm cancer cells. Some examples of such endogenous toxins are formaldehyde (FA) and reactive oxygen species (ROS) like lipid peroxides, which can trigger a form of cell death known as ferroptosis. Cancer cells need robust mechanisms to repeal these reactive metabolites, which might create cancer-specific vulnerabilities with therapeutic relevance. We have recently identified that the pathway that produces the antioxidant glutathione (GSH) is a metabolic vulnerability in acute lymphoblastic leukemia (ALL) and in tumours with mutations in the mechanisms that repair interstrand-crosslink DNA damage. In these tumors, GSH is required to limit the toxicity of lipid peroxides and of FA, creating selective dependencies that might be exploited in therapy. In this talk, I will discuss these recent findings from our lab, and will introduce a personalized approach to identify druggable vulnerabilities in hematopoietic cancer cells resilient to conventional therapies.