Venetoclax represents an effective therapy for several blood cancers including chronic lymphatic leukaemia (CLL) and acute myeloid leukaemia (AML). Unfortunately, venetoclax resistance remains a matter of concern. Combination therapies are considered to improve the activity of venetoclax to achieve deeper and more enduring responses in patients. Mechanistically, venetoclax inhibits the anti-apoptotic BCL-2 protein and induces mitochondrial outer membrane permeabilization (MOMP) leading to the release of cytochrome c, activation of the initiator caspase-9 (Casp9) and executioner caspase-3 and -7 (Casp3 and 7) ultimately causing apoptosis. It is however increasingly evident that caspases do not only induce apoptosis, but also interfere with cellular inflammatory signalling and coordinate the immune environment of the apoptotic cells. Furthermore, MOMP does not only lead to the release of cytochrome c, it also potentiates the release of other mitochondrial factors such as SMAC or mitochondrial DNA that interfere with cellular inflammatory signalling. Independently, lack of mitochondrial membrane integrity upon venetoclax treatment leads to mitochondrial dysfunction which may additionally impact on the cellular responses to therapeutic protocols involving venetoclax. 

The central objective of the current project is to investigate the role of caspase activation in response to venetoclax treatment and resistance mechanisms. The project involves a number of newly established mouse models to study the role of caspases in the pathogenesis of CLL in mice. We will use venetoclax to treat CLL mice and will investigate the efficacy of venetoclax, inflammatory signalling and tumour microenvironment in mice lacking caspase activity. By involving patient samples and using caspase inhibitors we will provide synergies between the data derived from mice and CLL patients together aiming to gain specific knowledge about the role of caspases in patients’ outcome after venetoclax treatment.

Molecular Immunology