APOSWITCH

Programmed cell death, or apoptosis, is essential for tissue health, eliminating damaged or unnecessary cells. When this process is disrupted, severe diseases arise: insufficient apoptosis enables cancer cell survival, whereas excessive apoptosis contributes to tissue loss in stroke, heart failure, and neurodegenerative disorders. Precisely controlling cell death is therefore a major challenge and opportunity for modern medicine. Current therapeutic strategies largely rely on blocking repressors of apoptosis, thereby unleashing the final executioners of cell death, BAX and BAK. While this approach has shown clinical efficacy in some cancers, responses are frequently transient, with resistance emerging within months, underscoring the urgent need for novel therapeutic strategies.

Recent studies have identified a mitochondrial protein, VDAC2, as a key regulator of apoptotic commitment. By controlling the activation of BAX and BAK at the mitochondrial membrane, VDAC2 determines whether cells survive or die. Targeting this regulatory node offers the potential to fine-tune apoptotic sensitivity with reduced side effects. Proof-of-concept studies show that compounds acting on this pathway can either protect tissues from excessive cell loss or sensitize cancer cells to existing treatments. However, clinical translation has stalled because these compounds were identified empirically in mouse systems and lack molecular understanding, with some failing to act on the human protein.

This PhD project aims to overcome these limitations by combining structural biology, biophysics, and cellular assays to develop new molecules that target VDAC2 and control the apoptotic switch. We will compare mouse and human systems to explain species-specific drug responses, and leverage high-resolution structures to adapt existing compounds for activity on the human VDAC2-BAX/BAK complex. In parallel, we will establish a new in vitro and in cellulo screening assay to directly measure VDAC2:BAX/BAK interactions and enable the identification and prioritization of new drug candidates, which will be tested in clinically relevant patient-derived samples. By delivering the first mechanistic framework to enable structure-guided targeting of this apoptotic control point, the project aims to open the way to a new class of therapies capable of either protecting tissues from degeneration or restoring cell death in cancer.