Invited Lecture
The Mitochondria Protein VDAC1 as a Pan Target: from Concepts to Cancer Therapy

The outer mitochondrial membrane protein VDAC controls metabolic crosstalk between mitochondria and cytosol and functions in both cellular metabolism and mitochondria-mediated apoptosis. Given these roles of VDAC, we have developed VDAC1-based cancer therapies designed to disrupt metabolism and induce apoptosis. Having demonstrated that apoptosis induction is associated with VDAC1 oligomerization, we have developed small molecules triggering VDAC1 oligomerization and thus, apoptotic cell death.

Using specifically designed VDAC1-based cell-penetrating peptides, we targeted these anti-apoptotic proteins to prevent their pro-survival/anti-apoptotic activities. We demonstrated the ability of these peptides to abolish the cell’s abilities to bypass the apoptotic pathway. Moreover, these peptides promoted cell death in a panel of genetically characterized cell lines derived from different human cancers, yet spared non-cancerous cells. Furthermore, the peptides inhibited tumor growth by killing cancer cells in a mouse model of glioblastoma, the most aggressive brain cancer.

Finally, depletion of VDAC1 in glioblastoma reverses cancer-reprogrammed metabolism, leading to a multi-pronged attack on cancer hallmarks. This includes inhibiting cell proliferation, tumor growth, invasion, angiogenesis and cancer stem cell differentiation into non-replicating end-stage neuronal cells, thereby preventing tumor relapse. Simultaneously attacks all of these processes, VDAC1 depletion can replace several anti-cancer drugs separately targeting angiogenesis, proliferation or metabolism. This treatment overcomes tumor heterogeneity and recurrence, thus representing an innovative and potent therapeutic strategy.

These findings point to VDAC1 as standing at the crossroads between cell metabolism and apoptosis, thereby representing an emerging cancer drug target, as reflected in the therapeutic strategies for treating cancer described here.