Restoring the Immune Response in Glioblastoma by Microglial-Targeting of Autophagy Inhibitors.

Glioblastoma is a highly aggressive type of brain cancer that kills around 15,000 people per year in Europe alone. It also has a devastating effect on patients' quality of life.

Therefore, the clinical need in glioblastoma management is one of the highest in oncology: effective treatments are dearly needed. Over the past decade, the brain tissue surrounding glioblastoma tumors has been intensively studied. In this so-called 'tumor microenvironment' (TME), microglial cells make up the bulk cell type.

Although immune cells by nature, TME microglial cells are reprogrammed to take on a tumor-supporting role: they become immunosuppressive and start secreting growth factors and nutrients that fuel tumor proliferation.

Autophagy, best known as a cellular recycling pathway, is a masterswitch that determines the immune status in microglial and other immune cells. It also supports the process of nutrient secretion in TME microglia.

Therefore, inhibition of microglial autophagy can be a viable strategy to restore the immune response against glioblastoma tumors. Strong preclinical evidence in favor of this approach is available.

However, translation into a new glioblastoma therapy is difficult, because the presence of autophagy inhibitors in the brain could also be dangerous to neurons.

In response, this proposal wants to deliver and investigate autophagy inhibitors that selectively target brain microglial cells. A vectorizing approach is proposed for ULK1/2 inhibitors and PROTACS, which are very potent autophagy inhibitors. The proposal will thorougly investigate the compounds in vitro and in cellulo.

For selected, highly promising molecules, in vivo proof of concept will be sought in a murine, orthotopic glioblastoma model.

Next to obtaining selective and effective microglial autophagy inhibitors, the design of metabolically stable compounds with sufficient bioavailability in brain can be expected to be additional, prime challenges of the project.