These are drugs called BACE1 inhibitors, which are used to treat Alzheimer’s disease and work by inhibiting the protein called BACE1, responsible for producing β-amyloid plaques in the brain. However, after showing poor efficacy in clinical trials, the field of neuroscience has moved away from BACE1 inhibitors.
But it is known that this protein is also expressed in a class of immune cells, called tumor-associated macrophages (TAM), which are found in the tumor microenvironment or in the non-cancerous cell components of solid tumors.
And these types of cells are particularly abundant in glioblastoma, prompting this research team to question whether BACE1 inhibitors might be effective in treating or preventing the highly aggressive form of brain cancer.
“There are two main types of TAM,” explains Shideng Bao, who runs the Cancer Stem Cell Research Center».
‘Most TAMs promote tumors and contribute to resistance to treatment, but there are some that suppress them. If we can develop a treatment that manipulate this balance, tip the balance for more tumor suppressor TAMs, maybe we can better treat glioblastoma »
The researchers screened a wide range of compounds to identify the most promising candidates against tumor-promoting macrophages (pTAMs), and found a BACE1 inhibitor called MK-8931 (verubecestat) that, in a glioblastoma model, reprogrammed pTAMs in macrophages. tumor suppressors (sTAM).
As a result, the more abundant sTAMs helped destroy tumor cells, including glioma stem cells, which are a particularly aggressive type of cancer cell that can self-renew and repopulate a tumor.
‘We found that these changes significantly reduced tumor growth. The benefits were even more pronounced when verubecestat was given in combination with low-dose radiation, as this improves the infiltration of TAM into the tumor, ”adds Bao.
“Verubecestat had already been approved for use in its previous Alzheimer’s disease trials,” says Bao, “which would help speed up the translation of our promising preclinical findings. This is a major benefit of drug reuse – being able to bridge the gap between preclinical research and clinical testing, which can often be a lengthy process. ‘