Brain tumours subject to therapy can become resistant to it through interactions with their tumour microenvironment rather than because of anything intrinsic about the tumour itself, a new study in mice suggests.

The resistance mechanism outlined in the study involves a particular enzyme and can be overcome using other drugs that target this newly identified signalling pathway.

Glioblastoma multiforme (GBM) is a common and aggressive type of adult brain tumour; current standard treatment only minimally prolongs survival.

Macrophages, types of white blood cell that ingest debris, are found in abundance in GMB tumours, and tend to express high levels of colony stimulating factor-1 (CSF-1).

Here, Daniela Quail et al. showed that inhibiting CSF-1 with a drug called BLZ945 caused tumour regression in mice; however, the majority of GBM tumours ultimately developed resistance to BLZ945, a phenomenon of interest as cancer drugs targeting CSF-1 are currently in clinical trials in multiple settings.

Further investigation revealed that GMB recurrence correlated with elevated activity of a tumour enzyme called PI3-K, which was in turn driven by an environmental influence, macrophage-secreted IGF-1.

Mice that were treated with BLZ945 plus a PI3-K or IGF-1 inhibitor benefited from significantly longer survival than control mice, the researchers showed.

By implanting BLZ945-resistant tumours into naïve mice, Quail et al. demonstrated that GBM tumours use this this PI3-K/IGF-1 mechanism to manipulate the surrounding microenvironment to their advantage.

Thus, they say, tumours can also develop resistance through microenvironment-dependent mechanisms, independent of the tumour itself.

Whether the findings will translate to a human model of glioma remains to be seen.

Source: The American Association for the Advancement of Science