Download TARGET: TUMOR MICROENVIRONMENT Study led by Ludwig

TARGET: TUMOR MICROENVIRONMENT
Study led by Ludwig collaborator Johanna Joyce at the Lausanne Branch probes
resistance to drugs that target a brain tumor’s microenvironment—and shows
how it might be overcome
A number of cancer therapies under development target not the malignant cells
themselves but the cells and biomolecules they hijack to survive and thrive. Until now,
however, it's been unclear whether a cancer's biochemical environment and cellular
support crew— collectively known as the tumor microenvironment—can develop
resistance to such drugs, much as cancer cells do to drugs that target them directly.
In a study led by Ludwig collaborator Johanna Joyce and published in Science,
researchers show that immune cells often found in the microenvironment can indeed
acquire resistance against single-drug therapies. They also identify several combination
therapies that might counter such resistance.
"Our study is among the first to show that acquired resistance in the microenvironment
does happen and how it happens," said Joyce, who recently moved from Memorial
Sloan Kettering Cancer Center in New York.
In their study, Joyce and her colleagues investigated acquired resistance in the tumor
microenvironment of glioblastoma, a particularly aggressive type of brain cancer.
A large proportion of the glioblastoma microenvironment is made up of white blood cells
known as macrophages that have been recruited by the tumor and produce factors that
support the growth of cancer cells. "The tumor cells recruit immune cells from inside and
outside the brain and then re-educate them to become tumor promoting," Joyce said.
A drug that blocks a critical receptor in macrophages known as CSF-1R can target
macrophages in the glioblastoma tumor microenvironment, which in turn helps kill tumor
cells. Joyce and her colleagues report in their paper that, after prolonged treatment, a
subset of the tumors in mice became resistant to the CSF-1R blocking drug. They
found, however, that when these drug-resistant tumor cells were transplanted into the
brains of healthy animals, they were once again responsive to the drug.
This indicated that the drug resistance stemmed not from the tumor cells themselves,
but from something in their microenvironment. That turned out to be a protein secreted
by macrophages called insulin-like growth factor-1 (IGF-1), which in turn activated a
signaling pathway in the cancer cells that is mediated by a protein named
phosphatidylinositol-3-kinase (PI3K).
Joyce and her team then examined whether the CSF-1R resistance might be overcome
if the treatment were combined with drugs that block IGF-1R or PI3K activity. "What we
wanted to do with these drugs was to break the lines of communication between tumor
cells and the macrophages in their microenvironment," Joyce said.
When the team tested their combination therapies on recurrent tumors in mice, they
found that the animals lived significantly longer.
"Our findings have important clinical relevance because CSF-1R therapies against
macrophages are being tested in clinical trials across a number of cancer types," Joyce
said. "We're also very interested in extending our work to look at whether we can disrupt
communications between glioblastoma cells and other immune cells in the tumor
microenvironment, and extend this to other brain malignancies."