The brain metastases due to breast cancer could be fought by a potential combination therapy: a study of Ludwig Cancer Research who has identified and validated preclinically the therapy in question that has how target tumor-associated macrophages and microglia (TAM), immune cells found within brain metastases that cancer cells can manipulate to support their growth and survival.
There Research was published in the scientific journal Nature Cancer.
Breast Cancer Brain Metastases: How the Combined Treatments of the New Therapy Work
The study, carried out by Johanna Joyce and Florian Klemm of Ludwig Lausanne, together with Lisa Sevenich of the Georg-Speyer-Haus Institute for Tumor Biology and Experimental Therapy, in Frankfurt, showed that a therapy aimed at TAM – which inhibits a signaling called CSF1R— is initially effective but ultimately promotes an adaptive resistance mechanism in immune cells.
That mechanism, which activates an alternative signaling pathway in TAMs focused on a secreted protein factor called CSF2 and a protein that helps transmit its signals, STAT5, revives tumor growth by promoting the expression of genes involved in inflammation and in wound repair. Researchers show that blocking this signaling pathway in concert with inhibition of CSF1R significantly extends survival in mouse models of breast-brain metastasis.
“There is an urgent and unmet need for effective treatments for brain metastases“Said Joyce, a member of the Ludwig Institute for Cancer Research, Lausanne. “Current therapies can alleviate some of the side effects of these cancers, but they do not appreciably extend the lives of patients. Our study identifies a rationally devised combination therapy that activates an antitumor immune response and simultaneously undermines a resistance mechanism that, we have now shown, can develop in response to initial therapy, inhibition of CSF1R“.
Joyce’s lab previously explored the targeting of TAMs associated with primary brain tumors, in particular gliomas, using CSF1R inhibitors, whose activity is essential for cells. These studies demonstrated that inhibition of CSF1R significantly prolongs survival in preclinical mouse models of these tumors.
Notably, Joyce’s team found that the treatment did not result in the death of the TAMs in these mouse models, but rather their “re-education“In antitumor immunity agents. The same CSF1R inhibitor (BLZ945) that Joyce’s lab used in its preclinical studies is currently being evaluated in an early-stage clinical trial in patients with a range of solid tumors, including glioblastomas.
Joyce, Klemm, Sevenich and colleagues wanted to examine whether the CSF1R inhibitor would have a similar effect on TAMs in breast and brain cancer metastases, and to obtain key insights from preclinical studies on how treatment might unfold in the long-term in patients.
The researchers explained that the treatment with the CSF1R inhibitor, BLZ945, initially reduces the proliferation of brain metastases from breast cancer, follows a stalemate in their growth for several weeks, and induces some regressions of brain tumors established in mouse models. However, the inhibition of CSF1R resulted in the killing of all but a subset of TAMs, not their re-education into an effective anticancer immune body, as was the case in gliomas.
Long-term, the treatment also triggered adaptive changes in the TAMs that drive inflammation and cause damage to the neural tissue around the brain metastases.
Subsequent analysis revealed that TAMs had compensated for blocking CSF1R signaling by engaging an alternative signaling axis activated by the relative CSF2 receptor (CSF2R) and mediated by STAT5 within the cells. The researchers found that combining BLZ945 with a STAT5 signaling inhibitor (or anti-CSF2 antibody) durably blocked the growth of breast cancer brain metastases in the mouse model. STAT5 inhibition also stopped inflammation and reversed nerve damage associated with CSF1R inhibition in these metastatic tumors. It also reprogrammed the TAMs into an anticancer state.
“Our results reveal the potential risk of triggering pro-inflammatory responses in brain metastases following CSF1R inhibition and suggest a compelling strategy to overcome this adaptive resistance mechanism,” Joyce said.
“These findings have important translational implications for efforts aimed at modify the immune microenvironment of brain tumors for therapy, showing how important it is to have a detailed understanding of the unique landscape of each tumor type in developing these rational combined treatment strategies “, concluded the scientist.