Tmic-02. targeting carcinoma-astrocyte gap junctions in brain metastasis

We have recently demonstrated that brain metastatic breast and lung cancer cells assemble carcinoma–astrocyte gap junctions composed of connexin 43 (Cx43) to engage with the astrocyte gap-junctional network. We found that brain metastatic cancer cells use these channels to transfer the second messenger cGAMP to astrocytes, activating the STING pathway and production of inflammatory cytokines such as interferon-α (IFNα) and tumor necrosis factor (TNF). As paracrine signals, these factors activate the STAT1 and NF-B pathways in brain metastatic cells, thereby supporting tumor growth and chemoresistance. We employed the orally bioavailable modulators of gap junctions meclofenamate and tonabersat to break this paracrine loop to treat established brain metastasis in preclinical mouse models. A pilot study of meclofenamate in patients with recurrent brain metastasis from solid tumor primary cancers is currently underway. This trial, with target accrual of 25 patients, focuses on primary outcomes of feasibility and safety. Thus, this bench-to-bedside strategy has uncovered a key interaction between cancer and the brain parenchyma as well as a novel therapeutic approach to brain metastasis.
Source: Neuro-Oncology - Category: Cancer & Oncology Authors: Tags: TUMOR MICROENVIRONMENT Source Type: research