Cmet-27. Evaluation of Dynamin 2 (Dnm2) as a Therapeutic Target in Leptomeningeal Metastatic Disease

Abstract

Leptomeningeal metastasis (LM), a spread of cancer to the meninges and cerebrospinal fluid, carries extremely poor prognosis due to fast progression and no effective treatment. Given that LM mostly develops in specific types of cancer, notably melanoma, breast and lung cancer, it is likely that predisposition for LMD is shaped by specific genetic footprints and/or anti-cancer therapies. In this regard, it is interesting that among all breast cancers the triple-negative (i.e. estrogen and progesterone receptor-negative and HER2 overexpression-negative) breast cancer (TNBC) type develops a disproportionally high percentage of LM, accounting for the majority (~40%) of all breast cancer LM cases. TNBCs trace their origin to the genomic instability stemming from defects in DNA repair (notably homology-directed repair, HDR). We have recently shown that the efficiency of HDR depends on dynamin 2 (DNM2) best known for its role in endocytic protein trafficking. Higher DNM2 was associated with more efficient HDR and the resistance to DNA-crosslinking chemotherapy. Importantly, elevated DNM2 was associated with lower relapse-free survival and shorter times to relapse after chemotherapy only in TNBCs and not in other types of breast cancer. As DNM2 also fuels migration and invasion, the cells with high DNM2 are not only the most resistant to chemotherapy but also are the most mobile, and thus may represent the core population of LM. Here we test the inhibition of the DNM2-dependent endocytic trafficking as a potential therapeutic strategy to halt LM in TNBC. As a model of LM we use the human-in-mouse model of brain metastasis based on internal carotid injection of MDA-MB-231-BR3 cells, which we have shown to faithfully recapitulate human LM. We show that DNM2 knockdown delays metastatic spread to the brain and potentiates the effect of DNA-crosslinking chemotherapeutic cyclophosphamide, providing justification for further testing of DNM2 inhibitors for targeted therapy of LM.