Liposomal formulation of HIF-1α inhibitor echinomycin eliminates established metastases of triple-negative breast cancer

Hypoxia-inducible factor 1 alpha (HIF-1 alpha) is recognized as a prime molecular target for metastatic cancer. However, no specific HIF-1 alpha inhibitor has been approved for clinical use. Here, we demonstrated that in vivo efficacy of echinomycin in solid tumors with HIF-1 alpha overexpression is formulation-dependent. Compared to previously-used Cremophor-formulated echinomycin, which was toxic and ineffective in clinical trials, liposomal-echinomycin provides significantly more inhibition of primary tumor growth and only liposome-formulated echinomycin can eliminate established triple-negative breast cancer (TNBC) metastases, which are the leading cause of death from breast cancer, as available therapies remain minimally effective at this stage. Pharmacodynamic analyses reveal liposomal-echinomycin more potently inhibits HIF-1 alpha transcriptional activity in primary and metastasized TNBC cells in vivo, the latter of which are HIF-1 alpha enriched. The data suggest that nanoliposomal-echinomycin can provide safe and effective therapeutic HIF-1 alpha inhibition and could represent the most potent HIF-1 alpha inhibitor in prospective trials for metastatic cancer. (C) 2020 Elsevier Inc. All rights reserved.