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

Christopher M Bailey; Yan Liu; Gong Peng; Huixia Zhang; Miao He; Duxin Sun; Pan Zheng; Yang Liu; Yin Wang

doi:10.1016/j.nano.2020.102278

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

Nanomedicine. 2020 Oct:29:102278. doi: 10.1016/j.nano.2020.102278. Epub 2020 Jul 30.

Authors

Christopher M Bailey¹, Yan Liu², Gong Peng³, Huixia Zhang⁴, Miao He⁴, Duxin Sun⁴, Pan Zheng⁵, Yang Liu⁶, Yin Wang⁷

Affiliations

¹ Division of Immunotherapy, Institute of Human Virology, Department of Surgery and Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD; Graduate Program in Molecular Medicine, The George Washington University School of Medicine and Health Sciences, Washington, D.C.
² Division of Immunotherapy, Institute of Human Virology, Department of Surgery and Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD.
³ Institute of Translational Medicine, The First Hospital, Jilin University, Changchun, China.
⁴ Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, MI.
⁵ Division of Immunotherapy, Institute of Human Virology, Department of Surgery and Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD; Oncoimmune, Inc., Rockville, MD.
⁶ Division of Immunotherapy, Institute of Human Virology, Department of Surgery and Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD; Oncoimmune, Inc., Rockville, MD. Electronic address: yaliu@ihv.umaryland.edu.
⁷ Division of Immunotherapy, Institute of Human Virology, Department of Surgery and Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD. Electronic address: yin.wang@ihv.umaryland.edu.

Abstract

Hypoxia-inducible factor 1α (HIF-1α) is recognized as a prime molecular target for metastatic cancer. However, no specific HIF-1α inhibitor has been approved for clinical use. Here, we demonstrated that in vivo efficacy of echinomycin in solid tumors with HIF-1α 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-1α transcriptional activity in primary and metastasized TNBC cells in vivo, the latter of which are HIF-1α enriched. The data suggest that nanoliposomal-echinomycin can provide safe and effective therapeutic HIF-1α inhibition and could represent the most potent HIF-1α inhibitor in prospective trials for metastatic cancer.

Keywords: Breast cancer; Echinomycin; HIF-1α; Liposome; Nanomedicine.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Line, Tumor
Echinomycin / chemistry
Echinomycin / pharmacology*
Female
Humans
Hypoxia-Inducible Factor 1, alpha Subunit / antagonists & inhibitors*
Hypoxia-Inducible Factor 1, alpha Subunit / genetics
Liposomes / chemistry
Liposomes / pharmacology*
Mice
Neoplasm Metastasis
Triple Negative Breast Neoplasms / drug therapy*
Triple Negative Breast Neoplasms / genetics
Triple Negative Breast Neoplasms / pathology
Xenograft Model Antitumor Assays

Substances

HIF1A protein, human
Hypoxia-Inducible Factor 1, alpha Subunit
Liposomes
Echinomycin

Abstract

Publication types

MeSH terms

Substances

Grants and funding