echinomycin and Neoplasm-Metastasis

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.

Topics: Animals; Cell Line, Tumor; Echinomycin; Female; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Liposomes; Mice; Neoplasm Metastasis; Triple Negative Breast Neoplasms; Xenograft Model Antitumor Assays

Twenty-eight evaluable patients with advanced or recurrent squamous-cell carcinoma of the cervix were treated with 1,500 micrograms/m2 of echinomycin every 4 weeks. All patients had prior chemotherapy. Two patients had partial responses (7% response, 95% confidence interval for response of 1 to 24%). The major toxicity was nausea and vomiting. Myelosuppression and other toxicity were modest. Echinomycin, at this dose and schedule, displays minimal activity in patients with squamous-cell carcinoma of the cervix who have had prior chemotherapy.

Topics: Adult; Aged; Carcinoma, Squamous Cell; Drug Evaluation; Echinomycin; Female; Humans; Middle Aged; Nausea; Neoplasm Metastasis; Neoplasm Recurrence, Local; Quinoxalines; Uterine Cervical Neoplasms