Triple-negative breast cancer (TNBC) accounts for approximately 15% of
breast cancer cases in the United States. TNBC has poorer overall prognosis relative to other molecular subtypes due to rapid onset of drug resistance to conventional
chemotherapies and increased risk of visceral
metastases.
Taxanes like
paclitaxel are standard
chemotherapies that stabilize microtubules, but their clinical efficacy is often limited by drug resistance and neurotoxicities. We evaluated the preclinical efficacy of a novel, potent, and orally bioavailable
tubulin inhibitor,
VERU-111, in TNBC models.
VERU-111 showed potent cytotoxicity against TNBC cell lines, inducing apoptosis and cell-cycle arrest in a concentration-dependent manner.
VERU-111 also efficiently inhibited colony formation, cell migration, and invasion. Orally administered
VERU-111 inhibited MDA-MB-231 xenograft growth in a dose-dependent manner, with similar efficacies to
paclitaxel, but without acute toxicity.
VERU-111 significantly reduced
metastases originating from the mammary fat pad into lung, liver, and kidney
metastasis in an experimental
metastasis model. Moreover,
VERU-111, but not
paclitaxel, suppressed growth of
luciferase-labeled,
taxane-resistant, patient-derived metastatic TNBC
tumors. In this model,
VERU-111 repressed growth of preestablished axillary
lymph node metastases and lung, bone, and liver
metastases at study endpoint, whereas
paclitaxel enhanced liver
metastases relative to vehicle controls. Collectively, these studies strongly suggest that
VERU-111 is not only a potent inhibitor of aggressive TNBC phenotypes, but it is also efficacious in a
taxane-resistant model of metastatic TNBC. Thus,
VERU-111 is a promising new generation of
tubulin inhibitor for the treatment of TNBC and may be effective in patients who progress on
taxanes.Results presented in this study demonstrate the efficacy of
VERU-111 in vivo and provide strong rationale for future development of
VERU-111 as an effective treatment for metastatic
breast cancer.