Identification of Novel Agents for the Treatment of Brain Metastases of Breast Cancer

Abstract

Background Brain cancer from metastasized breast cancer has a high mortality rate in women. The treatment of lesions is hampered in large part by the blood-brain barrier (BBB), which prevents adequate distribution of anti-cancer compounds to brain metastases. Method In this study we used a novel screening method to identify candidate molecules that are well-suited to utilizing the BBB choline transporter for distribution into the brain parenchyma. Results From our screen we identified two compounds, Ch-1 and Ch-2 that were able to reduce the brain tumor burden in a murine mouse model of brain metastasis of breast cancer. These compounds also significantly increased the survival of mice by more than 10 days. Mechanistic studies indicated that Ch-1 is able to prevent the activation of the pro-survival mitogen-activated kinases (MAPKs) by osteoactivin (OA; Glycoprotein nonmetastatic melanoma protein B GPNMB). Conclusion The results from this study show that nutrient transporter virtual screening is a viable novel alternative to traditional drug screening programs to identify anti-cancer compounds for the treatment of brain cancers.

Glembatumumab vedotin for patients with metastatic, gpNMB overexpressing, triple-negative breast cancer (“METRIC”): a randomized multicenter study

“…Strategies for future research of GV could focus on a subset of patients with gpNMB-overexpressing advanced TNBC who have either previously responded to a taxane or have had minimal exposure to a taxane-containing regimen. In addition, in light of data suggesting that ADCs can cross the blood–brain barrier owing to disruption of the vasculature by malignant processes 14 , 30 , 31 , and the possible role of gpNMB in the development of brain metastases 32 , there may be an opportunity for GV to address the large unmet need for patients with breast cancer brain metastases.…”