Therapeutic potential of colchicine-binding site inhibitors in breast cancer brain metastasis.

Breast cancer brain metastasis (BCBM) represents one of the most aggressive and lethal complications of breast cancer, arising when malignant cells colonize the brain. Patients diagnosed with BCBM face a poor prognosis, with median survival times ranging from 2 to 25.3 months, and experience significantly reduced quality of life compared with those patients with extracranial metastases. Current therapeutic strategies, including surgical resection, whole-brain radiation therapy, and stereotactic radiosurgery, offer limited benefit and are rarely curative. Despite advances in breast cancer management, effective treatment for BCBM remains a major clinical challenge, primarily due to the restrictive nature of the blood-brain barrier (BBB), which hinders the delivery and accumulation of most chemotherapeutics within brain tissue. For example, paclitaxel, a widely used microtubule-targeting agent in breast cancer therapy, has limited efficacy against BCBM because it is a substrate of ATP-dependent efflux transporters, particularly P-glycoprotein, at the blood-brain barrier, with its physicochemical properties, such as high molecular weight, further restricting effective intracranial drug exposure. In contrast, emerging evidence suggests that colchicine-binding site inhibitors (CBSIs), a novel class of microtubule-targeting agents, possess the ability to penetrate the BBB, making them promising candidates for the treatment of BCBM. This review highlights recent advances in the development of CBSIs for BCBM and extends the discussion to their evaluation in other brain cancers, such as glioma. Furthermore, we examine strategies to enhance drug delivery across the BBB and to improve therapeutic selectivity toward cancer cells while sparing healthy brain tissue.