LMD is a devastating diagnosis for patients with TNBC. Given the universally poor prognosis and limited efficacy of standard-of-care treatments, the investigation of alternative therapies for LMD carries increased importance. Drug repurposing confers obvious advantages in time-to-approval, cost, and safety. We identified MBZ as a drug that through its ability to hamper dissemination of highly migratory TNBC cells may, therefore, be a suitable candidate for LMD treatment.
MBZ was developed in the 1960s to treat a range of gastrointestinal helminth infections, and it is still one of the most commonly used medications in the world. MBZ safety has been evaluated in 6276 subjects in 39 clinical trials [18]; it can be taken safely in humans at doses as high as 200 mg/kg/day [18, 41, 42] and in rare cases, has been used in humans to treat CNS infections, including neurocysticercosis and echinococcus [17, 43, 44]. Indeed, its relatively small size and lipophilic properties render it an appropriate agent to be repurposed for CNS pathologies [10, 13, 20].
MBZ was successfully tested in multiple preclinical tumor models, including glioma [11, 13, 45] and TNBC [14, 38]. Several active and/or recruiting clinical trials investigating the anticancer effect of MBZ, alone or in combination with other drugs, are currently registered at clinicaltrials.gov [18, 19]. This includes the recent Phase I study conducted by Patil et al. exploring the safety of high-dose MBZ among patients with recurrent glioblastoma [19]. In 11 patients, no dose-limiting toxicity was reached, and the rate of adverse events was low, even when used in combination with temozolomide or lomustine. Other studies, including those involving high-grade glioma, are actively enrolling patients.
Our study is the first effort to test the efficacy of the drug in the treatment of CNS metastasis. We were able to demonstrate that the oral administration of MBZ, at both 50 mg/kg and 100 mg/kg doses, was able to slow tumor growth and increase survival in an aggressive preclinical model of TNBC LMD. Importantly, our dosing protocol, in which mice voluntarily consumed MBZ in a mix of sesame oil and honey, reached therapeutic concentrations in the CSF. The median CSF concentration was 106 ng/mL for animals treated at the 100 mg/kg dose, which was almost twice the IC50 of 56 ng/mL. While CSF concentrations at the 50 mg/kg dose were not measured, animals treated at that concentration still experienced slower tumor growth and increased median survival, both at statistically significant levels, suggesting a robust therapeutic effect.
Bai et al. [13] reported the variability in the efficacy of MBZ across different batches, emphasizing its dependence on the polymorph content. Furthermore, bioavailability and efficacy of MBZ are known to be influenced by intake of fat, which strongly facilitates benzimidazole absorption [46]. These findings suggest that these factors alone could introduce substantial variability in drug efficacy across studies and potentially impact the outcome of clinical trials. Therefore, the dependence of MBZ bioavailability on the drug administration protocol (particularly, fat content) and dosage formulation should be taken into account. For instance, in our study MBZ consisted of highly bioavailable polymorphs B and C, which are optimal for maximum efficacy. Yet, the plasma levels of MBZ in our study, albeit therapeutically significant, were notably lower than those reported by Bai et al. [13]. The observed disparity in plasma MBZ levels compared to the reference study [13] may have resulted from significantly lower fat uptake per MBZ dose in our case.
Our data suggest that MBZ targets cancers with high migratory capacity, and may be particularly effective when these cancers spread into leptomeningeal space, where cancer cell migration could be further enhanced in response to abundant cytokine/chemokine signaling [47]. We’ve shown that among breast cancer subtypes, the TNBCs had the highest migration potential. Consistent with the strong inhibitory effect of MBZ on migration of TNBC MDA-MB-231-BR cells, MBZ extended survival of TNBC LMD mice. The non-migratory luminal A MCF7-BR cells produced less aggressive LMD, and were non-responsive to MBZ both in in vitro migration assay and in in vivo LMD model.