Enhancing Brain Retention of a KIF11 Inhibitor Significantly Improves its Efficacy in a Mouse Model of Glioblastoma.

Glioblastoma, the most lethal primary brain cancer, is extremely proliferative and invasive. Tumor cells at tumor/brain-interface often exist behind a functionally intact blood-brain barrier (BBB), and so are shielded from exposure to therapeutic drug concentrations. An ideal glioblastoma treatment needs to engage targets that drive proliferation as well as invasion, with brain penetrant therapies. One such target is the mitotic kinesin KIF11, which can be inhibited with ispinesib, a potent molecularly-targeted drug. Although, achieving durable brain exposures of ispinesib is critical for adequate tumor cell engagement during mitosis, when tumor cells are vulnerable, for efficacy. Our results demonstrate that the delivery of ispinesib is restricted by P-gp and Bcrp efflux at BBB. Thereby, ispinesib distribution is heterogeneous with concentrations substantially lower in invasive tumor rim (intact BBB) compared to glioblastoma core (disrupted BBB). We further find that elacridar-a P-gp and Bcrp inhibitor-improves brain accumulation of ispinesib, resulting in remarkably reduced tumor growth and extended survival in a rodent model of glioblastoma. Such observations show the benefits and feasibility of pairing a potentially ideal treatment with a compound that improves its brain accumulation, and supports use of this strategy in clinical exploration of cell cycle-targeting therapies in brain cancers.

Endoscopic transvestibular paramandibular exploration of the infratemporal fossa and parapharyngeal space: a minimally invasive approach to the middle cranial base.

OBJECTIVES/HYPOTHESIS: To describe a novel transvestibular endoscopic approach for the exposure, exploration, and resection of lesions in the infratemporal fossa (ITF) and parapharyngeal space (PPS). STUDY DESIGN: Surgical technique and clinical feasibilty of a novel approach to the middle cranial base. METHODS: The transvestibular endoscopic approach was applied to four patients with lesions involving the ITF and PPS. Through a vertical oral mucosal incision along the ascending ramus of the mandible, an optical corridor to the ITF and PPS was created and maintained with the aid of a Hardy speculum. The contents of the ITF and PPS were explored with the aid of a 0-degree 4-mm rigid endoscope. RESULTS: Four patients underwent exploration of their right-sided ITF and PPS. The approach provided exposure and access from the middle cranial base at the level of the foramen ovale to the mid-PPS. Branches of the trigeminal nerve in the ITF were safely explored and preserved. Exposure and visualization of the internal maxillary artery and branches were achieved. Of the four patients, two underwent resection of a primary and a recurrent pleomorphic adenoma, one had chronic pain relief from a large synovial chondromatosis, and one had debulking of a recurrent mucoepidermoid carcinoma. The only complications were self-limiting hypoesthesia of the lip in one patient and transient dysphagia in another patient. CONCLUSIONS: The transvestibular endoscopic approach to the ITF and PPS offers direct and minimally invasive access to select lesions within this region. Further use of this approach will allow us to determine its potential and limitations.