P04.91 ABC-drug efflux transporters at the blood-brain barrier limit the efficacy of treatment against primary and secondary brain tumors

摘要

BackgroundABCB1 (P-glycoprotein; Pgp) and ABCG2 (Breast Cancer Resistance Protein; BCRP) are drug efflux transporters that are abundantly expressed at the blood-brain barrier (BBB). They limit the brain penetration of numerous compounds including many anticancer agents and protect the brain from drug induced toxicities. In primary as well as in metastatic brain tumors, the BBB is often disrupted. But does this imply that anticancer agents will be able to readily reach the tumor and elicit an antitumor response? Materials and Methods: We tested a series of primary and metastatic brain tumor models, including primary human glioma stem cell (GSC) line models, DIPGs, metastases models of different origins (breast, skin) as well as inducible genetically engineered mouse models of glioblastoma (GBM). Transplantable tumors were implanted into ABCB1/ABCG2 proficient (wildtype; WT) or deficient (knockout; KO) recipient animals and/or we used elacridar, a dual pump inhibitor to block their function. We characterized these models for leakiness of the BBB using contrast-enhanced MRI, fluorescent dyes and ¹⁴C-labeled amino isobutyric acid. We have stained tissue specimens by IHC for ABCB1 and ABCG2. We have determined drug levels in brain and brain tumors and we have performed efficacy experiments with cytotoxic drugs or relevant targeted agents.