Novel glioblastoma treatment: a novel dual P-gp/BCRP inhibitor can increase brain penetration of cancer drugs
Glioblastoma (GBM) is the most common and malignant brain tumor in adults. There were about 240,000 new cases per year worldwide1,2. GBM has a very poor prognosis, with a median survival of 12-15 months2. Temozolomide (TMZ) is the current chemotherapy for treating GBM after surgical resection, but with frequent resistance3. Many potent cancer drugs cannot be used to treat GBM because they failed to cross the blood-brain barrier (BBB) in normal circumstances. There are efflux transporters P-glycoprotein (P-gp/ABCB1) and Breast Cancer Resistance Protein (BCRP/ ABCG2) at the BBB to restrict substrate compounds from entering the brain.
In order to allow the most potent chemotherapy to reach the aggressive brain tumor, we employ our patented technology, flavonoid dimers, to inhibit both P-gp and BCRP at the BBB and eventually improve the drug penetration to the brain. It was found that a highly potent triazole-bridged flavonoid dimer is a dual inhibitor that can inhibit P-gp and BCRP simultaneously at sub-nanomolar range. Sorafenib is a tyrosine kinase inhibitor and clinically used for treating liver cancer and kidney cancer. However, it has not been used for treating GBM because of its low brain-to-plasma ratio. It was found that flavonoid dimer can increase the brain accumulation of sorafenib and allow it to reach the therapeutic concentration. This novel combination chemotherapy can significantly suppress the tumor growth and prolong the survival in orthotopic animal models using GBM wild type cells, TMZ-resistant cells and patient-derived xenograft (PDX) cells, respectively. This work provided a novel and effective strategy to increase the brain penetration of sorafenib, opening a new way to treat primary and TMZ-resistant GBM cases in clinic.
Flavonoid dimer can simultaneously inhibit both P-gp and BCRP at the BBB and increase the brain penetration of cancer drugs, opening a new strategy for treating primary and TMZ-resistant GBM cases which previously cannot be treated by the conventional chemotherapy.
1Neuro-oncology, 2022, 24(Suppl 5):v1-v95.
2Genes & diseases, 2016, 3(3): 98-210.
3Journal of Pharmacology and Experimental Therapeutics, 2011, 336(1): 223-233.
