Targeted therapies for malignant gliomas: novel agents, same barrier

Abstract

Malignant gliomas are common and devastating brain malignancies. Despite this extensive treatment the mean overall survival is still only 14.6 months and more effective treatments are urgently needed. Targeted therapy holds the promise for the new generation of chemotherapy due to the selectively target inhibition of deregulated signaling pathways in cancer cell but not normal cells. However, recent researches suggested that the blood-brain barrier (BBB) restricting the brain delivery of most traditional chemotherapies, are still a major factor that limiting the therapeutic effects of targeted agents. Importantly, like conventional chemotherapeutics, most of the small molecular inhibitors are also substrates of one or several ABC (ATP-binding cassette) multidrug efflux transporters expressed at the BBB as well as in tumor cells. Therefore, these small molecular pumps such as ABCB1/Abcb1 (P-glycoprotein, P-gp or MDR) and ABCG2/Abcg2 (BCRP) could severely compromise their target inhibitory effects.

The thesis first describes the two major limiting factors, namely, drug efflux transporters and intrinsic resistance of tumor cells that challenging the therapeutic effects of current small molecular targeted therapies in malignant gliomas. In the following chapters, we firstly describe two sensitive analytic assays for determining Palomid 529, a dual mTORC1 and mTORC2 inhibitor, and NVP-BEZ235, a dual PI3K and mTOR inhibitor in murine and human plasma and tissue samples. Furthermore, the roles of Abcb1 (P-glycoprotein) and Abcg2 (Bcrp1) in brain penetrations and anti-glioma therapeutic effects of several selected targeted agents have been investigated. Two agents, Palomid 529 and ZSTK474 (PI3K inhibitor) have been identified as non- or poor substrates of Abcb1 and Abcg2, so their brain penetrations have not been compromised by these transporters. We also reports Abcb1 and Abcg2 could cause severe impacts on the brain penetrations of agents which are substrates of one of them, like rapamycin and NVP-BEZ235; or both of them, like ABT-888. However, co-administration of elacridar could reverse the drug efflux of Abcb1 and Abcg2 at both blood-brain barrier and at tumor cells, and consequently improve the therapeutic effect of targeted agents. The last chapter describes an important role of another drug efflux transporters expressed at blood-brain barrier, ABCC4 (Mrp4) in brain pharmacokinetics of camptothecin analogs topotecan, gimatecan, irinotecan and SN-38; and also reports that sildenafil (viagra) is not a useful inhibitor of ABCB1 and ABCG2 mediated drug resistance in vivo