Abstract A148: Palomid 529, a dual mTor1/2 inhibitor, efficiently penetrates the blood-brain barrier and may be an attractive agent for treatment of glioblastoma

Abstract

Abstract High-grade gliomas (WHO grade III anaplastic astrocytoma and grade IV glioblastoma multiforme) are the most common primary tumors in the central nervous system in adults and uniformly lethal. The current standard treatment (radiotherapy and temozolomide chemotherapy) has only a modest efficacy and better treatments are urgently needed. Activation of the EGFR/PI3K/Akt/mTor signaling cascade is a common event, especially in de novo glioblastoma (GBM) and, therefore, an attractive target for intervention by inhibitors. However, the blood-brain barrier (BBB) is an impediment for the delivery of many agents into the brain. Although GBM has the capacity to disrupt the blood-brain barrier, it is also a very invasive tumor with many tumor cells residing within areas of the brain where the BBB is still intact. Consequently it is important to consider the BBB penetration of novel candidate drugs for treatment of gliomas. We here present a pre-clinical pharmacokinetic study of Palomid 529, which is a novel small molecule inhibitor of mTor. This agent is attractive because it inhibits both the Torc1 and Torc2 complexes, thereby preventing upstream Akt activation through feedback loops. We have used in vitro transwell assays and found that Palomid 529 has negligible affinities for P-glycoprotein (Pgp) and Bcrp1, the two most dominant drug transporters that are expressed at the BBB. Subsequent studies in transporter knockout mouse models receiving i.v. P529 as a micronized drug formulation at a high dose (54 mg/kg) or low dose (5.4 mg/kg) confirmed these results and demonstrated that Palomid 529 penetrates the BBB efficiently with brain-to-plasma ratios exceeding 1. Only at the lowest dose level a minor effect of Pgp and Bcrp1 was observed. Based on these results we are now executing pre-clinical testing of Palomid 529 against orthotopic brain tumor models. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A148.