Proteasome Inhibitor Therapy in a Brain Tumor Model

Abstract

Bortezomib (formerly known as PS-341) inhibits the ubiquitin—proteasome pathway with a hypothesized high degree of specificity for cell-cycle proteins. Preclinical activity has been observed in prostate and mammary cancer. Phase I data have defined tolerable toxicity, and thus analysis for brain tumor therapy is warranted. A rat intracranial 9L gliosarcoma model was given 1.0 mg/kg iv of C-14-labeled bortezomib to assess distribution. Intravenous and intratumoral bortezomib administration 10 d after implant was used to assess efficacy. At 1 h, tumor penetration reached 0.2–0.4 μM concentrations with negligible amounts found in the contralateral normal hemisphere. Survivals of rats given bortezomib 0.1 mg/kg iv twice a week and of controls were 20.8 ± 0.5 and 18.5 ± 0.7 d (p = 0.014), respectively. At 0.2 mg/kg, the bortezomib and control survivals were 22 ± 1.5and 16 ± 0.9 d (p = 0.0045), respectively. The single iv median lethal dose was 0.4 mg/ kg. Intratumoral injections had less toxicity than systemic injections, and 0.2 mg/kg of bortezomib given intratumorally provided benefit over vehicle injection, with survivals of 28 ± 6.4 d and 16.5 ± 0.6 d (p = 0.0013), respectively. In vivo, a single iv dose of 0.2 mg/kg of bortezomib increased 9L tumor p21 protein content 6–24 h after exposure; baseline was reached at 48 h, supporting its impact on the cell cycle. Quantification of intrinsic 20 S proteasome activity in human brain tumors may offer insight into which tumors might respond to inhibitors. Mean 20S proteasome specific activity values (in pmol/s/mg protein) from a small series of frozen fresh human specimens of glioblastoma (GBM), anaplastic astrocytoma, oligodendroglioma, adenocarcinoma, schwannoma, and meningioma were 5.0, 4.6,5.2,8.3,12.0, and 14.3, respectively. A range of values (3.5– 8.2), occurred for GBM (n = 5). It is hypothesized that this measurement may be predictive of the responsiveness of GBM to bortezomib. As a first step, a phase I study of the safety and tolerability of bortezomib has been initiated to determine a maximum tolerated dosage (MTD). In the 9L model bortezomib clearly enhances survival, but at high enough doses systemic bortezomib is not without toxicity. The hypothesized function inhibited by the drug, proteasome activity, is measurable. Therefore, with a MTD in hand, a study correlating this quantity as a predictive surrogate marker with efficacy is possible.