Purpose: Phase I-II studies indicate that imatinib is active in glioblastoma multiforme.To better understand the molecular and clinical effects of imatinib in glioblastoma multiforme, we conducted a neoadjuvant study of imatinib with pretreatment and posttreatment biopsies. Experimental Design: Patients underwent a computerized tomography-guided biopsy of their brain tumors. If diagnosed with glioblastoma multiforme, they were immediately treated with 7 days of imatinib 400 mg orally twice daily followed by either definitive surgery or re-biopsy. Pretreatment and posttreatment tissue specimens were tested by immunohistochemistry for Ki67 and microvessel destiny, and posttreatment specimens were analyzed for the presence of intact imatinib in tissue. Furthermore, pretreatment and posttreatment pairs were analyzed by Western blotting for activation of platelet-derived growth factor receptor, epidermal growth factor receptor (EGFR), phosphoinositide 3-kinase/AKT, and mitogen-activated protein kinase signaling pathways. Pharmacokinetic studies were also done. Results: Twenty patients were enrolled. Median survival was 6.2 months. Intact imatinib was detected in the posttreatment tissue specimens using mass spectrometry. There was no evidence of a drug effect on proliferation, as evidenced by a change in Ki67 expression. Biochemical evidence of response, as shown by decreased activation of AKT and mitogen-activated protein kinase or increased p27 level, was detected in 4 of 11 patients with evaluable, matched pre-and post-imatinib biopsies. Two patients showed high-level EGFR activation and homozygous EGFR mutations, whereas one patient had high-level platelet-derived growth factor receptor-B activation. Conclusions: Intact imatinib was detected in glioblastoma multiforme tissue. However, the histologic and immunoblotting evaluations suggest that glioblastoma multiforme proliferation and survival mechanisms are not substantially reduced by imatinib therapy in most patients. (Clin Cancer Res 2009;15(19):6258-66)

2023 Background: Glioblastoma multiforme (GBM) carries a grave prognosis. There are phase I-II studies indicating that imatinib is active in GBM in pre-treated patients. To better understand the molecular basis of imatinib’s activity in this disease we performed a pharmacodynamic neoadjuvant study with imatinib in GBM. Methods: Patients underwent CT guided biopsy of their brain tumors. If diagnosed with GBM they were immediately treated with 7 days of imatinib 400mg po BID followed by either definitive surgery or, if that was not feasible, followed by re-biopsy. Corticosteroid dose was stable during this period and valproic acid was the only anti-epileptic drug allowed in order to avoid pharmacokinetic interaction with imatinib. Treatment after recovery was as per usual institutional policy. Pre and post treatment tissue specimens were analyzed by immunohistochemistry, proteomic technology and molecular biological methods. Pharmacokinetic studies were also performed. Results: Twenty patients were enrolled in 2 institutions with a median age of 64, of which 14 were male and 6 female. PS was 0 in 2, 1 in 9 and 2 in 9. Seventeen patients had pure GBM, 2 had mixed GBM with astrocytoma and one had anaplastic astrocytoma. Eighteen patients had stable disease on pre and post treatment MRI, one had progressed and one was not evaluable. Median survival was 6.2 months (1.1–18mo). Intact imatinib was quantified in the post treatment tissue specimens and correlations were made with serum imatinib levels per patient. No correlation was seen. Tissue specimens were analyzed by in situ MALDI mass spectroscopy and differential protein expression profiles were detected, when pre and post treatment specimens were compared. The identification of candidate proteins is ongoing. In 11 patients with evaluable, high-quality, matched pre and post imatinib biopsies, 4 had biochemical evidence of tumor response (decreased AKT or MAPK, or increased p27). In addition, 2 patients showed high-level EGFR activation, and one patient had high-level PDGFR activation. Conclusions: Treatment of GBM patients with imatinib results in measurable levels of the drug in the tumor. Potential indicators of biochemical response in a subset of patients were identified. No significant financial relationships to disclose.