Phase II Study of Neoadjuvant Imatinib in Glioblastoma: Evaluation of Clinical and Molecular Effects of the Treatment

Abstract

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)

The Potential and Challenges of siRNA-Based Targeted Therapy for Treatment of Patients with Glioblastoma

“…Imatinib mesylate (Gleevec ® , Novartis) was developed to specifically inhibit Bcr-Abl signal transduction in chronic myeloid leukemia, and was later shown to also inhibit c-Kit and platelet-derived growth factor receptor (PDGFR) activity. The latter finding supported clinical testing of imatinib for GBM treatment, and similarly to the EGFR inhibitors, response rates were variable but promising (Razis et al, 2009;Wen et al, 2006). Other targeted therapy compounds currently evaluated for use in GBM treatment are described in section 5.…”

Repurposing antipsychotics as glioblastoma therapeutics: Potentials and challenges

“…Upon activation, GDP is replaced by guanosine triphosphate (GTP), resulting in subunit dissociation into a βγ dimer and the GTP-bound α-monomer (67). The Ga subunit is classified into four families: Ga s , Ga i , Ga q and Ga 12 . Each Ga family can transmit different downstream signals, thereby affecting diverse biological functions (68).…”

“…The first-generation small-molecule EGFR inhibitors, such as gefitinib, have performed poorly against GBM in several clinical trials (8)(9)(10). While the Bcr-Abl-targeting drug imatinib revealed notable efficacy for patients with chronic myeloid leukemia, clinical trials of imatinib in GBM have failed to demonstrate any therapeutic advantages (11)(12)(13). Finally, dasatinib, a platelet-derived growth factor and Src inhibitor failed to show benefit in recurrent GBM patients, either alone or in combination with bevacizumab (14).…”

Future Perspectives of Enhancing the Therapeutic Efficacy of Epidermal Growth Factor Receptor Inhibition in Malignant Gliomas

“…In another experimental study, imatinib significantly inhibited the proliferation of human U87 glioblastoma cells and significantly increased the radiosensitivity of this glioma cell line in vitro and in vivo (Oertel et al, 2006). However, in clinical phase I and II trials, imatinib was shown to exert only moderate antitumor activity (Razis et al, 2009;Wen et al, 2006). In a phase I/II study, 34 patients with glioblastoma were treated with imatinib monotherapy at a dose of 800 mg/d .…”

“…In a different phase II study, 20 patients with glioblastoma were diagnosed by tumor biopsy and treated with 400 mg imatinib administered twice a day for a period of 7 days prior to re-biopsy or tumor resection. Molecular examination of the tumor specimens showed that treatment with imatinib did not significantly change Ki67 expression, suggesting that treatment with imatinib did not affect tumor proliferation (Razis et al, 2009). …”