Glioblastoma (GBM) is an aggressive malignant brain tumor that still lacks effective therapy. Glioblastoma stem cells (GBM-SCs) were identified to contribute to aggressive phenotypes and poor ...clinical outcomes for GBM. Netrin-1, an axon guidance molecule, has been found in several tumors in adults. However, the role of Netrin-1 in GBM-SCs remains largely unknown. In this study, CD133-positive U251 GBM cells were used as a putative GBM-SC population to identify the functions of Netrin-1. Using lentiviral transduction, Netrin-1 miR RNAi vectors were transduced into CD133-positive U251 cells. We demonstrated that cell proliferation and survival were decreased following targeted deletion of Netrin-1. Cell invasion was dramatically diminished in Netrin-1 knockdown GBM-SCs. Moreover, Netrin-1 knockdown GBM-SCs exhibited less proangiogenic activity. In conclusion, Netrin-1 may represent a therapeutic target in glioblastoma.
Glioblastoma multiforme (GBM), the most common primary malignant brain tumor in adults, is associated with high mortality. Current standard-of-care treatments, including surgery, radiation and ...chemotherapy, offer only palliation. Recent research in cancer therapy has shifted towards targeting the specific molecular aberrations that underlie the pathogenesis of cancers including GBM. Protein kinases are a family of enzymes that are key components in regulating cellular homeostasis. Protein kinases can be deregulated by several mechanisms, which contribute to cancer initiation and maintenance. Several protein kinases are important in gliomagenesis, thus representing new therapeutic targets in GBM. Low molecular weight inhibitors are the most commonly used agents to target protein kinases in the treatment of cancers. However, first-generation kinase inhibitors targeting only single kinases have demonstrated limited efficacy in unselected GBM patient populations. Several mechanisms of failure of monotherapy with single-targeted kinase inhibitors have been explained as new therapeutic strategies have emerged to overcome resistance. Simultaneous disruption of several kinases can be achieved by either multitargeted kinase inhibitors or combination of single-targeted kinase inhibitors with one another or with traditional cytotoxics. In this review, we will discuss the current clinical status of targeted therapy in GBM and recent approaches to target multiple kinases in this devastating cancer.
We performed a phase II study to evaluate the combination of imatinib mesylate, an adenosine triphosphate mimetic, tyrosine kinase inhibitor, plus hydroxyurea, a ribonucleotide reductase inhibitor, ...in patients with recurrent glioblastoma multiforme (GBM).
Patients with GBM at any recurrence received imatinib mesylate plus hydroxyurea (500 mg twice a day) orally on a continuous, daily schedule. The imatinib mesylate dose was 500 mg twice a day for patients on enzyme-inducing antiepileptic drugs (EIAEDs) and 400 mg once a day for those not on EIAEDs. Assessments were performed every 28 days. The primary end point was 6-month progression-free survival (PFS).
Thirty-three patients enrolled with progressive disease after prior radiotherapy and at least temozolomide-based chemotherapy. With a median follow-up of 58 weeks, 27% of patients were progression-free at 6 months, and the median PFS was 14.4 weeks. Three patients (9%) achieved radiographic response, and 14 (42%) achieved stable disease. Cox regression analysis identified concurrent EIAED use and no more than one prior progression as independent positive prognostic factors of PFS. The most common toxicities included grade 3 neutropenia (16%), thrombocytopenia (6%), and edema (6%). There were no grade 4 or 5 events. Concurrent EIAED use lowered imatinib mesylate exposure. Imatinib mesylate clearance was decreased at day 28 compared with day 1 in all patients, suggesting an effect of hydroxyurea.
Imatinib mesylate plus hydroxyurea is well tolerated and associated with durable antitumor activity in some patients with recurrent GBM.
We determined the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT) of the oral vascular endothelial growth factor receptor (VEGFR) inhibitor, sunitinib, when administered with ...irinotecan among recurrent malignant glioma (MG) patients. For each 42-day cycle, sunitinib was administered once a day for four consecutive weeks followed by a 2 week rest. Irinotecan was administered intravenously every other week. Each agent was alternatively escalated among cohorts of 3–6 patients enrolled at each dose level. Patients on CYP3A-inducing anti-epileptic drugs were not eligible. Twenty-five patients with recurrent MG were enrolled, including 15 (60%) with glioblastoma (GBM) and 10 (40%) with grade 3 MG. Five patients progressed previously on bevacizumab and two had received prior VEGFR tyrosine kinase inhibitor therapy. The MTD was 50 mg of sunitinib combined with 75 mg/m
2
of irinotecan. DLT were primarily hematologic and included grade 4 neutropenia in 3 patients and one patient with grade 4 thrombocytopenia. Non-hematologic DLT included grade 3 mucositis (
n
= 1) and grade 3 dehydration (
n
= 1). Progression-free survival (PFS)-6 was 24% and only one patient achieved a radiographic response. The combination of sunitinib and irinotecan was associated with moderate toxicity and limited anti-tumor activity. Further studies with this regimen using the dosing schedules evaluated in this study are not warranted.
To determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of dasatinib, an inhibitor of the Src family kinase proteins, with erlotinib, an epidermal growth factor receptor ...tyrosine kinase inhibitor, among recurrent malignant glioma patients. Once daily dasatinib was escalated in successive cohorts while erlotinib was administered daily at established doses based on concurrent CYP3A-inducing anticonvulsant (EIAEDS) use. Dasatinib pharmacokinetic analyzes were performed. Forty-seven patients enrolled including 37 (79 %) with grade IV and 10 (21 %) with grade III malignant glioma. Thirty patients (64 %) were at ≥second recurrence, while 27 (57 %) had received prior bevacizumab. The dasatinib MTD was 180 mg when combined with either 150 mg of erlotinib for patients not on EIAEDs, or 450 mg of erlotinib for patients on EIAEDs. The most common DLTs were diarrhea and fatigue, while most adverse events were grade 2. Pharmacokinetic data suggests that dasatinib exposure increased with increased dasatinib dose and concurrent erlotinib administration, while concurrent EIAED use diminished dasatinib exposure. No radiographic responses were observed, and only one patient (2 %) remained progression-free at 6 months. We demonstrate that dasatinib plus erlotinib can be safely co-administered on a continuous, daily dosing schedule with erlotinib, and established the recommended dose level of this combination.
To evaluate the usefulness of advanced MRI techniques in differentiating high-grade (HGG) from low-grade gliomas (LGG).
Sixty-four patients with suspected gliomas were prospectively evaluated by ...conventional and advanced MRI studies including MR spectroscopy (MRS), diffusion tensor imagining (DTI), and dynamic susceptibility contrast (DSC) MRI. The parametric measurements of metabolic profile, cerebral blood volume, flow (CBV, CBF), apparent diffusion coefficient (ADC), fractional anisotropy, and their ratios by internal normalization were analyzed to differentiate LGG from HGG. Histopathologic findings were used as the gold standard.
Forty-three cases with pathologically-proven gliomas were included The best discriminating features between HGG and LGG were CBV and CBF of the solid tumoral region (p < 0.05) whereas the minADC/corpus callosum ratio for DTI and the ratio of Cho/Cr for MRS of the solid tumoral region provided the best diagnostic performance (p < 0.05). With a predetermined threshold for each parametric measurement, the combination of all advanced MRI modalities was associated with the best accuracy whereas the combination of DSC MRI and MRS provided the highest specificity. When all parametric measurements were positive, the probability of HGG was 0.889.
Comprehensive advanced MRI studies provided better diagnostic performance than using conventional MRI alone in the evaluation of gliomas.
Although outcome following bevacizumab among recurrent grade IV malignant glioma patients is documented as poor by several analyses, outcome for recurrent grade III patients following bevacizumab ...therapy has not been specifically evaluated. We performed a pooled analysis of 96 recurrent grade III malignant glioma patients enrolled on three consecutive phase II bevacizumab salvage trials to evaluate overall outcome following bevacizumab trial discontinuation. Outcome on the three bevacizumab trials, which included similar eligibility, treatment and assessment criteria, was comparable. Forty-nine patients who progressed on bevacizumab trial therapy and remained alive for at least 30 days elected to receive additional therapy. These patients achieved a median PFS-6 and OS of 30.6% (95% CI: 18.4, 43.6) and 10.3 months (95% CI: 5.2, 11.7), respectively. Among patients who continued bevacizumab therapy (
n
= 23) after study progression, PFS-6 and median OS were 39.1% (95% CI: 19.9, 58.0) and 9.2 months (95% CI: 5.2, 13.6), respectively, compared to 23.1% (95% CI: 9.4, 40.3;
P
= 0.51) and 10.3 months (95% CI: 2.5, 14.4;
P
= 0.91) for patients who initiated non-bevacizumab containing therapy (
n
= 26). Outcome after discontinuation of bevacizumab therapy for recurrent grade III malignant glioma patients is associated with improved outcome compared to historical data for recurrent grade IV malignant glioma patients. Salvage therapies following bevacizumab failure have modest activity for grade III malignant glioma patients that is independent of further bevacizumab continuation.
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