Progression Pattern and Adverse Events with Bevacizumab in Glioblastoma

Mamo, Aline; Baig, Ayesha; Azam, M.; Rho, Young Soo; Sahebjam, Solmaz; Muanza, Thierry; Owen, Scott; Petrecca, Kevin; Guiot, Marie‐Christine; Alshami, Jad; Sharma, Rajesh; Kavan, Petr

doi:10.3747/co.23.3108

Cited by 9 publications

(9 citation statements)

References 21 publications

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“…It has become evident in recent years that bevacizumab treatment is not without risk, in particular from wound breakdown and the possibility of inducing a more infiltrative/aggressive tumor after treatment [14]. Our analysis suggests that bevacizumab should be considered more carefully in classical and EGFR-amplified tumors and may be more beneficial for mesenchymal, neural and proneural tumors.…”

Section: Discussionmentioning

confidence: 89%

“…Additional experience with bevacizumab has allowed for clarification of complications of treatment in GBM that include thrombocytopenia, cerebral hemorrhages, arterial thrombo-embolic events, proteinuria, hypertension, visceral perforation, and inhibition of wound healing [8–12]. Furthermore, as the experience with this therapy grew, a more invasive pattern of progression of GBM has been observed to develop while under anti-angiogenic therapy [13, 14]. A potential mechanism involving the inhibition of the HIF1α mediated hypoxic response in the tumor micro-environment has been proposed to underlie the more invasive or multifocal phenotype [15].…”

Section: Introductionmentioning

confidence: 99%

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EGFR amplification and classical subtype are associated with a poor response to bevacizumab in recurrent glioblastoma

et al. 2019

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Purpose The highly vascular malignant brain tumor glioblastoma (GBM) appears to be an ideal target for anti-angiogenic therapy; however, clinical trials to date suggest the VEGF antibody bevacizumab affects only progression-free survival. Here we analyze a group of patients with GBM who received bevacizumab treatment at recurrence and are stratified according to tumor molecular and genomic profile (TCGA classification), with the goal of identifying molecular predictors of the response to bevacizumab. Methods We performed a retrospective review of patients with a diagnosis of glioblastoma who were treated with bevacizumab in the recurrent setting at our hospital, from 2006 to 2014. Treatment was discontinued by the treating neuro-oncologists, based on clinical and radiographic criteria. Pre- and post-treatment imaging and genomic subtype were available on 80 patients. We analyzed time on bevacizumab and time to progression. EGFR gene amplification was determined by FISH. Results Patients with classical tumors had a significantly shorter time on bevacizumab than mesenchymal, and proneural patients (2.7 vs. 5.1 vs. 6.4 and 6.0 months respectively, p = 0.011). Classical subtype and EGFR gene amplification were significantly associated with a shorter time to progression both in univariate (p < 0.001 and p = 0.007, respectively) and multivariate analysis (both p = 0.010). Conclusion EGFR gene amplification and classical subtype by TCGA analysis are associated with significantly shorter time to progression for patients with recurrent GBM when treated with bevacizumab. These findings can have a significant impact on decision-making and should be further validated prospectively.

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Section: Discussionmentioning

confidence: 89%

Section: Introductionmentioning

confidence: 99%

EGFR amplification and classical subtype are associated with a poor response to bevacizumab in recurrent glioblastoma

et al. 2019

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“…That is, histologic examination of organs such as the brain, heart, liver, and kidney in rodents exposed to high-dose NDAT for weeks has shown no abnormalities (S.A. Mousa, S. Sell, unpublished observations). We would also point out that the use of anti-angiogenic agents in GBM clinical management increases the risk of intratumoral hemorrhage [ 51 , 52 ]. Despite the multifactorial anti-angiogenic properties of Nanotetrac, no hemorrhages occurred in the xenografts of Nanotetrac-treated animals in the present study.…”

Section: Discussionmentioning

confidence: 99%

Nanoparticulate Tetrac Inhibits Growth and Vascularity of Glioblastoma Xenografts

et al. 2017

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Thyroid hormone as L-thyroxine (T4) stimulates proliferation of glioma cells in vitro and medical induction of hypothyroidism slows clinical growth of glioblastoma multiforme (GBM). The proliferative action of T4 on glioma cells is initiated nongenomically at a cell surface receptor for thyroid hormone on the extracellular domain of integrin αvβ3. Tetraiodothyroacetic acid (tetrac) is a thyroid hormone derivative that blocks T4 action at αvβ3 and has anticancer and anti-angiogenic activity. Tetrac has been covalently bonded via a linker to a nanoparticle (Nanotetrac, Nano-diamino-tetrac, NDAT) that increases the potency of tetrac and broadens the anticancer properties of the drug. In the present studies of human GBM xenografts in immunodeficient mice, NDAT administered daily for 10 days subcutaneously as 1 mg tetrac equivalent/kg reduced tumor xenograft weight at animal sacrifice by 50%, compared to untreated control lesions (p < 0.01). Histopathological analysis of tumors revealed a 95% loss of the vascularity of treated tumors compared to controls at 10 days (p < 0.001), without intratumoral hemorrhage. Up to 80% of tumor cells were necrotic in various microscopic fields (p < 0.001 vs. control tumors), an effect attributable to devascularization. There was substantial evidence of apoptosis in other fields (p < 0.001 vs. control tumors). Induction of apoptosis in cancer cells is a well-described quality of NDAT. In summary, systemic NDAT has been shown to be effective by multiple mechanisms in treatment of GBM xenografts.Electronic supplementary materialThe online version of this article (doi:10.1007/s12672-017-0293-6) contains supplementary material, which is available to authorized users.

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“…Considering the primary role of the Eph/ephrin system in GBM and the availability of a compound able to specifically target the Eph receptors, we examined whether UniPR1331 was capable of inhibiting GBM growth in vivo . Since anti-angiogenic compounds targeting endothelial cells have been considered for treatment of recurrent GBM [ 17 ] but their clinical benefit was unsatisfactory [ 18 , 19 ], we decided to test the association of UniPR1331 with Bevacizumab, a specific and selective inhibitor of VEGF-VEGFR interaction.…”

Section: Introductionmentioning

confidence: 99%

UniPR1331, a small molecule targeting Eph/ephrin interaction, prolongs survival in glioblastoma and potentiates the effect of antiangiogenic therapy in mice

et al. 2018

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Glioblastoma multiforme (GBM) is the most malignant brain tumor, showing high resistance to standard therapeutic approaches that combine surgery, radiotherapy, and chemotherapy. As opposed to healthy tissues, EphA2 has been found highly expressed in specimens of glioblastoma, and increased expression of EphA2 has been shown to correlate with poor survival rates. Accordingly, agents blocking Eph receptor activity could represent a new therapeutic approach. Herein, we demonstrate that UniPR1331, a pan Eph receptor antagonist, possesses significant in vivo anti-angiogenic and anti-vasculogenic properties which lead to a significant anti-tumor activity in xenograft and orthotopic models of GBM. UniPR1331 halved the final volume of tumors when tested in xenografts (p<0.01) and enhanced the disease-free survival of treated animals in the orthotopic models of GBM both by using U87MG cells (40 vs 24 days of control, p<0.05) or TPC8 cells (52 vs 16 days, p<0.01). Further, the association of UniPR1331 with the anti-VEGF antibody Bevacizumab significantly increased the efficacy of both monotherapies in all tested models. Overall, our data promote UniPR1331 as a novel tool for tackling GBM.

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Progression Pattern and Adverse Events with Bevacizumab in Glioblastoma

Abstract: BackgroundThe use of bevacizumab in the management of glioblastoma multiforme (gbm) remains controversial.

Cited by 9 publications

References 21 publications

EGFR amplification and classical subtype are associated with a poor response to bevacizumab in recurrent glioblastoma

EGFR amplification and classical subtype are associated with a poor response to bevacizumab in recurrent glioblastoma

Nanoparticulate Tetrac Inhibits Growth and Vascularity of Glioblastoma Xenografts

UniPR1331, a small molecule targeting Eph/ephrin interaction, prolongs survival in glioblastoma and potentiates the effect of antiangiogenic therapy in mice

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