Phase II study of tivozanib, an oral VEGFR inhibitor, in patients with recurrent glioblastoma

Kalpathy–Cramer, Jayashree; Chandra, Vyshak; Xiao, Da; Ou, Yangming; Emblem, Kyrre E.; Muzikansky, Alona; Cai, Xiao; Douw, Linda; Evans, J.G.; Dietrich, Jörg; Andrew, S.; Wen, Patrick Y.; Stufflebeam, Stephen; Rosen, Bruce R.; Duda, Dan G.; Jain, Rakesh K.; Batchelor, Tracy T.; Gerstner, Elizabeth R.

doi:10.1007/s11060-016-2332-5

Cited by 69 publications

(37 citation statements)

References 32 publications

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“…Previous studies investigating effect of either plasma or serum IL-6 levels on glioma survival mostly involve small cohorts and use a range of cut-offs, sampling times, and methods of detection (Supplementary File 1). Despite these limitations, eight out of 10 studies (12,(23)(24)(25)(26)(27)(28)(29)(44)(45)(46) with reported survival outcome do not find association of high plasma IL-6 with short survival (Supplementary File 1), supporting our results. A study on cytokine networks including IL-6 in GBM, found a trend toward survival benefit using a combined IL-4/IL-5/IL-6 serum profile, but no benefit with a partial combination (24), suggesting that combined immune-profiles may be related to GBM propagation and survival.…”

Section: Discussionsupporting

confidence: 86%

Systemic Immune Modulation in Gliomas: Prognostic Value of Plasma IL-6, YKL-40, and Genetic Variation in YKL-40

et al. 2020

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Background: Complex local and systemic immune dysfunction in glioblastoma (GBM) may affect survival. Interleukin (IL)-6 and YKL-40 are pleiotropic biomarkers present in the tumor microenvironment and involved in immune regulation. We therefore analyzed plasma IL-6, YKL-40, and genetic variation in YKL-40 and explored their ability to distinguish between glioma subtypes and predict survival in GBM. Methods: One hundred fifty-eight patients with glioma WHO grade II-IV were included in the study. Plasma collected at surgery was analyzed for IL-6 and YKL-40 (CHI3L1) by ELISA. CHI3L1 rs4950928 genotyping was analyzed on whole-blood DNA. Results: Neither plasma IL-6 nor YKL-40 corrected for age or rs4950928 genotype could differentiate GBM from lower grade gliomas. GC and GG rs4950928 genotype were associated with lower plasma YKL-40 levels (CC vs. GC, p = 0.0019; CC vs. GG, p = 0.01). Only 10 and 14 out of 94 patients with newly diagnosed GBM had elevated IL-6 or YKL-40, respectively. Most patients received corticosteroid treatment at time of blood-sampling. Higher pretreatment plasma IL-6 was associated with short overall survival (OS) [HR = 1.19 (per 2-fold change), p = 0.042] in univariate analysis. The effect disappeared in multivariate analysis. rs4950928 genotype did not associate with OS [HR = 1.30, p = 0.30]. In recurrent GBM, higher YKL-40 [HR = 2.12 (per 2fold change), p = 0.0005] but not IL-6 [HR = 0.99 (per 2-fold change), p = 0.92] were associated with short OS in univariate analysis. Conclusion: In recurrent GBM high plasma YKL-40 may hold promise as a prognostic marker. In newly diagnosed GBM perioperative plasma IL-6, YKL-40, and genetic variation in YKL-40 did not associate with survival. Corticosteroid use may complicate interpretation of results.

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Section: Discussionsupporting

confidence: 86%

Systemic Immune Modulation in Gliomas: Prognostic Value of Plasma IL-6, YKL-40, and Genetic Variation in YKL-40

et al. 2020

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“…Since angiogenesis plays a major role in GBM growth, there are treatment options based on angiogenesis which have shown clinical efficacy in GBM patients 24 . The administration of the potentially therapeutic antiangiogenic agents [such as anti-vascular endothelial growth factor VEGF/VEGF receptor (VEGFR) agents] has shown clinical benefits in GBM patients [30][31][32][33] .The possibility of inhibiting signaling to the angiogenic factors VEGF and hepatocyte growth factor (HGF) by targeting CD44v6 variant is a very important approach to antitumor treatment 20,26,[30][31][32][33] .…”

Section: Discussionmentioning

confidence: 99%

Prognostic Role of Cd44 Expression and Neovascularization Determined by Endoglin (Cd105) in Glioblastoma Patients

Mihić

Rotim

Vučić

et al. 2019

ACC

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-Glioblastoma multiforme (GBM) is the most common and most aggressive malignant primary brain tumor in humans. Clinically useful molecular markers that help predict response to therapy and prognosis are still rare. The research was conducted in 55 patients with GBM, 26 (47.3%) women and 29 (52.7%) men, mean age 62.58 years. On immunohistochemical analysis, primary antibody to CD44 (dilution 1:50) and primary antibody to endoglin (CD105) (dilution 1:250) were used to evaluate neovascularization. Statistical analysis showed negative correlation between CD44 and survival (p=0.023) (higher expression of CD44 was correlated with shorter survival), but there was no correlation between neovascularization determined by CD105 in GBM and patient survival. Thus, significant individual predictors of longer survival were lower expression of CD44 (p=0.004), higher Karnofsky score (p=0.045), and female gender (p=0.017). The results obtained suggested the possible role of CD44 in the progression and tumor neovascularization of GBM.

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“…However, it's efficacy on glioma seems to be unsatisfactory. A variety of clinical trials of TKIs have demonstrated a limited antitumor effect on glioma [16][17][18][19] . Recently, several studies have shown good results, which was encouraging.…”

Section: Discussionmentioning

confidence: 99%

Adeno-associated virus 2 mediated gene transfer of vascular endothelial growth factor Trap: a new treatment option for glioma

Zhao

Zhang

Wang

et al. 2018

Cancer Biology & Therapy

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Background: Adeno-associated virus 2 mediated gene transfer of vascular endothelial growth factor Trap (AAV2-VEGF-Trap) has been reported to inhibit the growth of primary tumor as well as distant metastasis in 4T1 metastatic breast cancer models. The aim of this study was to investigate the inhibiting efficacy of AAV2-VEGF-Trap for glioma. Methods: The intracranial transplanted model of glioma in rats was established. They were treated with AAV2-VEGF-Trap, bevacizumab (BEV), temozolomide (TMZ), TMZ combined with AAV2-VEGF-Trap, TMZ combined with BEV and the control group, respectively. A 7.0 Tesla magnetic resonance (MR) was used to assess the tumor volumes and obtain the apparent diffusion coefficient (ADC) values. Immunohistochemical and terminal dexynucleotidyl transferase (TdT)-mediated dUTP nick end labeling (TUNEL) staining were used to evaluate the effects on tumor angiogenesis, proliferation and apoptosis. Results: The combination of TMZ with AAV2-VEGF-Trap or BEV showed greater tumor growth inhibition than the other groups, and the ADC values in these two groups were larger than that of the control group. The decreased microvessel density in treatment groups which contain AAV2-VEGF-Trap or BEV was observed. The reduced proliferation activity in groups containing TMZ and increased apoptotic tumor cells in TMZ combined with AAV2-VEGF-Trap group and TMZ combined with BEV group were detected. In addition, there were no differences in antitumor effect, ADC values, Ki-67 and CD31 staining and apoptosis analysis between the two combined therapy groups. Conclusion: AAV2-VEGF-Trap has an obvious anti-angiogenic effect and inhibits the growth of glioma just by a single intravenous injection, which is similar to BEV. Moreover, there is a synergistic antitumor effect between AAV2-VEGF-Trap and TMZ.

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Phase II study of tivozanib, an oral VEGFR inhibitor, in patients with recurrent glioblastoma

Cited by 69 publications

References 32 publications

Systemic Immune Modulation in Gliomas: Prognostic Value of Plasma IL-6, YKL-40, and Genetic Variation in YKL-40

Systemic Immune Modulation in Gliomas: Prognostic Value of Plasma IL-6, YKL-40, and Genetic Variation in YKL-40

Prognostic Role of Cd44 Expression and Neovascularization Determined by Endoglin (Cd105) in Glioblastoma Patients

Adeno-associated virus 2 mediated gene transfer of vascular endothelial growth factor Trap: a new treatment option for glioma

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