Katharina Seystahl

Therapeutic options in recurrent glioblastoma—An update

INTRODUCTION Standards of care are not yet defined in recurrent glioblastoma. METHODS We reviewed the literature on clinical trials for recurrent glioblastoma available in PubMed and American Society of Clinical Oncology (ASCO) abstracts until June 2015. RESULTS Evidence is limited due to the paucity of randomized controlled studies. Second surgery or re-irradiation are options for selected patients. Alkylating chemotherapy such as nitrosoureas or temozolomide and the vascular endothelial growth factor (VEGF) antibody, bevacizumab, exhibit comparable single agent activity. Phase III data exploring the benefit of combining bevacizumab and lomustine are emerging. Novel approaches in the fields of targeted therapy, immunotherapy, and tumor metabolism are coming forward. Several biomarkers are being explored, but, except for O(6)-methylguanine DNA methyltransferase (MGMT) promoter methylation, none has assumed a role in clinical practice. CONCLUSION Proper patient selection, development of predictive biomarkers and randomized controlled studies are required to develop evidence-based concepts for recurrent glioblastoma.

Differential regulation of TGF-β–induced, ALK-5–mediated VEGF release by SMAD2/3 versus SMAD1/5/8 signaling in glioblastoma

BACKGROUND The transforming growth factor (TGF)-β and vascular endothelial growth factor (VEGF) pathways have a major role in the pathogenesis of glioblastoma, notably immunosuppression, migration, and angiogenesis, but their interactions have remained poorly understood. METHODS We characterized TGF-β pathway activity in 9 long-term glioma cell lines (LTCs) and 4 glioma-initiating cell lines (GICs) in relation to constitutive and exogenous TGF-β-induced VEGF release. Results were validated using The Cancer Genome Atlas transcriptomics data. RESULTS Glioma cells exhibit heterogeneous patterns of constitutive TGF-β pathway activation reflected by phosphorylation not only of SMAD2 and SMAD3 but also of SMAD1/5/8. Constitutive TGF-β pathway activity depends on the type I TGF-β receptor, ALK-5, and accounts for up to 69% of constitutive VEGF release, which is positively regulated by SMAD2/3 and negatively regulated by SMAD1/5/8 signaling in a cell line-specific manner. Exogenous TGF-β induces VEGF release in most cell lines in a SMAD- and ALK-5-dependent manner. There is no correlation between the fold induction of VEGF secretion induced by TGF-β compared with hypoxia. The role of SMAD5 signaling is highly context and cell-line dependent with a VEGF inhibitory effect at low TGF-β and pSMAD2 levels and a stimulatory effect when TGF-β is abundant. CONCLUSIONS TGF-β regulates VEGF release by glioma cells in an ALK-5-dependent manner involving SMAD2, SMAD3, and SMAD1/5/8 signaling. This crosstalk between the TGF-β and VEGF pathways may open up new avenues of biomarker-driven exploratory clinical trials focusing on the microenvironment in glioblastoma.

Is there a world beyond bevacizumab in targeting angiogenesis in glioblastoma

Introduction: Antiangiogenic approaches are currently the dominating experimental therapeutic strategy in glioblastoma. First enthusiasm was provoked by promising radiological response rates and an apparent clinical benefit with some of these agents. Major limitations include the modest number of durable responses, the lack of cytotoxic antitumor activity, of synergy when combined with chemotherapy and of an overall survival benefit. Areas covered: We review the rationale as well as preclinical and clinical evidence for the future development of antiangiogenic agents in glioblastoma. The most prominent approach targets VEGF and includes agents such as the VEGF antibody bevacizumab, the VEGF receptor fusion protein aflibercept or the tyrosine kinase inhibitors cediranib and XL-184. Inhibition of angiogenic pathways by small molecules, for example, enzastaurin, or anti-integrin-based approaches, for example, cilengitide, represent alternative strategies. Expert opinion: Enzastaurin and cediranib failed in randomized Phase III trials in recurrent glioblastoma, aflibercept in Phase II. By contrast, bevacizumab was conditionally approved in many countries. Recently completed Phase III trials for bevacizumab and cilengitide in the first-line setting will define the future role of these agents. This intense clinical trial activity reflects the hope that antiangiogenic agents will become part of the limited therapeutic options for glioblastoma.

Bevacizumab Alone or in Combination with Irinotecan in Recurrent WHO Grade II and Grade III Gliomas

Background: The repertoire of salvage regimens for patients with WHO grade II and III gliomas recurring or progressing after surgery, radiotherapy and temozolomide chemotherapy is limited. Based on promising response and progression-free survival (PFS) data in recurrent glioblastoma, the use of bevacizumab (BEV) has been extended to recurrent grade II/III gliomas. Methods: We retrospectively assessed the safety and efficacy of BEV alone or combined with irinotecan in 39 patients with recurrent grade II/III gliomas. Results: Both BEV monotherapy and its combination with irinotecan were well tolerated. Response rates were 26% as monotherapy and 33% in combination using Macdonald and RANO criteria. The median PFS was 4.2 months and the PFS rate at 6 months 29% for BEV alone, and 4.7 months and 42% for the combination. The median overall survival was 14.8 months for BEV monotherapy and 8.1 months for the combination. Outcome after failure of BEV was better when patients continued BEV beyond progression. Conclusion: BEV has limited activity in recurrent grade II/III gliomas. The additional value of irinotecan remains questionable. Prospective studies with BEV-free control groups are required to better define the role of BEV among the limited options in patients with recurrent grade II/III gliomas.

Kinetics of tumor size and peritumoral brain edema before, during, and after systemic therapy in recurrent WHO grade II or III meningioma

BACKGROUND The efficacy of systemic antineoplastic therapy on recurrent World Health Organization (WHO) grades II and III meningiomas is unclear. METHODS We performed a retrospective multicenter analysis of serial cranial MRI in patients with recurrent WHO II and III meningiomas treated with antineoplastic systemic therapies. Growth rates for tumor volume and diameter, as well as change rates for edema size, were calculated for all lesions. RESULTS We identified a total of 34 patients (23 atypical, 11 anaplastic meningiomas) with a total of 57 meningioma lesions who had been treated at 6 European institutions. Systemic therapies included bevacizumab, cytotoxic chemotherapy, somatostatin analogues, and tyrosine kinase inhibitors. Overall, tumor growth rates decreased during systemic therapy by 51% for tumor diameter and 14% for tumor volume growth rates compared with the period before initiation of systemic therapy. The most pronounced decrease in meningioma growth rates during systemic therapy was evident in patients treated with bevacizumab, with a reduction of 80% in diameter and 59% in volume growth. Furthermore, a decrease in size of peritumoral edema after initiation of systemic therapy was exclusively observed in patients treated with bevacizumab (-107%). CONCLUSIONS Our data indicate that systemic therapy may inhibit growth of recurrent WHO grades II and III meningiomas to some extent. In our small cohort, bevacizumab had the most pronounced inhibitory effect on tumor growth, as well as some anti-edematous activity. Prospective studies are needed to better define the role of medical therapies in this tumor type.

Autocrine VEGFR1 and VEGFR2 signaling promotes survival in human glioblastoma models in vitro and in vivo.

Background Although the vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR) system has become a prime target for antiangiogenic treatment, its biological role in glioblastoma beyond angiogenesis has remained controversial. Methods Using neutralizing antibodies to VEGF or placental growth factor (PlGF) or the tyrosine kinase inhibitor, cediranib, or lentiviral gene silencing, we delineated autocrine signaling in glioma cell lines. The in vivo effects of VEGFR1 and VEGFR2 depletion were evaluated in orthotopic glioma xenograft models. Results VEGFR1 and VEGFR2 modulated glioma cell clonogenicity, viability, and invasiveness in vitro in an autocrine, cell–line-specific manner. VEGFR1 silencing promoted mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) signaling, whereas VEGFR2 silencing resulted in cell-type dependent activation of the protein kinase B (PKB)/AKT and MAPK/ERK pathways. These responses may represent specific escape mechanisms from VEGFR inhibition. The survival of orthotopic glioma-bearing mice was prolonged upon VEGFR1 silencing in the LNT-229, LN-308, and U87MG models and upon VEGFR2 silencing in LN-308 and U87MG. Disruption of VEGFR1 and VEGFR2 signaling was associated with decreased tumor size, increased tumor necrosis, or loss of matrix metalloproteinase 9 (MMP9) immunoreactivity. Neutralizing VEGF and PlGF by specific antibodies was superior to either antibody treatment alone in the VEGFR1-dependent LNT-229 model. Conclusions Differential dependence on autocrine signaling through VEGFR1 and VEGFR2 suggests a need for biomarker–stratified VEGF(R)-based therapeutic approaches to glioblastoma.

Pharmacotherapies for the treatment of glioblastoma – current evidence and perspectives

ABSTRACT Introduction: Glioblastoma, the most common malignant brain tumor, exhibits a poor prognosis with little therapeutic progress in the last decade. Novel treatment strategies beyond the established standard of care with temozolomide-based radiotherapy are urgently needed. Areas covered: We reviewed the literature on glioblastoma with a focus on phase III trials for pharmacotherapies and/or innovative concepts until December 2015. Expert opinion: In the last decade, phase III trials on novel compounds largely failed to introduce efficacious pharmacotherapies beyond temozolomide in glioblastoma. So far, inhibition of angiogenesis by compounds such as bevacizumab, cediranib, enzastaurin or cilengitide as well as alternative dosing schedules of temozolomide did not prolong survival, neither at primary diagnosis nor at recurrent disease. Promising strategies of pharmacotherapy currently under evaluation represent targeting epidermal growth factor receptor (EGFR) with biomarker-stratified patient populations and immunotherapeutic concepts including checkpoint inhibition and vaccination. The clinical role of the medical device delivering ‘tumor-treating fields’ in newly diagnosed glioblastoma which prolonged overall survival in a phase III study has remained controversial. After failure of several phase III trials with previously promising agents, improvement of concepts and novel compounds are urgently needed to expand the still limited therapeutic options for the treatment of glioblastoma.

Addition of lomustine for bevacizumab-refractory recurrent glioblastoma.

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Antiangiogenic Treatment for Multiple CNS Hemangioblastomas

Background: Hemangioblastomas represent rare benign tumors of the central nervous system. In the case of metastatic spread and limited surgical options, systemic treatment may be considered. However there is no standard of care beyond surgery. Case Report: We report the cases of 2 patients with progressive multilocular hemangioblastomas, who showed clinical benefit and radiological stabilization of tumor growth after treatment with bevacizumab, an antibody against the vascular endothelial growth factor. Conclusion: Our case reports suggest activity of bevacizumab in hemangioblastomas after failure of standard therapeutic options.

Biological Role and Therapeutic Targeting of TGF-β 3 in Glioblastoma

Transforming growth factor (TGF)-β contributes to the malignant phenotype of glioblastoma by promoting invasiveness and angiogenesis and creating an immunosuppressive microenvironment. So far, TGF-β1 and TGF-β2 isoforms have been considered to act in a similar fashion without isoform-specific function in glioblastoma. A pathogenic role for TGF-β3 in glioblastoma has not been defined yet. Here, we studied the expression and functional role of endogenous and exogenous TGF-β3 in glioblastoma models. TGF-β3 mRNA is expressed in human and murine long-term glioma cell lines as well as in human glioma-initiating cell cultures with expression levels lower than TGF-β1 or TGF-β2 in most cell lines. Inhibition of TGF-β3 mRNA expression by ISTH2020 or ISTH2023, two different isoform-specific phosphorothioate locked nucleic acid (LNA)-modified antisense oligonucleotide gapmers, blocks downstream SMAD2 and SMAD1/5 phosphorylation in human LN-308 cells, without affecting TGF-β1 or TGF-β2 mRNA expression or protein levels. Moreover, inhibition of TGF-β3 expression reduces invasiveness in vitro. Interestingly, depletion of TGF-β3 also attenuates signaling evoked by TGF-β1 or TGF-β2. In orthotopic syngeneic (SMA-560) and xenograft (LN-308) in vivo glioma models, expression of TGF-β3 as well as of the downstream target, plasminogen-activator-inhibitor (PAI)-1, was reduced, while TGF-β1 and TGF-β2 levels were unaffected following systemic treatment with TGF-β3-specific antisense oligonucleotides. We conclude that TGF-β3 might function as a gatekeeper controlling downstream signaling despite high expression of TGF-β1 and TGF-β2 isoforms. Targeting TGF-β3 in vivo may represent a promising strategy interfering with aberrant TGF-β signaling in glioblastoma. Mol Cancer Ther; 16(6); 1177–86. ©2017 AACR.