Lack of functional normalisation of tumour vessels following anti-angiogenic therapy in glioblastoma.
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ABSTRACT:
SUBMITTER: Obad N
PROVIDER: S-EPMC6168744 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Anti-angiogenic therapy has become an important component in the treatment of many solid tumors given the importance of adequate blood supply for tumor growth and metastasis. Despite promising preclinical data and early clinical trials, anti-angiogenic agents have failed to show a survival benefit in randomized controlled trials of patients with glioblastoma. In particular, agents targeting vascular endothelial growth factor (VEGF) appear to prolong progression free survival, possibly improve quality of life, and decrease steroid usage, yet the trials to date have demonstrated no extension of overall survival. In order to improve duration of response and convey a survival benefit, additional research is still needed to explore alternative pro-angiogenic pathways, mechanisms of resistance, combination strategies, and biomarkers to predict therapeutic response.
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Project description:Glioblastoma is the most aggressive brain tumor with a median survival ranging from 6.2 to 16.7 months. The complex interactions between the tumor and the cells of tumor microenvironment leads to tumor evolution which ultimately results in treatment failure. Immunotherapy has shown great potential in the treatment of solid tumors but has been less effective in treating glioblastoma. Failure of immunotherapy in glioblastoma has been attributed to low T-cell infiltration in glioblastoma and dysfunction of the T-cells that are present in the glioblastoma microenvironment. Recent advances in single-cell sequencing have increased our understanding of the transcriptional changes in the tumor microenvironment pre and post-treatment. Another treatment modality targeting the tumor microenvironment that has failed in glioblastoma has been anti-angiogenic therapy such as the VEGF neutralizing antibody bevacizumab, which did not improve survival in randomized clinical trials. Interestingly, the immunosuppressed microenvironment and abnormal vasculature of glioblastoma interact in ways that suggest the potential for synergy between these two therapeutic modalities that have failed individually. Abnormal tumor vasculature has been associated with immune evasion and the creation of an immunosuppressive microenvironment, suggesting that inhibiting pro-angiogenic factors like VEGF can increase infiltration of effector immune cells into the tumor microenvironment. Remodeling of the tumor vasculature by inhibiting VEGFR2 has also been shown to improve the efficacy of PDL1 cancer immunotherapy in mouse models of different cancers. In this review, we discuss the recent developments in our understanding of the glioblastoma tumor microenvironment specially the tumor vasculature and its interactions with the immune cells, and opportunities to target these interactions therapeutically. Combining anti-angiogenic and immunotherapy in glioblastoma has the potential to unlock these therapeutic modalities and impact the survival of patients with this devastating cancer.
| S-EPMC8790087 | biostudies-literature
Project description:Angiogenesis has long been implicated as a crucial process in GBM growth and progression. GBM can adopt several strategies to build up its abundant and aberrant vasculature. Targeting GBM angiogenesis has gained more and more attention in anti-cancer therapy, and many strategies have been developed to interfere with this hallmark. However, recent findings reveal that the effects of anti-angiogenic treatments are temporally limited and that tumors become refractory to therapy and more aggressive. In this review, we summarize the GBM-associated neovascularization processes and their implication in drug resistance mechanisms underlying the transient efficacy of current anti-angiogenic therapies. Moreover, we describe potential strategies and perspectives to overcome the mechanisms adopted by GBM to develop resistance to anti-angiogenic therapy as new potential therapeutic approaches.
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Project description:Vascular endothelial growth factor (VEGF) dependent tumor angiogenesis is an essential step for the initiation and promotion of tumor progression. The hypothesis that VEGF-driven tumor angiogenesis is necessary and sufficient for metastatic progression of the tumor, has been the major premise of the use of anti-VEGF therapy for decades. While the success of anti-VEGF therapy in solid tumors has led to the success of knowledge-based-therapies over the past several years, failures of this therapeutic approach due to the development of inherent/acquired resistance has led to the increased understanding of VEGF-independent angiogenesis. Today, tumor-angiogenesis is not a synonymous term to VEGF-dependent function. The extensive study of VEGF-independent angiogenesis has revealed several key factors responsible for this phenomenon including the role of myeloid cells, and the contribution of entirely new phenomenon like vascular mimicry. In this review, we will present the cellular and molecular factors related to the development of anti-angiogenic resistance following anti-VEGF therapy in different solid tumors.
| S-EPMC4656750 | biostudies-literature
Project description:BackgroundAlthough anti-angiogenic therapy (AATx) holds great promise for treatment of malignant gliomas, its therapeutic efficacy is not well understood and can potentially increase the aggressive recurrence of gliomas. It is essential to establish sensitive, noninvasive biomarkers that can detect failure of AATx and tumor recurrence early so that timely adaptive therapy can be instituted. We investigated the efficacy of MRI biomarkers that can detect response to different classes of AATxs used alone or in combination with radiation.MethodsMurine intracranial glioma xenografts (NOD/SCID) were treated with sunitinib, VEGF-trap or B20 (a bevacizumab equivalent) alone or in combination with radiation. MRI images were acquired longitudinally before and after treatment, and various MRI parameters (apparent diffusion coefficient, T1w + contrast, dynamic contrast-enhanced [DCE], initial area under the contrast enhancement curve, and cerebral blood flow) were correlated to tumor cell proliferation, overall tumor growth, and tumor vascularity.ResultsCombinatorial therapies reduced tumor growth rate more efficiently than monotherapies. Apparent diffusion coefficient was an accurate measure of tumor cell density. Vascular endothelial growth factor (VEGF)-trap or B20, but not sunitinib, resulted in significant reduction or complete loss of contrast enhancement. This reduction was not due to a reduction in tumor growth or microvascular density, but rather was explained by a reduction in vessel permeability and perfusion. We established that contrast enhancement does not accurately reflect tumor volume or vascular density; however, DCE-derived parameters can be used as efficient noninvasive biomarkers of response to AATx.ConclusionsMRI parameters following therapy vary based on class of AATx. Validation of clinically relevant MRI parameters for individual AATx agents is necessary before incorporation into routine practice.
| S-EPMC4022230 | biostudies-literature
Project description:BackgroundDetermining failure to anti-angiogenic therapy in recurrent glioblastoma (GBM) (rGBM) remains a challenge. The purpose of the study was to assess treatment response to bevacizumab-based therapy in patients with rGBM using MR spectroscopy (MRS).MethodsWe performed longitudinal MRI/MRS in 33 patients with rGBM to investigate whether changes in N-acetylaspartate (NAA)/Choline (Cho) and Lactate (Lac)/NAA from baseline to subsequent time points after treatment can predict early failures to bevacizumab-based therapies.ResultsAfter stratifying based on 9-month survival, longer-term survivors had increased NAA/Cho and decreased Lac/NAA levels compared to shorter-term survivors. ROC analyses for intratumoral NAA/Cho correlated with survival at 1 day, 2 weeks, 8 weeks, and 16 weeks. Intratumoral Lac/NAA ROC analyses were predictive of survival at all time points tested. At the 8-week time point, 88% of patients with decreased NAA/Cho did not survive 9 months; furthermore, 90% of individuals with an increased Lac/NAA from baseline did not survive at 9 months. No other metabolic ratios tested significantly predicted survival.ConclusionsChanges in metabolic levels of tumoral NAA/Cho and Lac/NAA can serve as early biomarkers for predicting treatment failure to anti-angiogenic therapy as soon as 1 day after bevacizumab-based therapy. The addition of MRS to conventional MR methods can provide better insight into how anti-angiogenic therapy affects tumor microenvironment and predict patient outcomes.
| S-EPMC8193903 | biostudies-literature
Project description:Glioblastoma (GBM) is a rapidly progressive brain cancer that exploits the neural microenvironment, and particularly blood vessels, for selective growth and survival. Anti-angiogenic agents such as the vascular endothelial growth factor-A (VEGF-A) blocking antibody bevacizumab yield short-term benefits to patients due to blood vessel regression and stabilization of vascular permeability. However, tumor recurrence is common, and this is associated with acquired resistance to bevacizumab. The mechanisms that drive acquired resistance and tumor recurrence in response to anti-angiogenic therapy remain largely unknown. Here, we report that Neuropilin-1 (Nrp1) regulates GBM growth and invasion by balancing tumor cell responses to VEGF-A and transforming growth factor ?s (TGF?s). Nrp1 is expressed in GBM cells where it promotes TGF? receptor internalization and signaling via Smad transcription factors. GBM that recur after bevacizumab treatment show down-regulation of Nrp1 expression, indicating that altering the balance between VEGF-A and TGF? signaling is one mechanism that promotes resistance to anti-angiogenic agents. Collectively, these data reveal that Nrp1 plays a critical role in balancing responsiveness to VEGF-A versus TGF? to regulate GBM growth, progression, and recurrence after anti-vascular therapy.
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Project description:PolyP (inorganic polyphosphate) is a linear polymer of many tens or hundreds of orthophosphate residues found in a wide range of organisms, including bacteria, fungi, insects, plants and vertebrates. Despite its wide distribution in mammalian tissues and plasma, the biological functions of polyP on tumour metastasis and angiogenesis have not been previously examined. In the present study, we have shown that polyP effectively blocked in vivo pulmonary metastasis of B16BL6 cells by suppression of neovascularization, whereas it did not affect proliferation or adhesion to extracellular matrix proteins. PolyP not only inhibited bFGF (basic fibroblast growth factor)-induced proliferation and ERK (extracellular-signal-regulated kinase)/p38 MAPK (mitogen-activated protein kinase) activation of human endothelial cells, but also blocked the binding of bFGF to its cognate cell-surface receptor. Furthermore, polyP inhibited bFGF-induced in vitro and in vivo angiogenesis, suggesting that polyP possesses an anti-angiogenic activity. Since neovascularization is essential for tumour metastasis, our present findings clearly indicate that polyP has an in vivo anti-metastatic activity via its anti-angiogenic activity. Taken together with the fact that angiogenesis occurs under various normal and pathological conditions, our observations suggest that endogenous polyP may play a critical role during embryonic development, wound healing and inflammation, as well as in the progress of pathological diseases such as rheumatoid arthritis and cancer.
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Project description:Glioblastoma is the most common primitive tumor in adult central nervous system (CNS), classified as grade IV according to WHO 2016 classification. Glioblastoma shows a poor prognosis with an average survival of approximately 15 months, representing an extreme therapeutic challenge. One of its distinctive and aggressive features is aberrant angiogenesis, which drives tumor neovascularization, representing a promising candidate for molecular target therapy. Although several pre-clinical studies and clinical trials have shown promising results, anti-angiogenic drugs have not led to a significant improvement in overall survival (OS), suggesting the necessity of identifying novel therapeutic strategies. Metformin, an anti-hyperglycemic drug of the Biguanides family, used as first line treatment in Type 2 Diabetes Mellitus (T2DM), has demonstrated in vitro and in vivo antitumoral efficacy in many different tumors, including glioblastoma. From this evidence, a process of repurposing of the drug has begun, leading to the demonstration of inhibition of various oncopromoter mechanisms and, consequently, to the identification of the molecular pathways involved. Here, we review and discuss metformin's potential antitumoral effects on glioblastoma, inspecting if it could properly act as an anti-angiogenic compound to be considered as a safely add-on therapy in the treatment and management of glioblastoma patients.
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Project description:Glioblastoma multiforme (GBM) possesses florid angiogenesis. However, the anti-angiogenic agent, Bevacizumab, did not improve overall survival of GBM patients. For more durable anti-angiogenic treatment, we interrogated resistant mechanisms of GBM against Bevacizumab. Serial orthotopic transplantation of in vivo Bevacizumab-treated GBM cells provoked complete refractoriness to the anti-angiogenic treatment. These tumors were also highly enriched with malignant phenotypes such as invasiveness, epithelial to mesenchymal transition, and stem-like features. Through transcriptome analysis, we identified that Talin1 (TLN1) significantly increased in the refractory GBMs. Inhibition of TLN1 not only attenuated malignant characteristics of GBM cells but also reversed the resistance to the Bevacizumab treatment. These data implicate TLN1 as a novel therapeutic target for GBM to overcome resistance to anti-angiogenic therapies.
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