New Directions in Anti-Angiogenic Therapy for Glioblastoma

Wang, Nancy; Jain, Rakesh K.; Batchelor, Tracy T.

doi:10.1007/s13311-016-0510-y

Cited by 100 publications

(88 citation statements)

References 144 publications

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“…Tumor vessels are tortuous, often large and uneven in diameter, slow flowing, and leaky. [5][6][7] Leakage of contrast from tumor vessels is visible as enhancement on conventional postcontrast T 1 -weighted MRI. However, with perfusion MRI it is possible to determine the blood volume and flow as well as the leakage component, thereby extending information about the tumor vasculature.…”

Section: Accreditationmentioning

confidence: 99%

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Perfusion MRI in treatment evaluation of glioblastomas: Clinical relevance of current and future techniques

Dijken

Laar

Smits

et al. 2018

Magnetic Resonance Imaging

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Treatment evaluation of patients with glioblastomas is important to aid in clinical decisions. Conventional MRI with contrast is currently the standard method, but unable to differentiate tumor progression from treatment‐related effects. Pseudoprogression appears as new enhancement, and thus mimics tumor progression on conventional MRI. Contrarily, a decrease in enhancement or edema on conventional MRI during antiangiogenic treatment can be due to pseudoresponse and is not necessarily reflective of a favorable outcome. Neovascularization is a hallmark of tumor progression but not for posttherapeutic effects. Perfusion‐weighted MRI provides a plethora of additional parameters that can help to identify this neovascularization. This review shows that perfusion MRI aids to identify tumor progression, pseudoprogression, and pseudoresponse. The review provides an overview of the most applicable perfusion MRI methods and their limitations. Finally, future developments and remaining challenges of perfusion MRI in treatment evaluation in neuro‐oncology are discussed. Level of Evidence: 3 Technical Efficacy: Stage 4 J. Magn. Reson. Imaging 2019;49:11–22.

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Section: Accreditationmentioning

confidence: 99%

“…The net result of neovascularization is an extensive network of poorly organized tumor vessels. Tumor vessels are tortuous, often large and uneven in diameter, slow flowing, and leaky . Leakage of contrast from tumor vessels is visible as enhancement on conventional postcontrast T 1 ‐weighted MRI.…”

mentioning

confidence: 99%

Perfusion MRI in treatment evaluation of glioblastomas: Clinical relevance of current and future techniques

Dijken

Laar

Smits

et al. 2018

Magnetic Resonance Imaging

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“…Taken together, resistance to ponatinib may not be primarily related to hypoxia—induced by vascular rarefaction after VEGFR/FGFR inhibition—but rather to increased inflammatory cytokines. Indeed, some preclinical data suggest that certain immune cytokines may play a role in resistance to anti‐angiogenic therapy …”

Section: Discussionmentioning

confidence: 99%

“…In a phase II study, adding chemotherapy to bevacizumab in patients whose tumors already progressed on bevacizumab monotherapy was associated with little to no benefit . Mechanisms underlying resistance to antiangiogenesis agents in GBM are inadequately understood, but may include upregulation of alternative pro‐angiogenic pathways, vessel co‐option, increased invasiveness, and immune activation . Plasma levels of basic fibroblast growth factor (bFGF) increase in GBM patients treated with anti‐VEGF receptor (VEGFR) at the time of tumor progression, suggest that signaling by bFGF may play a role in resistance to antiangiogenesis agents .…”

Section: Introductionmentioning

confidence: 99%

Phase II trial of ponatinib in patients with bevacizumab‐refractory glioblastoma

et al. 2019

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Background Responses to bevacizumab in glioblastoma (GBM) are not durable. Plasma levels of basic fibroblast growth factor (bFGF) increase at the time of tumor progression. By targeting vascular endothelial growth factor receptor (VEGFR), platelet‐derived growth factor receptor, Src, and FGF receptor pathways, ponatinib may potentially help to overcome some of the putative mechanisms of adaptive resistance. Methods We performed a phase II trial of ponatinib in patients with bevacizumab‐refractory GBM and variants. Adult patients with Karnofsky performance score (KPS) ≥60, measurable disease, and normal organ and marrow function received 45 mg ponatinib daily. No limit on the number of prior therapies but only one prior bevacizumab‐containing regimen was allowed. Primary endpoint was 3‐month progression‐free survival. Plasma biomarkers of angiogenesis and inflammation were evaluated before and after treatment. Results The study closed after the first stage. Fifteen patients enrolled: median age 61 [27‐74]; median KPS 80 [70‐90]; median number of prior relapses 2 [2‐4]. Three‐month progression‐free survival rate was 0, median overall survival was 98 days [95% CI 56, 257], and median PFS was 28 days [95% CI 27, 30]. No responses were seen. The most common grade ≥3 adverse events included fatigue (n = 3), hypertension (2), and lipase elevation (2). Ponatinib treatment significantly increased plasma VEGF, soluble (s)VEGFR1, sVEGFR2, sTIE2, interferon gamma (IFNγ), tumor necrosis factor alpha (TNF‐α), interleukin (IL)‐6, IL‐8, and IL‐10 and decreased sVEGFR2. Conclusions Ponatinib was associated with minimal activity in bevacizumab‐refractory GBM patients. Circulating biomarker data confirmed pharmacodynamic changes and suggested that resistance to ponatinib may be related to an increase in inflammatory cytokines.

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“…The perfusion and oxygenation of tumors is thus improved, and this may limit invasion and metastasis as well as improve chemotherapeutic drug access to the tumor. High‐grade gliomas usually present an extreme case of tumor angiogenesis, but anti‐angiogenic therapy has so far not lived up to expectations in this tumor type (Wang et al , ).…”

Section: Macrophage Depletion Treatment By Targeting Csf‐1 In Combinmentioning

confidence: 99%

Fighting vessel dysmorphia to improve glioma chemotherapy

Lohela

Alitalo

2017

EMBO Mol Med

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High‐grade gliomas are aggressive and abundantly vascular tumors, and as in most cancer types, blood vessels in advanced lesions are highly abnormal. Poor perfusion and vascular leakage in tumor tissue resulting in hypoxia, necrosis, and high interstitial fluid pressure can hamper the efficient delivery of chemotherapy. Tumor angiogenesis is known to be supported by host leukocytes recruited to the tumor microenvironment, but the mechanisms leading to dysfunctional vascular network formation are incompletely understood. In this issue of EMBO Molecular Medicine, Mathivet et al (2017) present an elegant study, where longitudinal intravital imaging gives new insight on how recruitment and polarization of tumor‐associated macrophages regulate aberrant angiogenesis in experimental gliomas. They show that macrophage targeting results in vessel normalization and improved chemotherapy response, suggesting that the combination of these therapeutic modalities could improve the outcome of glioma treatment in the clinic.

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New Directions in Anti-Angiogenic Therapy for Glioblastoma

Cited by 100 publications

References 144 publications

Perfusion MRI in treatment evaluation of glioblastomas: Clinical relevance of current and future techniques

Perfusion MRI in treatment evaluation of glioblastomas: Clinical relevance of current and future techniques

Phase II trial of ponatinib in patients with bevacizumab‐refractory glioblastoma

Fighting vessel dysmorphia to improve glioma chemotherapy

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