Cediranib: profile of a novel anti-angiogenic agent in patients with glioblastoma

Dietrich, Jörg; Wang, Daphne; Batchelor, Tracy T.

doi:10.1517/13543780903183528

Cited by 55 publications

(39 citation statements)

References 56 publications

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“…The critical role of VEGF/VEGFR2 in tumour angiogenesis has been demonstrated in both animal studies and clinical trials in numerous human malignancies, including glioblastoma [20]–[22]. PDGFRA and KIT too, may be expressed in the glioblastoma-associated vasculature, although they have been less extensively studied.…”

Section: Introductionmentioning

confidence: 99%

Distinct Phenotypic Differences Associated with Differential Amplification of Receptor Tyrosine Kinase Genes at 4q12 in Glioblastoma

et al. 2013

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Gene amplification at chromosome 4q12 is a common alteration in human high grade gliomas including glioblastoma, a CNS tumour with consistently poor prognosis. This locus harbours the known oncogenes encoding the receptor tyrosine kinases PDGFRA, KIT, and VEGFR2. These receptors are potential targets for novel therapeutic intervention in these diseases, with expression noted in tumour cells and/or associated vasculature. Despite this, a detailed assessment of their relative contributions to different high grade glioma histologies and the underlying heterogeneity within glioblastoma has been lacking. We studied 342 primary high grade gliomas for individual gene amplification using specific FISH probes, as well as receptor expression in the tumour and endothelial cells by immunohistochemistry, and correlated our findings with specific tumour cell morphological types and patterns of vasculature. We identified amplicons which encompassed PDGFRA only, PDGFRA/KIT, and PDGFRA/KIT/VEGFR2, with distinct phenotypic correlates. Within glioblastoma specimens, PDGFRA amplification alone was linked to oligodendroglial, small cell and sarcomatous tumour cell morphologies, and rare MGMT promoter methylation. A younger age at diagnosis and better clinical outcome in glioblastoma patients is only seen when PDGFRA and KIT are co-amplified. IDH1 mutation was only found when all three genes are amplified; this is a subgroup which also harbours extensive MGMT promoter methylation. Whilst PDGFRA amplification was tightly linked to tumour expression of the receptor, this was not the case for KIT or VEGFR2. Thus we have identified differential patterns of gene amplification and expression of RTKs at the 4q12 locus to be associated with specific phenotypes which may reflect their distinct underlying mechanisms.

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Section: Introductionmentioning

confidence: 99%

Distinct Phenotypic Differences Associated with Differential Amplification of Receptor Tyrosine Kinase Genes at 4q12 in Glioblastoma

et al. 2013

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“…Bevacizumab, sorafenib, sunitinib, and pazopanib have all been approved to treat solid tumors. Cediranib (AZD2171) is an oral small-molecule inhibitor of VEGF receptor 1 (VEGFR-1), VEGFR-2, VEGFR-3, PDGFR, and c-kit that is currently in phase II testing for the treatment of tumors such as epithelial ovarian carcinoma, nonsmall cell lung cancer, glioblastoma, and colon cancer (1)(2)(3)(4). Because the primary toxicities of this drug class are on-target effects related to VSP inhibition, toxicities may be more common or severe with the newer, more potent members of this drug class currently in development.…”

mentioning

confidence: 99%

Rapid Development of Hypertension and Proteinuria with Cediranib, an Oral Vascular Endothelial Growth Factor Receptor Inhibitor

Robinson

Matulonis²,

Ivy

et al. 2010

Clinical Journal of the American Society of Nephrology

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Background and objectives: Hypertension and proteinuria are common but poorly understood renal toxicities of vascular endothelial growth factor (VEGF) receptor signaling pathway inhibitors. In this phase II study of cediranib (AZD2171) for recurrent epithelial ovarian cancer, the time course and severity of BP changes and proteinuria were characterized.Design, setting, participants, & measurements: 46 women ages 41 to 77 years were treated with cediranib. 26% had baseline hypertension. Twice-daily BP was recorded. Urinalyses were performed every 2 weeks, and in some patients proteinuria was further quantified.Results: 31 women (67%) developed hypertension by day 3; 87% by the end of the study. 43% developed grade >3 hypertension. Mean systolic BP increase over 3 days was 18 mmHg. Women above the mean age (>57 years) had a larger rise in systolic BP by day 3 (15.9 versus 7.0 mmHg). 14 women developed proteinuria. There was a dose response (45 versus 30 mg daily). Proteinuria also developed rapidly, with 7 of 14 women developing proteinuria within 2 weeks. Only 7 of 20 women who developed grade 3 hypertension developed proteinuria.Conclusions: Cediranib induced a rapid but variable rise in BP within 3 days of initiation in most patients. Proteinuria was common and also developed rapidly. The rapid development of hypertension suggests that acute inhibition of VEGFdependent vasodilation might explain the BP rise with VEGF inhibitors. Clinicians must be vigilant in early detection and management of toxicities of this expanding drug class, especially in older patients.

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“…In some tumors in which angiogenesis is inhibited genetically or pharmacologically, cancer cells could adapt by migrating more aggressively into normal tissue [165]. Two studies describing pro-invasive adaptation, as observed by MRI, in a subset of glioblastoma multiforme patients during anti-VEGF therapy with both cedinarib and bevacizumab have confirmed this in the clinical setting [26,166].…”

Section: Resistance To Antiangiogenesis Therapymentioning

confidence: 90%

Angiogenesis Inhibitors: Implications for Combination with Conventional Therapies

Moschetta

Cesca

Pretto

et al. 2010

CPD

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Angiogenesis is associated with tumor development and malignancy and is a validated target for cancer treatment. Preclinical and clinical evidence substantiates the feasibility of combining angiogenesis inhibitors with conventional anticancer therapy. This review discusses recent progress in combining antiangiogenic drugs, mainly acting on the VEGF/VEGFR pathway, with chemotherapy and other conventional therapies. Strategies for the optimization of combination therapy and the selection of appropriate treatment regimens are examined. As new drugs are entering clinical trials, reliable biomarkers are needed to stratify patients for antiangiogenic therapy, to identify resistant patients and to monitor response to treatment.

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Cediranib: profile of a novel anti-angiogenic agent in patients with glioblastoma

Cited by 55 publications

References 56 publications

Distinct Phenotypic Differences Associated with Differential Amplification of Receptor Tyrosine Kinase Genes at 4q12 in Glioblastoma

Distinct Phenotypic Differences Associated with Differential Amplification of Receptor Tyrosine Kinase Genes at 4q12 in Glioblastoma

Rapid Development of Hypertension and Proteinuria with Cediranib, an Oral Vascular Endothelial Growth Factor Receptor Inhibitor

Angiogenesis Inhibitors: Implications for Combination with Conventional Therapies

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