Phase I Clinical Trial of Cilengitide in Children With Refractory Brain Tumors: Pediatric Brain Tumor Consortium Study PBTC-012

MacDonald, Tobey J.; Stewart, Clinton F.; Kocak, Mehmet; Goldman, Stewart; Ellenbogen, Richard G.; Phillips, Peter C.B.; Lafond, Deborah; Poussaint, Tina Young; Kieran, Mark W.; Boyett, James M.; Kun, Larry E.

doi:10.1200/jco.2007.14.1812

Cited by 134 publications

(98 citation statements)

References 20 publications

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“…[43][44][45][46][47] The use of integrin antagonists in glioblastoma and colorectal carcinoma as a therapeutic modality has shown promise in clinical trials. 48,49 The finding of deregulated integrin signaling in our study is not surprising as the upregulation of different integrins has been previously demonstrated in cutaneous squamous cell carcinomas. 50,51 …”

Section: Integrin Signalingsupporting

confidence: 70%

Molecular discrimination of cutaneous squamous cell carcinoma from actinic keratosis and normal skin

Hui

Binder

2011

Modern Pathology

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Actinic keratosis is widely believed to be a neoplastic lesion and a precursor to invasive squamous cell carcinoma. However, there has been some debate as to whether actinic keratosis is in fact actually squamous cell carcinoma and should be treated as such. As the clinical management and prognosis of patients is widely held to be different for each of these lesions, our goal was to identify unique gene signatures using DNA microarrays to discriminate among normal skin, actinic keratosis, and squamous cell carcinoma, and examine the molecular pathways of carcinogenesis involved in the progression from normal skin to squamous cell carcinoma. Formalin-fixed and paraffin-embedded blocks of skin: five normal skins (pooled), six actinic keratoses, and six squamous cell carcinomas were retrieved. The RNA was extracted and amplified. The labeled targets were hybridized to the Affymetrix human U133plus2.0 array and the acquisition and initial quantification of array images were performed using the GCOS (Affymetrix). The subsequent data analyses were performed using DNA-Chip Analyzer and Partek Genomic Suite 6.4. Significant differential gene expression (42 fold change, Po0.05) was seen with 382 differentially expressed genes between squamous cell carcinoma and normal skin, 423 differentially expressed genes between actinic keratosis and normal skin, and 9 differentially expressed genes between actinic keratosis and squamous cell carcinoma. The differentially expressed genes offer the possibility of using DNA microarrays as a molecular diagnostic tool to distinguish between normal skin, actinic keratosis, and squamous cell carcinoma. In addition, the differentially expressed genes and their molecular pathways could be potentially used as prognostic markers or targets for future therapeutic innovations.

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Section: Integrin Signalingsupporting

confidence: 70%

Molecular discrimination of cutaneous squamous cell carcinoma from actinic keratosis and normal skin

Hui

Binder

2011

Modern Pathology

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“…Etaracizumab is a monoclonal antibody to α V β 3 that is undergoing early clinical development for treatment of melanoma [59][60] and solid tumours 61 . The cyclic-RGD peptide cilengitide is a specific α V β 3 antagonist and is currently under going clinical trials for use in glioblastoma [62][63] and in other brain cancers 64 and has recently become the first anti-integrin to enter Phase III trials for cancer 65 . The orally-active, non-peptide α V β 3 antagonist MK 0429 is under going clinical development for prostate cancer 66 .…”

Section: Integrins and Diseasementioning

confidence: 99%

Integrins as therapeutic targets: lessons and opportunities

Cox

Brennan

Moran

2010

Nat Rev Drug Discov

410

350

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“…Results from a number of clinical trials reveal consistent pharmacokinetic measures [42,44,[83][84][85].…”

Section: Pharmacokinetics and Metabolismmentioning

confidence: 99%

“…One patient with a recurrent GBM experienced a complete response and two had stable disease. The recommended dose for subsequent studies in children is 1800 mg/m 2 [44].…”

Section: Clinical Efficacymentioning

confidence: 99%

“…Preclinical studies demonstrate that cilengitide monotherapy has anti-tumor activity in xenograft tumor models and cilengitide can augment the activity of radiation and chemotherapy, including TMZ [36][37][38][39][40]. Cilengitide monotherapy and the combination of cilengitide with standard temozolomide (TMZ) and radiation have demonstrated consistent anti-tumor activity as well as a highly favorable safety profile across a spectrum of phase I and II clinical trials for both recurrent and newly diagnosed GBM patients [9,[41][42][43][44]. Cilengitide is currently being evaluated in a multi-national, randomized, pivotal phase III study (CENTRIC) for newly diagnosed GBM patients with methylation of the methylguanine-methyltransferase (MGMT) gene promoter.…”

Section: Introductionmentioning

confidence: 99%

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Cilengitide: An RGD Pentapeptide ανβ3 and ανβ5 Integrin Inhibitor in Development for Glioblastoma and Other Malignancies

et al. 2011

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Cilengitide, a cyclicized arginine-glycine-aspartic acid-containing pentapeptide, potently blocks 3 and 5 integrin activation. Integrins are upregulated in many malignancies and mediate a wide variety of tumor-stroma interactions. Cilengitide and other integrin-targeting therapeutics have preclinical activity against many cancer subtypes including glioblastoma (GBM), the most common and deadliest CNS tumor. Cilengitide is active against orthotopic GBM xenografts and can augment radiotherapy and chemotherapy in these models. In Phase I and II GBM trials, cilengitide and the combination of cilengitide with standard temozolomide and radiation demonstrate consistent antitumor activity and a favorable safety profile. Cilengitide is currently under evaluation in a pivotal, randomized Phase III study cancer subtypes including glioblastoma (GBM), the most common and deadliest central nervous system (CNS) tumor. Cilengitide is active against orthotopic GBM xenografts and can augment radiotherapy and chemotherapy in these models. In phase I and II GBM trials, cilengitide and the combination of cilengitide with standard temozolomide (TMZ) and radiation demonstrate consistent anti-tumor activity and a favorable safety profile. Cilengitide is currently under evaluation in a pivotal, randomized phase III study (CENTRIC) for newly diagnosed GBM. In addition, randomized, controlled phase II studies with cilengitide are ongoing for non-small cell lung cancer and squamous cell carcinoma of the head and neck.Cilengitide is the first integrin-inhibitor in clinical phase III development for oncology.

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Phase I Clinical Trial of Cilengitide in Children With Refractory Brain Tumors: Pediatric Brain Tumor Consortium Study PBTC-012

Abstract: The phase II dosage of intravenous cilengitide in children with refractory brain tumors is 1,800 mg/m(2). A phase II trial to assess the efficacy of cilengitide therapy for children with refractory brain tumors is being developed by the Children's Oncology Group.

Cited by 134 publications

References 20 publications

Molecular discrimination of cutaneous squamous cell carcinoma from actinic keratosis and normal skin

Molecular discrimination of cutaneous squamous cell carcinoma from actinic keratosis and normal skin

Integrins as therapeutic targets: lessons and opportunities

Cilengitide: An RGD Pentapeptide ανβ3 and ανβ5 Integrin Inhibitor in Development for Glioblastoma and Other Malignancies

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