Cilengitide: an RGD pentapeptide ανβ3 and ανβ5 integrin inhibitor in development for glioblastoma and other malignancies

Abstract

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.

Emerging insights into the molecular and cellular basis of glioblastoma

“…Integrins, particularly the avb3 and avb5 heterodimers (Bello et al 2001a), also likely contribute to glioma cell adherence to the ECM in a process that activates cytoskeletal rearrangement through cytoplasmic mediators, including FAK (Rutka et al 1999;Riemenschneider et al 2005) and/or Pyk2 (Lipinski et al 2008). Their putative involvement in glioma pathobiology (D'Abaco and Kaye 2007; Desgrosellier and Cheresh 2010) has prompted the testing of the avb3 and avb5 integrin inhibitor cilengitide in an ongoing phase III CENTRIC clinical trial for newly diagnosed glioblastoma in combination with radiation therapy and temozolomide (Reardon et al 2011a).…”

Cilengitide downmodulates invasiveness and vasculogenic mimicry of neuropilin 1 expressing melanoma cells through the inhibition of αvβ5 integrin

“…In this regard, cilengitide, a cyclic arginine-glycine-aspartic acid containing pentapeptide that potently blocks the activation of av integrins (e.g., amb3 and amb5 integrins), represents the most clinically advanced integrin-targeting therapeutics. In fact, cilengitide is currently under evaluation in a phase III study (in combination with radio-chemotherapy) for newly diagnosed glioblastoma and in phase II studies for other tumour types, including metastatic melanoma [9][10][11] (www.clinicaltrials.gov). However, cilengitide as single agent has shown minimal clinical efficacy in patients with metastatic melanoma, suggesting that the integrin inhibitor may prove more effective in combination therapies.…”

Biomarker Discovery, Validation and Clinical Application for Patients Diagnosed with Glioma

“…This is predominantly because there is only a modest overall survival benefit of 7.8-9.2 months suggesting a further improvement of efficacy is needed. Numerous phase II studies have shown modest survival benefits with bevacizumab either as a monotherapy or in combination with irinotecan (Chinot et al 2011;Jakobsen et al 2011;Lai et al 2011;Prados et al 2011;Reardon et al 2011). Consistent to all trials examining bevacizumab efficacy is the reduction of steroids for patients and valuable palliation with preservation of key performance status (KPS), supporting a role for bevacizumab as a therapy in late stage disease (Hofer et al 2011).…”