Cilengitide (EMD 121974) is a molecule designed and synthesized at the

Technical University Munich The Technical University of Munich (TUM or TU Munich; german: Technische Universität München) is a public research university in Munich, Germany. It specializes in engineering, technology, medicine, and applied and natural sciences. Establis ...

in collaboration with

Merck KGaA The Merck Group, branded and commonly known as Merck, is a German multinational science and technology company headquartered in Darmstadt, with about 60,000 employees and present in 66 countries. The group includes around 250 companies; the ma ...

Darmstadt Darmstadt () is a city in the States of Germany, state of Hesse in Germany, located in the southern part of the Frankfurt Rhine Main Area, Rhine-Main-Area (Frankfurt Metropolitan Region). Darmstadt has around 160,000 inhabitants, making it th ...

. It is based on the cyclic

peptide Peptides (, ) are short chains of amino acids linked by peptide bonds. Long chains of amino acids are called proteins. Chains of fewer than twenty amino acids are called oligopeptides, and include dipeptides, tripeptides, and tetrapeptides. A ...

cyclo(-RGDfV-), which is selective for α_v integrins, which are important in

angiogenesis Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels, formed in the earlier stage of vasculogenesis. Angiogenesis continues the growth of the vasculature by processes of sprouting and splitting ...

(forming new blood vessels), and other aspects of tumor biology. Hence, it is under investigation for the treatment of

glioblastoma Glioblastoma, previously known as glioblastoma multiforme (GBM), is one of the most aggressive types of cancer that begin within the brain. Initially, signs and symptoms of glioblastoma are nonspecific. They may include headaches, personality ch ...

, where it may act by inhibiting angiogenesis, and influencing tumor invasion and proliferation. The

European Medicines Agency The European Medicines Agency (EMA) is an agency of the European Union (EU) in charge of the evaluation and supervision of medicinal products. Prior to 2004, it was known as the European Agency for the Evaluation of Medicinal Products or Euro ...

has granted cilengitide

orphan drug An orphan drug is a pharmaceutical agent developed to treat medical conditions which, because they are so rare, would not be profitable to produce without government assistance. The conditions are referred to as orphan diseases. The assignment of ...

status. Cilengitide seems to function by inhibiting the FAK/ Src/

AKT Protein kinase B (PKB), also known as Akt, is the collective name of a set of three serine/threonine-specific protein kinases that play key roles in multiple cellular processes such as glucose metabolism, apoptosis, cell proliferation, tran ...

pathway and inducing apoptosis in endothelial cells. Preclinical studies in mice of cilengitide were able to demonstrate efficacious tumor regression. In a rat xenograft model, cilengitide was able to potentiate the cytotoxic effects of radiation when cilengitide was administered prior to radiation therapy. When combined with radiation, inhibition of integrin expression by cilengitide synergistically improves the cytotoxic effects of ionizing radiation for glioblastoma.

Clinical trials

Phase II studies were able to demonstrate that cilengitide as a potential

monotherapy Combination therapy or polytherapy is therapy that uses more than one medication or modality. Typically, the term refers to using multiple therapies to treat a ''single'' disease, and often all the therapies are pharmaceutical (although it can also ...

in patients with recurrent

with high intratumor drug levels when 2000 mg of cilengitide is given twice weekly. Cilengitide is well tolerated, in combination with radiation and temozolomide, at a dose of 2000 mg in patients with newly diagnosed glioblastoma, regardless of

MGMT promoter ''O''6-alkylguanine DNA alkyltransferase (also known as AGT, MGMT or AGAT) is a protein that in humans is encoded by the ''O''6-methylguanine DNA methyltransferase (''MGMT'') gene. O6-methylguanine DNA methyltransferase is crucial for genome stabi ...

status. In a phase I/IIa study, the addition of cilengitide to the standard of care for newly diagnosed glioblastoma (surgical resection followed by temozolomide and radiation therapy) improves progression-free survival and overall survival in patients with MGMT promoter methylation. However, in a subsequent study, cilengitide does not seem to alter the pattern of glioblastoma progression, and in an EORTC phase III randomized, controlled, multicenter clinical trial, consisting of over 500 patients in 23 countries, the addition of cilengitide to the standard of care did not improve overall survival in patients with newly diagnosed glioblastoma and methylated MGMT promoter status A phase II study, the CORE trial, is currently being conducted in patients with newly diagnosed glioblastoma and unmethylated MGMT promoter status.ASCO Meeting Library

"Cilengitide combined with standard treatment for patients with newly diagnosed glioblastoma and methylated O6-methylguanine-DNA methyltransferase (MGMT) gene promoter: Key results of the multicenter, randomized, open-label, controlled, phase III CENTRIC study, Date accessed: 3/24/2014."

References

{{Reflist Macrocycles Peptides Orphan drugs Merck brands Experimental cancer drugs Cancer treatments