Cilengitide: Difference between revisions

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| IUPHAR_ligand = 6597

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| SMILES = O=C1N[C@H](C(=O)NCC(=O)N[C@H](C(=O)N[C@@H](C(=O)N(C)[C@H]1C(C)C)Cc2ccccc2)CC(=O)O)CCC/N=C(\N)N

| MeSHName = Cilengitide

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| C=27 | H=40 | N=8 | O=7

| MolarMass = 588.656 g/mol

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| Density = 1.417 g/mL

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'''Cilengitide''' (EMD 121974) is a molecule designed and synthesized at the [[Technical University Munich]] in collaboration with [[Merck KGaA]] in [[Darmstadt]]. It is based on the cyclic [[peptide]] [[Arginylglycylaspartic acid|cyclo(-RGDfV-)]], which is selective for [[αv integrins|α_v integrins]], which are important in [[angiogenesis]] (forming new blood vessels), and other aspects of tumor biology. Hence, it is under investigation for the treatment of [[glioblastoma]], where it may act by inhibiting angiogenesis, and influencing tumor invasion and proliferation.<ref>{{cite journal | vauthors = Burke PA, DeNardo SJ, Miers LA, Lamborn KR, Matzku S, DeNardo GL | title = Cilengitide targeting of alpha(v)beta(3) integrin receptor synergizes with radioimmunotherapy to increase efficacy and apoptosis in breast cancer xenografts | journal = Cancer Research | volume = 62 | issue = 15 | pages = 4263–72 | date = August 2002 | pmid = 12154028 }}</ref><ref>{{cite journal | vauthors = Goodman SL, Hölzemann G, Sulyok GA, Kessler H | title = Nanomolar small molecule inhibitors for alphav(beta)6, alphav(beta)5, and alphav(beta)3 integrins | journal = Journal of Medicinal Chemistry | volume = 45 | issue = 5 | pages = 1045–51 | date = February 2002 | pmid = 11855984 | doi = 10.1021/jm0102598 }}</ref>

The [[European Medicines Agency]] has granted cilengitide [[orphan drug]] status.<ref>{{cite journal | vauthors = Spreitzer H | date = October 27, 2008 | title = Neue Wirkstoffe - Cilengitide | journal = Österreichische Apothekerzeitung | issue = 22/2008 | pages = 1136–7 | language = de }}</ref>

Cilengitide seems to function by inhibiting the [[Focal Adhesion Kinase|FAK]]/[[c-Src|Src]]/[[AKT]] pathway and inducing apoptosis in endothelial cells.<ref name=Yamada2006>{{cite journal | vauthors = Yamada S, Bu XY, Khankaldyyan V, Gonzales-Gomez I, McComb JG, Laug WE | title = Effect of the angiogenesis inhibitor Cilengitide (EMD 121974) on glioblastoma growth in nude mice | journal = Neurosurgery | volume = 59 | issue = 6 | pages = 1304–12; discussion 1312 | date = December 2006 | pmid = 17277694 | doi = 10.1227/01.NEU.0000245622.70344.BE | s2cid = 19861713 }}</ref> Preclinical studies in mice of cilengitide were able to demonstrate efficacious tumor regression.<ref name=Yamada2006/>

In a rat xenograft model, cilengitide was able to potentiate the cytotoxic effects of radiation when cilengitide was administered prior to radiation therapy.<ref name=Mikkelsen2009>{{cite journal | vauthors = Mikkelsen T, Brodie C, Finniss S, Berens ME, Rennert JL, Nelson K, Lemke N, Brown SL, Hahn D, Neuteboom B, Goodman SL | title = Radiation sensitization of glioblastoma by cilengitide has unanticipated schedule-dependency | journal = International Journal of Cancer | volume = 124 | issue = 11 | pages = 2719–27 | date = June 2009 | pmid = 19199360 | doi = 10.1002/ijc.24240 | doi-access = | s2cid = 12073569 }}</ref> When combined with radiation, inhibition of integrin expression by cilengitide synergistically improves the cytotoxic effects of ionizing radiation for glioblastoma.<ref name=Mikkelsen2009/>

==Clinical trials==

Phase II studies were able to demonstrate that cilengitide as a potential [[monotherapy]] in patients with recurrent [[glioblastoma]]<ref name="pmid18981465">{{cite journal | vauthors = Reardon DA, Fink KL, Mikkelsen T, Cloughesy TF, O'Neill A, Plotkin S, Glantz M, Ravin P, Raizer JJ, Rich KM, Schiff D, Shapiro WR, Burdette-Radoux S, Dropcho EJ, Wittemer SM, Nippgen J, Picard M, Nabors LB | display-authors = 6| title = Randomized phase II study of cilengitide, an integrin-targeting arginine-glycine-aspartic acid peptide, in recurrent glioblastoma multiforme | journal = Journal of Clinical Oncology | volume = 26 | issue = 34 | pages = 5610–7 | date = December 2008 | pmid = 18981465 | doi = 10.1200/JCO.2008.16.7510 | citeseerx = 10.1.1.688.8987}}</ref>

with high intratumor drug levels when 2000&nbsp;mg of cilengitide is given twice weekly.<ref name="Gilbert_2012">{{cite journal | vauthors = Gilbert MR, Kuhn J, Lamborn KR, Lieberman F, Wen PY, Mehta M, Cloughesy T, Lassman AB, Deangelis LM, Chang S, Prados M | title = Cilengitide in patients with recurrent glioblastoma: the results of NABTC 03-02, a phase II trial with measures of treatment delivery | journal = Journal of Neuro-Oncology | volume = 106 | issue = 1 | pages = 147–53 | date = January 2012 | pmid = 21739168 | pmc = 4351869 | doi = 10.1007/s11060-011-0650-1 }}</ref>

Cilengitide is well tolerated, in combination with radiation and temozolomide, at a dose of 2000&nbsp;mg in patients with newly diagnosed glioblastoma, regardless of [[MGMT promoter]] status.<ref name="pmid22517399">{{cite journal | vauthors = Nabors LB, Mikkelsen T, Hegi ME, Ye X, Batchelor T, Lesser G, Peereboom D, Rosenfeld MR, Olsen J, Brem S, Fisher JD, Grossman SA | title = A safety run-in and randomized phase 2 study of cilengitide combined with chemoradiation for newly diagnosed glioblastoma (NABTT 0306) | journal = Cancer | volume = 118 | issue = 22 | pages = 5601–7 | date = November 2012 | pmid = 22517399 | pmc = 3423527 | doi = 10.1002/cncr.27585 }}</ref>

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.<ref name="pmid20439646">{{cite journal | vauthors = Stupp R, Hegi ME, Neyns B, Goldbrunner R, Schlegel U, Clement PM, Grabenbauer GG, Ochsenbein AF, Simon M, Dietrich PY, Pietsch T, Hicking C, Tonn JC, Diserens AC, Pica A, Hermisson M, Krueger S, Picard M, Weller M | display-authors = 6 | title = Phase I/IIa study of cilengitide and temozolomide with concomitant radiotherapy followed by cilengitide and temozolomide maintenance therapy in patients with newly diagnosed glioblastoma | journal = Journal of Clinical Oncology | volume = 28 | issue = 16 | pages = 2712–8 | date = June 2010 | pmid = 20439646 | doi = 10.1200/JCO.2009.26.6650 | url = http://www.zora.uzh.ch/id/eprint/35461/4/MW_Stupp_Cil_Rev2_JCO%2709_266650.pdf }}</ref>

However, in a subsequent study, cilengitide does not seem to alter the pattern of glioblastoma progression,<ref name="pmid24442484">{{cite journal | vauthors = Eisele G, Wick A, Eisele AC, Clément PM, Tonn J, Tabatabai G, Ochsenbein A, Schlegel U, Neyns B, Krex D, Simon M, Nikkhah G, Picard M, Stupp R, Wick W, Weller M | display-authors = 6 | title = Cilengitide treatment of newly diagnosed glioblastoma patients does not alter patterns of progression | journal = Journal of Neuro-Oncology | volume = 117 | issue = 1 | pages = 141–5 | date = March 2014 | pmid = 24442484 | doi = 10.1007/s11060-014-1365-x | s2cid = 21636884 | url = http://doc.rero.ch/record/325810/files/11060_2014_Article_1365.pdf }}</ref> 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 <ref>Merck Group. [http://news.merck.de/N/0/BE2FE07AD630830EC1257B1D001F007B/$File/CENTRIC-E.pdf "Phase III Trial of Cilengitide Did Not Meet Primary Endpoint in Patients With Newly Diagnosed Glioblastoma, Date accessed: 3/24/2014."]</ref> In 2014, a phase II study, the CORE trial, was conducted in patients with newly diagnosed glioblastoma and unmethylated MGMT promoter status.<ref>ASCO Meeting Library. [http://meetinglibrary.asco.org/content/112780-132] "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."</ref>{{update inline|date=July 2023}}

== References ==

[[Category:Peptide therapeutics]]

[[Category:Drugs developed by Merck]]