title: Inhibition of TGF-beta2 with AP 12009 in recurrent malignant gliomas: from preclinical to phase I/II studies.
abstract: Transforming growth factor-beta2 (TGF-beta2) is known to suppress the immune response to cancer cells and plays a pivotal role in tumor progression by regulating key mechanisms including proliferation, metastasis, and angiogenesis. For targeted protein suppression the TGF-beta2-specific antisense oligodeoxynucleotide AP 12009 was developed. In vitro experiments have been performed to prove specificity and efficacy of the TGF-beta2 inhibitor AP 12009 employing patient-derived malignant glioma cells as well as peripheral blood mononuclear cells (PBMCs) from patients. Clinically, the antisense compound AP 12009 was assessed in three Phase I/II-studies for the treatment of patients with recurrent or refractory malignant (high-grade) glioma WHO grade III or IV. Although the study was not primarily designed as an efficacy evaluation, prolonged survival compared to literature data and response data were observed, which are very rarely seen in this tumor indication. Two patients experienced long-lasting complete tumor remissions. These results implicate targeted TGF-beta2-suppression using AP 12009 as a promising novel approach for malignant gliomas and other highly aggressive, TGF-beta-2-overexpressing tumors.
authors.affiliation: Department of Neurology, University of Regensburg, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Hau
authors.forename: Piotr
authors.initials: P
authors.lastname: Jachimczak
authors.forename: Reimar
authors.initials: R
authors.lastname: Schlingensiepen
authors.forename: Frank
authors.initials: F
authors.lastname: Schulmeyer
authors.forename: Tanya
authors.initials: T
authors.lastname: Jauch
authors.forename: Andreas
authors.initials: A
authors.lastname: Steinbrecher
authors.forename: Alexander
authors.initials: A
authors.lastname: Brawanski
authors.forename: Martin
authors.initials: M
authors.lastname: Proescholdt
authors.forename: Jürgen
authors.initials: J
authors.lastname: Schlaier
authors.forename: Johanna
authors.initials: J
authors.lastname: Buchroithner
authors.forename: Josef
authors.initials: J
authors.lastname: Pichler
authors.forename: Gabriele
authors.initials: G
authors.lastname: Wurm
authors.forename: Maximilian
authors.initials: M
authors.lastname: Mehdorn
authors.forename: Rainer
authors.initials: R
authors.lastname: Strege
authors.forename: Gerhard
authors.initials: G
authors.lastname: Schuierer
authors.forename: Victoria
authors.initials: V
authors.lastname: Villarrubia
authors.forename: Franz
authors.initials: F
authors.lastname: Fellner
authors.forename: Olav
authors.initials: O
authors.lastname: Jansen
authors.forename: Thorsten
authors.initials: T
authors.lastname: Straube
authors.forename: Virinder
authors.initials: V
authors.lastname: Nohria
authors.forename: Michael
authors.initials: M
authors.lastname: Goldbrunner
authors.forename: Mechthild
authors.initials: M
authors.lastname: Kunst
authors.forename: Susanne
authors.initials: S
authors.lastname: Schmaus
authors.forename: Gerhard
authors.initials: G
authors.lastname: Stauder
authors.forename: Ulrich
authors.initials: U
authors.lastname: Bogdahn
authors.forename: Karl-Hermann
authors.initials: KH
authors.lastname: Schlingensiepen
mesh_terms: D000328:Adult; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000378:metabolism / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005910:Glioma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D020319:Oligodeoxyribonucleotides, Antisense / Q000009:adverse effects / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use*; D012008:Recurrence; D053781:Transforming Growth Factor beta2 / Q000235:genetics* / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D020319:Oligodeoxyribonucleotides, Antisense; D053781:Transforming Growth Factor beta2