Inhibition of TGF-beta2 with AP 12009 in recurrent malignant gliomas: from preclinical to phase I/II studies.
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.
Hau
Peter
P
Department of Neurology, University of Regensburg, Germany.
Jachimczak
Piotr
P
Schlingensiepen
Reimar
R
Schulmeyer
Frank
F
Jauch
Tanya
T
Steinbrecher
Andreas
A
Brawanski
Alexander
A
Proescholdt
Martin
M
Schlaier
Jürgen
J
Buchroithner
Johanna
J
Pichler
Josef
J
Wurm
Gabriele
G
Mehdorn
Maximilian
M
Strege
Rainer
R
Schuierer
Gerhard
G
Villarrubia
Victoria
V
Fellner
Franz
F
Jansen
Olav
O
Straube
Thorsten
T
Nohria
Virinder
V
Goldbrunner
Michael
M
Kunst
Mechthild
M
Schmaus
Susanne
S
Stauder
Gerhard
G
Bogdahn
Ulrich
U
Schlingensiepen
Karl-Hermann
KH
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*
D000970:Antineoplastic Agents; D020319:Oligodeoxyribonucleotides, Antisense; D053781:Transforming Growth Factor beta2