OSU-03012, the "Synthetic" Anti-PAK1 Drug, Blocks the Growth of NF2 Tumor Xenografts in Mice.

In 2007 a group led by Matthew Ringel at OSU (Ohio State University) found
that a synthetic compound called OSU-03012 selectively inhibits PAK1 in
vitro with IC50 around 1 micro M, and blocks the growth of several thyroid
cancer cell lines. In other words thyroid cancer is among PAK1-depenent
cancers. This compound is a derivative of the cyclooxygenese-2 inhibitor
"celecoxib", and was initially developed as a PDK1 inhibitor by Ching-Shih Chen's
group at OSU in 2004. It eventually inactivates another kinase AKT
by inhibiting the kinase PDK1. However, since it inhibits the growth of
PAK1-dependent (and AKT-independent) cancer cell lines such as PC-3 (PTEN-deficient
prostate cancer) and pancreatic cancer cells, it had been suggested that
OSU-03012 might block the kinase PAK1. In 2009 OSU-03012 (200 mg/kg, daily)
was found by Long-Sheng Chang's group at OSU to suppress the growth of NF2-deficient tumors
(Schwannoma) xenografts in mice by more than 50% (for detail, see the abstract below).

It should be worth to point it out that like ARC (Artepillin C) from Brazilian
green propolis, OSU-03012 is among the first single chemical drugs that
were shown to block the growth of NF2 tumors in vivo, although Bio 30
(100 mg/kg, twice a week) a mixture of several anti-cancer ingredients
including CAPE, was proven to block completely the growth of NF2 tumors in vivo, and is inexpensively available
on the market. If OSU-03012 is successful in the time and money-consuming
clinical trials for these PAK1-dependent cancers and NF tumors, this "synthetic"
compound would become available on the market in a decade or so... Hope
(unlike FK228) this drug can pass BBB (blood brain barrier) so that it works
on formidable brain tumors such as glioma and NF2 tumors.

Eur J Cancer. 2009 Jun; 45(9):1709-20

Growth inhibitory and anti-tumour activities of OSU-03012, a novel PDK-1
inhibitor, on vestibular schwannoma and malignant schwannoma cells.

Lee TX, Packer MD, Huang J, Akhmametyeva EM, Kulp SK, Chen CS, Giovannini
M, Jacob A, Welling DB, Chang LS.

Department of Otolaryngology, The Ohio State University College of Medicine,
Center for Childhood Cancer, The Research Institute at Nationwide Children's
Hospital, Columbus, OH, USA.

BACKGROUND: Vestibular schwannomas (VS) frequently express high levels of
activated AKT. Small-molecule inhibitors of AKT signalling may have therapeutic
potential in suppressing the growth of benign VS and malignant schwannomas.
METHOD: Primary VS and Schwann cells, human malignant schwannoma HMS-97
cells and mouse Nf2(-/-) Schwann cells and schwannoma cells were prepared
to investigate the growth inhibitory and anti-tumour activities of OSU-03012,
a celecoxib-derived small-molecule inhibitor of phosphoinositide-dependent
kinase-1. Cell proliferation assays, apoptosis, Western blot, in vivo xenograft
analysis using SCID mice and immunohistochemistry were performed.

RESULTS: OSU-03012 inhibited cell proliferation more effectively in both
VS and HMS-97 cells than in normal human Schwann cells. The IC5) of OSU-03012
at 48h was approximately 3 micro M for VS cells and HMS-97 cells, compared
with the IC(50) of greater than 12 micro M for human (normal) Schwann cells.
Similarly, mouse Nf2(-/-) schwannoma and Nf2(-/-) Schwann cells were more
sensitive to growth inhibition by OSU-03012 than wild-type mouse Schwann
cells and mouse schwannoma cells established from transgenic mice carrying
the NF2 promoter-driven SV40 T-antigen gene. Like VS cells, malignant schwannoma
HMS-97 cells expressed high levels of activated AKT. OSU-03012 induced apoptosis
in both VS and HMS-97 cells and caused a marked reduction of AKT phosphorylation
at both the Ser-308 and Thr-473 sites in a dose-dependent manner.

In vivo xenograft analysis showed that OSU-03012 was well tolerated and
inhibited the growth of HMS-97 schwannoma xenografts by 55% after 9 weeks
of oral treatment. The anti-tumour activity correlated with reduced AKT
phosphorylation.

CONCLUSION: OSU-03012 is a potential chemotherapeutic agent for VS and malignant
schwannomas.