Novogen's NV-128 Targets the mTOR Pathway to Block Differentiation and Induce Cell Death in Ovarian Cancer Stem Cells
April 20 2009 - 8:00AM
Marketwired
Data presented yesterday at the Annual Meeting of the American
Association for Cancer Research in Denver has demonstrated that
NV-128, a Novogen, Limited (ASX: NRT) (NASDAQ: NVGN) synthetic
isoflavonoid compound, not only induces cell death in Ovarian
Cancer Stem Cells (OCSCs), but also blocks their differentiation
into structures which are required to support tumor growth.
In a poster presentation by Ayesha Alvero, M.D., of Yale
University School of Medicine, Department of Obstetrics, Gynecology
and Reproductive Science, it was revealed that in addition to an
inhibitory effect on OCSC growth, NV-128 displays a remarkable
ability to inhibit differentiation of OCSCs into formation of new
blood vessels.
The anti-proliferative effects were demonstrated to be achieved
as a result of NV-128 inhibiting phosphorylation of the
pro-survival mTOR pathway resulting in mitochondrial depolarization
and cell death. Time lapsed photographic morphometry revealed in
graphic detail how NV-128 induces morphological changes in OCSCs
after 24 hours, even when dosed as low as 1�g/ml with a progressive
"clearing" of cytoplasm and condensation of nuclear material.
The effect of NV-128 on OCSC vessel formation was observed by
plating OCSCs in high-density matrigel either without NV-128
(controls) or in the presence of 0.1 mg/ml NV-128 and observing for
48 hours. Whereas the control cultures showed differentiation of
the stem cells into endothelial-type cells forming structurally
intact blood vessels in the culture plates, cells cultured in the
presence of NV-128 showed no differentiation and no structural
elements were observed.
OCSCs represent a highly chemo-resistant cell population,
allowing them to survive conventional chemotherapy. Thus these
cells are considered to be the potential source of tumor induction
and post-treatment recurrence.
The team from Yale University, headed by Professor Gil Mor,
recently reported the identification and characterization of OCSCs
using the CD44 marker and demonstrated pronounced up-regulation of
the mTOR survival pathway in these cells. They previously reported
that NV-128 is able to specifically induce mTOR dephosphorylation
resulting in inhibition of both mTORC1 and mTORC2 activity in
mature ovarian cancer cells derived from established human cancers
and cultured in vitro. In mice with human ovarian cancers
established by grafting techniques (xenografts) NV-128 caused
substantial cancer cell death, reducing tumor growth with no
apparent toxic side-effects.
"We have now demonstrated that by inhibiting the mTOR pathway in
both the cancer stem cells and the mature cancer cells, we are able
to inhibit development of structural elements necessary for tumor
development as well as limit the number of cancer cells," Professor
Mor said. "These results open a new avenue for the development of
better treatment modalities for ovarian cancer patients."
"We are encouraged by these data from animal studies showing a
combination of anti-cancer activities of NV-128, coupled with an
apparently high safety profile," said Professor Alan Husband, Group
Director of Research for the Novogen group. "This anti-angiogenic
effect, coupled with the absolute effects on cell survival,
demonstrate the potential for NV-128 to become a powerful new tool
in prevention as well as treatment of cancer."
Novogen has previously reported on the parallel effects of
NV-128 in non-small cell lung cancer models and the Company intends
to pursue this, as well as ovarian cancer, as target
indications.
Novogen is currently in advanced negotiations with its majority
owned subsidiary, Marshall Edwards, Inc. (MEI), to out-license
NV-128 to MEI for its clinical development as a potential cancer
therapeutic. To view an online abstract relating to this study,
http://www.abstractsonline.com/viewer/viewAbstractPrintFriendly.asp?CKey={0F9F2C53-E4B7-4F42-80CE-BD32342EF4C2}&SKey={148E626F-033E-415F-BED6-C9578240222B}&MKey={D007B270-E8F6-492D-803B-7582CE7A0988}&AKey={728BCE9C-121B-46B9-A8EE-DC51FDFC6C15}.
About NV-128
NV-128 does not rely on the traditional approach of
caspase-mediated apoptosis, a death mechanism which is not
effective in cancer cells that have become resistant to
chemotherapy. Rather, NV-128 uncouples a signal transduction
cascade which has a key role in driving protein translation and
uncontrolled cancer cell proliferation. Further, NV-128 induces
mitochondrial depolarization via the novel mTOR pathway. In cancer
cells, mTOR signals enhance tumor growth and may be associated with
resistance to conventional therapies. Inhibition of the mTOR
pathway appears to shut down many of these survival pathways,
including proteins that protect the mitochondria of cancer cells.
Animal studies have shown that NV-128 not only significantly
retards tumor proliferation, inhibiting the progression of ovarian
cancers-engrafted into mice, but produces this effect without
apparent toxicity. This effect was shown to be due to
caspase-independent pathways involving inhibition of the mTOR
pathway. Unlike analogues of rapamycin, which target only mTORC1,
NV-128's capacity to inhibit mTOR phosphorylation enables it to
inhibit both mTORC1 and mTORC2 activity. This blocks growth
factor-driven activation of AKT and the potential for development
of chemoresistance.
About Novogen Limited
Novogen Limited (ASX: NRT) (NASDAQ: NVGN) is an Australian
biotechnology company based in Sydney, Australia, that is
developing a range of oncology therapeutics from its proprietary
flavonoid synthetic chemistry technology platform. More information
on NV-128 and on the Novogen group of companies can be found at
www.novogen.com.
Under U.S. law, a new drug cannot be marketed until it has been
investigated in clinical trials and approved by the FDA as being
safe and effective for the intended use. Statements included in
this press release that are not historical in nature are
"forward-looking statements" within the meaning of the "safe
harbor" provisions of the Private Securities Litigation Reform Act
of 1995. You should be aware that our actual results could differ
materially from those contained in the forward-looking statements,
which are based on management's current expectations and are
subject to a number of risks and uncertainties, including, but not
limited to, our failure to successfully commercialize our product
candidates; costs and delays in the development and/or FDA
approval, or the failure to obtain such approval, of our product
candidates; uncertainties in clinical trial results; our inability
to maintain or enter into, and the risks resulting from our
dependence upon, collaboration or contractual arrangements
necessary for the development, manufacture, commercialization,
marketing, sales and distribution of any products; competitive
factors; our inability to protect our patents or proprietary rights
and obtain necessary rights to third party patents and intellectual
property to operate our business; our inability to operate our
business without infringing the patents and proprietary rights of
others; general economic conditions; the failure of any products to
gain market acceptance; our inability to obtain any additional
required financing; technological changes; government regulation;
changes in industry practice; and one-time events. We do not intend
to update any of these factors or to publicly announce the results
of any revisions to these forward-looking statements.
CONTACT: Prof. Alan Husband +61 2 9878 0088 David Sheon 202
547-2880
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