Novogen's NV-128 Targets the mTOR Pathway to Induce Cell Death in Epithelial Ovarian Cancer Stem Cells
March 18 2009 - 11:15AM
Marketwired
NV-128, a Novogen, Ltd. (ASX: NRT) (NASDAQ: NVGN) compound, induced
cell death in ovarian cancer stem cells in a dose-dependent manner.
The study will be presented by Ayesha Alvero, M.D., of Yale
University School of Medicine, Department of Obstetrics, Gynecology
and Reproductive Science, at the 2009 Annual Meeting of the
American Association for Cancer Research in Denver, April 18-22.
Because ovarian cancer stem cells usually survive conventional
chemotherapy, these cells are considered to be the potential source
of recurrence. It appears that NV-128 promotes cell death in these
cancer stem cells through inhibition of the mTOR and other
pathways. These findings may open up a new avenue for treating
ovarian cancer patients who become resistant to chemotherapy.
The team from Yale University, headed by Professor Gil Mor,
recently reported the identification and characterization of the
epithelial ovarian cancer stem cells using the marker CD44 and
demonstrated the up-regulation of the mTOR survival pathway in
these cells. They previously reported that the synthetic
isoflavonoid compound, NV-128, is able to specifically induce mTOR
dephosphorylation resulting in inhibition of both mTORC1 and mTORC2
activity. In epithelial ovarian cancer cell lines NV-128 caused
substantial apoptotic cell death in mice engrafted with human
ovarian cancers. NV-128 not only significantly inhibited tumor
growth, but produced this effect without apparent toxicity.
The objective of this study was to determine the cytotoxic
effect of NV-128 on the ovarian cancer stem cells.
NV-128 had a dramatic effect on the growth and differentiation
of CD44+ ovarian cancer cell lines. CD44+ ovarian cancer stem cells
were treated with increasing concentrations of NV-128 and positive
results were observed as early as 15 minutes post-treatment. In
addition, NV-128 prevented ovarian cancer stem cell differentiation
in the Matrigel differentiation system.
"We are encouraged by the selective cytotoxic effects and the
impact on cancer stem cells that NV-128 demonstrated in this study
in ovarian cancer," said Professor Alan Husband, Group Director of
Research for the Novogen group.
"We have observed similar selective cytotoxicity with NV-128 in
non-small cell lung cancer models and we look forward to the
further clinical development of this compound so that these
aggressive diseases may be more safely and effectively treated
using this new opportunity presented by NV-128," said Professor
Husband.
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 mTOR 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 dephosphorylate mTOR
enables it to inhibit both mTORC1 and mTORC2 activity. This blocks
growth factor driven activation of AKT and the potential for
development of chemoresistance.
When NV-128 is used in combination with the Marshall Edwards,
Inc., compound phenoxodiol, apoptosis is enhanced because two
pathways to cell death appear to be activated, according to
pre-clinical studies.
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. Marshall
Edwards, Inc. (NASDAQ: MSHL) is a majority owned US subsidiary of
Novogen which has licensed rights from Novogen to undertake
clinical trials to bring three of its oncology drugs --
phenoxodiol, triphendiol (NV-196) and NV-143 -- to market globally.
More information on phenoxodiol, triphendiol, NV-128 and on the
Novogen group of companies can be found at www.novogen.com and at
www.marshalledwardsinc.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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