Contact Information: CONTACT: Prof. Alan Husband +61 2 9878 0088 David Sheon 202 547-2880
Novogen's NV-128 Targets the mTOR Pathway to Induce Cell Death in Epithelial Ovarian Cancer Stem Cells
AACR Abstract #1848 to Be Presented April 19, 3:00-5:00 pm
| Source: Novogen, Limited
NEW CANAAN, CT--(Marketwire - March 18, 2009) - 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.