UNITED
STATES
SECURITIES
AND EXCHANGE COMMISSION
Washington,
D.C. 20549
______________________________________________
Form
6-K
REPORT
OF FOREIGN PRIVATE ISSUER PURSUANT TO RULE 13a-16 OR 15d-16 UNDER
THE
SECURITIES
EXCHANGE ACT OF 1934
For the
month of May, 2008
Commission
File Number
________________
Novogen
Limited
(Translation
of registrant’s name into English)
140 Wicks
Road, North Ryde, NSW, Australia
(Address
of principal executive office)
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connection with Rule 12g3-2(b):
ASX
& MEDIA RELEASE
15
APRIL, 2008
NOVOGEN’S
NV-128 IS A UNIQUE INHIBITOR OF mTOR DEPHOSPHORYLATION LEADING TO CASPASE
INDEPENDENT DEATH IN CHEMORESISTANT CANCER CELLS
San Diego
– 15 April - Pre-clinical studies reviewed during an oral presentation here
today at the annual meeting of the American Association for Cancer Research,
demonstrate that the Novogen drug candidate NV-128 engages a novel mode of cell
death targeting the akt-mTOR pathway in multi-drug resistant ovarian cancer
cells. The data were presented by Dr Ayesha Alvero, MD, and Associate
Professor Gil Mor, MD, Department of Obstetrics and Gynecology, Yale University
School of Medicine.
NV-128 is
unique in that it does not induce caspase-mediated apoptosis which can be
non-functional in chemoresistant cancer cells due to accumulated mutations in
tumour suppressor/promoter genes and over-expression of anti-apoptotic
proteins. Rather, NV-128 uncouples the akt-mTORP70S6K signal
transduction cascade which has a key role in driving protein translation and
uncontrolled cancer cell proliferation. Further, NV-128 induces
mitochondrial depolarization via a novel pathway involving the autophagy protein
Beclin-1 and Bcl-2, thereby resulting in endonuclease G translocation to the
nucleus and cell death.
“We
consider that the capacity of NV-128 to trigger mTOR dephosphorylation leading
to caspase-independent cell death, in otherwise chemoresistant ovarian cancer
cells, opens new possibilities for the use of NV-128 as a potential addition to
conventional chemotherapy targeting ovarian cancer cells,” said Dr
Mor.
In the
context of developing therapies indicated against late stage ovarian cancer, Dr
Mor said, “the demonstration of a functional caspase-independent cell death
pathway in apoptotic-resistant ovarian cancer cells is a key step to the
development of alternative targeted therapy for refractory
patients.”
Structurally,
NV-128 is an analogue of triphendiol (NV-196) and phenoxodiol, both of which are
investigational drugs that have been licensed by Novogen to Marshall Edwards,
Inc. Phenoxodiol is currently in a multinational, multi-centre Phase
III clinical trial for patients with late stage ovarian
cancer. Triphendiol has recently been granted orphan drug status by
the FDA for pancreatic and bile duct cancers, and late stage
melanoma.
“The
ability of our suite of analogues to invoke discreet modes of cell death
suggests that they have potential to be used synergistically, thereby inhibiting
alternative modes of cancer cell survival which may be invoked post
therapy. This could lower the incidence of residual disease
clinically,” said Professor Alan Husband, Group Director of Research, Novogen,
Limited.
Unlike
analogues of rapamycin, like temsirolimus and everolimus, 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. Further, unlike NV-128, rapalogs invoke
caspase-mediated apoptosis making them less effective in those cancer cells that
have developed rapalog-resistance and have a dysfunctional apoptotic
cascade.
Also
presented in Dr Alvero’s paper was a proof of concept study in an animal model
of drug resistant ovarian cancer, where it has been demonstrated that NV-128 not
only significantly retards tumour proliferation, but is more efficacious than
other standard of care drugs. It was also reported that
phosphorylated p70s6K was decreased, and endonucelase G was increased in tumours
taken from mice dosed with NV-128 thereby confirming that the NV-128 mechanism
of action
in vivo
is
the same as that observed
in
vitro,
and that both proteins can be employed as markers of NV-128
efficacy.
“We are
just now beginning to realise the depth of oncology drug candidates that our
technology will uncover,” said Professor Husband. “We anticipate that refinement
of our proprietary molecular scaffold driven by computer-based molecular
modelling, will continue to yield novel derivatives not only indicated as
oncology leads, but also for cardiovascular and inflammatory
diseases.“
About
NV
‐
128:
In
contrast to phenoxodiol and triphendiol, NV-128 has been shown to induce
caspase-independent DNA degradation and cancer cell death. It appears
that in conjunction with autophagy induction, NV-128 induces caspase
independent cell death via the AKT-mTOR pathway resulting in beclin
sequestration of Bcl-2, Bax up-regulation and mitochondrial
depolarization. As a consequence, endonuclease G translocates to the
nucleus where it initiates DNA degradation and cell death. This
offers an opportunity for use as a monotherapy in chemoresistant cancers and
enhanced efficacy against cancer targets less susceptible to
phenoxodiol. The option for co-administration of combinations of
these drugs is also under investigation to extend the potential therapeutic
range of this unique class of oncology compounds.
About
Novogen Limited:
Novogen
Limited (ASX: NRT; NASDAQ: NVGN) is an Australian biotechnology company that has
patented isoflavone technology for the treatment and prevention of degenerative
diseases and disorders. Over the past ten years, Novogen has conducted the
largest and most comprehensive isoflavone clinical testing programs in the
world. Novogen is involved in drug discovery and product development
for a range of degenerative disorders including cancer, cardiovascular diseases
and inflammatory diseases. The Company coordinates an international
clinical research and development program with external collaborators, hospitals
and universities. For more information, visit
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.