SOURCE: Novogen, Limited

April 15, 2008 17:25 ET

Novogen's NV-128 Is a Unique Inhibitor of mTOR Dephosphorylation Leading to Caspase Independent Death in Chemoresistant Cancer Cells

SAN DIEGO, CA--(Marketwire - April 15, 2008) - 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 tumor 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-center 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, Ltd.

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 tumor 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 tumors 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 realize 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 modeling, 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.

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