Novogen's NV-128, a Novel mTOR Inhibitor, Shows Potential Activity Against Cancer Ste
Dec 1 2008, 5:10 AM EST
Novogen's NV-128, a Novel mTOR Inhibitor, Shows Potential Activity Against Cancer Stem Cells
MARKETWIRE
Dec 01, 2008SYDNEY, AUSTRALIA and NEW CANAAN, CTMARKET WIRE
Pharmaceutical company Novogen Limited (NASDAQ: NVGN) (ASX: NRT) today announced that work performed in collaboration with a Yale University research team led by Associate Professor Gil Mor, MD, PhD, has revealed its novel mTOR inhibitor NV-128 has the potential to act against cancer stem cells in addition to rapidly proliferating cells in established solid tumors.
"Yale's research team is finding that NV-128 has a high level of potency against cancer stem cells," said Dr. Gil Mor. "In fact, of the investigational therapies Yale has tried, NV-128 is one of the most exciting to us."
Published research indicates that mTOR pathways, in addition to their involvement in maintaining survival among rapidly dividing cells in established tumors, also guarantee survival in cancer stem cells.(1) Cancer stem cells are slowly dividing undifferentiated cells with capacity to regenerate tumors rapidly after their surgical or chemical removal. These cells are now becoming recognized as the underlying mechanism by which tumors recur and metastasize after primary treatment. As such they represent a promising target by which improved cancer control may be achieved.
NV-128 has been shown to function as a potent inhibitor of the mTOR pathway and therefore has the potential to be effective against cancer stem cells. Novogen is now aligning its research priorities for NV-128, and other related pipeline compounds, to look specifically at their activity in cancer stem cells. This presents a unique opportunity to develop NV-128, and other potential derivatives, not only for use as a therapeutic agent in established cancers, but also to target the stem cells which lead to cancer recurrence.
At last year's annual meeting of the American Association for Cancer Research, a presentation by one of the Yale team, Associate Research Fellow Ayesha Alvero, MD, showed in animal studies that NV-128 not only significantly retards tumor proliferation, but is more efficacious than other standard of care drugs, and without apparent toxicity. This effect was shown to be due to caspase-independent pathways involving inhibition of the mTOR pathway. But 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.
Structurally, NV-128 is an analogue of triphendiol 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 (see www.OVATUREtrial.com ). Triphendiol has recently been granted orphan drug status by the FDA for pancreatic and bile duct cancers, and late stage melanoma.
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 (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 disorders that are commonly associated with aging and 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 arty 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.
NV-128 Display Divergent Combined With Anti-ovarian Cancer Drug Display Lung-cancer Potential Benefits
03 Nov 2008
Pre-clinical studies presented at the 9th International Conference on Membrane Redox Systems in Wellington New Zealand this week demonstrate that Novogen's NV-128 (a novel mTOR inhibitor), when used in combination with the Marshall Edwards, Inc.'s Phase III anti-ovarian cancer drug, phenoxodiol, produces potent synergistic anti-cancer activity against non-small cell lung carcinoma cell lines (NSCLC). Importantly, the synergistic cytotoxicity observed between NV-128 and phenoxodiol was superior to the synergy observed between NV-128 and paclitaxel against NSCLC. These data were presented by Dr. David Brown, Program Manager (Cancer Biology), Novogen.
"In NSCLC targets, these two drugs in combination produced an anti-cancer effect superior to that achieved with either drug alone or in combination with current approved anti-cancer cytotoxic drugs. The potential for improved efficacy, coupled with the safety profile of these novel drugs, suggests the potential for clinical benefits in lung cancer patients which cannot be achieved with current standard of care drugs," Dr. Brown said.
Phenoxodiol is being developed as a therapy for late-stage, chemoresistant prostate and ovarian cancers. It is a novel-acting drug that inhibits key pro-survival signaling pathways operating via sphingosine-1-phosphate and Akt. Inhibition of these pathways leads to prevention of phosphorylation of key anti-apoptotic proteins such as XIAP and FLIPs. Loss of activity of these proteins restores the ability of chemoresistant tumor cells to undergo caspase-mediated apoptosis in response to chemotherapy. The putative molecular target for phenoxodiol is a surface oxidase which is preferentially expressed on cancer cells and is linked to the expression of pro-survival pathways in these cells. The ability of the drug to bind preferentially to cancer cells rather than normal cells is reflected in its high safety profile in clinical use.
In contrast to phenoxodiol, NV-128 does not induce caspase-mediated apoptosis, a death mechanism which is often 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-mTOR-P70S6K 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. Importantly, when NV-128 is used in combination with phenoxodiol, XIAP is degraded in these cells allowing the caspase-mediated apoptosis cascade to be engaged in addition to NV-128-endonuclease G mediated apoptosis resulting in two pathways to cell death.
"These data provide direct evidence that while invoking discrete modes of cell death, NV-128 and phenoxodiol can be used synergistically to force the convergence of caspase-mediated and caspase-independent cell death pathways to drive overall cell death," said Dr. Brown.
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.
Marshall Edwards, Inc. (NASDAQ: MSHL) is majority owned by Novogen. It as a specialist oncology company focused on the clinical development of novel anti-cancer therapeutics derived from the flavonoid technology platform. This platform has generated a number of novel anti-cancer compounds characterized by broad ranging activity against a range of cancer cell types with few side effects. The combination of anti-tumor cell activity and low toxicity is believed to be a result of the ability of these compounds to target an enzyme present on the surface of cancer cells, thereby inhibiting the production of pro-survival proteins within the cell. Marshall Edwards, Inc. has licensed rights from Novogen Limited (NASDAQ: NVGN) to bring three oncology drugs -- phenoxodiol, triphendiol and NV-143 -- to market globally. The Company's lead investigational drug, phenoxodiol, is in a Phase III multinational multi-centered clinical trial for patients with recurrent ovarian cancer. More information on the trial can be found at http://www.OVATUREtrial.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.
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