Novogen's NV-128, a Novel mTOR Inhibitor, Shows Potential Activity Against Cancer Stem Cells
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.
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(1) Nature Reviews - Cancer 2008 Oct;8(10):755-68. Epub 2008 Sep 11