Novogen’s NV-128 Targets mTOR Pathway To Block Differentiation and Induce Cell Death in Ovarian Cancer Stem Cells

“Data just presented at the Annual Meeting of the American Association for Cancer Research in Denver has demonstrated that NV-128, a Novogen, Limited (ASX: NRT NASDQ: NVGN) synthetic isoflavonoid compound, not only induces cell death in Ovarian Cancer Stem Cells (OCSCs), but also blocks their differentiation into structures which are required to support tumor growth.  In a poster presentation by Ayesha Alvero, MD, of Yale University School of Medicine, Department of Obstetrics, Gynecology and Reproductive Science, it was revealed that in addition to an inhibitory effect on OCSC growth, NV-128 displays a remarkable ability to inhibit differentiation of OCSCs into formation of new blood vessels. … ‘We have now demonstrated that by inhibiting the mTOR pathway in both the cancer stem cells and the mature cancer cells, we are able to inhibit development of structural elements necessary for tumor development as well as limit the number of cancer cells,’ Professor Mor said. ‘These results open a new avenue for the development of better treatment modalities for ovarian cancer patients.’ …”

“(Sydney Australia and New Canaan, Connecticut – 20 April, 2009) – Data just presented at the Annual Meeting of the American Association for Cancer Research in Denver has demonstrated that NV-128, a Novogen, Limited (ASX: NRT NASDQ: NVGN) synthetic isoflavonoid compound, not only induces cell death in Ovarian Cancer Stem Cells (OCSCs), but also blocks their differentiation into structures which are required to support tumor growth.

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Ayesha Alvero, M.D., Associate Research Fellow, Department of Obstetrics, Gynecology and Reproductive Science, Yale University School of Medicine

In a poster presentation by Ayesha Alvero, MD, of Yale University School of Medicine, Department of Obstetrics, Gynecology and Reproductive Science, it was revealed that in addition to an inhibitory effect on OCSC growth, NV-128 displays a remarkable ability to inhibit differentiation of OCSCs into formation of new blood vessels.

The anti-proliferative effects were demonstrated to be achieved as a result of NV-128 inhibiting phosphorylation of the pro-survival mTOR pathway resulting in mitochondrial depolarisation and cell death. Time lapsed photographic morphometry revealed in graphic detail how NV-128 induces morphological changes in OCSCs after 24 hours, even when dosed as low as 1μg/ml with a progressive “clearing” of cytoplasm and condensation of nuclear material.

The effect of NV-128 on OCSC vessel formation was observed by plating OCSCs in high-density matrigel either without NV-128 (controls) or in the presence of 0.1 mg/ml NV-128 and observing for 48 hours. Whereas the control cultures showed differentiation of the stem cells into endothelial-type cells forming structurally intact blood vessels in the culture plates, cells cultured in the presence of NV-128 showed no differentiation and no structural elements were observed.

OCSCs represent a highly chemo-resistant cell population, allowing them to survive conventional chemotherapy. Thus these cells are considered to be the potential source of tumor induction and post-treatment recurrence.

The team from Yale University, headed by Professor Gil Mor, recently reported the identification and characterisation of OCSCs using the CD44 marker and demonstrated pronounced up-regulation of the mTOR survival pathway in these cells. They previously reported that NV-128 is able to specifically induce mTOR dephosphorylation resulting in inhibition of both mTORC1 and mTORC2 activity in mature ovarian cancer cells derived from established human cancers and cultured in vitro. In mice with human ovarian cancers established by grafting techniques (xenografts) NV-128 caused substantial cancer cell death, reducing tumor growth with no apparent toxic side-effects.

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Gil Mor, M.D., Ph.D., Associate Professor, Department of Obstetrics, Gynecology and Reproductive Science, Yale University School of Medicine

‘We have now demonstrated that by inhibiting the mTOR pathway in both the cancer stem cells and the mature cancer cells, we are able to inhibit development of structural elements necessary for tumor development as well as limit the number of cancer cells,’ Professor Mor said. ‘These results open a new avenue for the development of better treatment modalities for ovarian cancer patients.’

‘We are encouraged by these data from animal studies showing a combination of anti-cancer activities of NV-128, coupled with an apparently high safety profile,’ said Professor Alan Husband, Group Director of Research for the Novogen group. ‘This anti-angiogenic effect, coupled with the absolute effects on cell survival, demonstrate the potential for NV-128 to become a powerful new tool in prevention as well as treatment of cancer.’

Novogen has previously reported on the parallel effects of NV-128 in non-small cell lung cancer models and the Company intends to pursue this, as well as ovarian cancer, as target indications.

Novogen is currently in advanced negotiations with its majority owned subsidiary, Marshall Edwards, Inc. (MEI), to out-license NV-128 to MEI for its clinical development as a potential cancer therapeutic. To view an online abstract relating to this study, [CLICK HERE].

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 depolarisation via the novel mTOR pathway. In cancer cells, mTOR signals enhance tumor growth and may be associated with resistance to conventional therapies. Inhibition of the mTOR pathway 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 inhibit mTOR phosphorylation enables it to inhibit both mTORC1 and mTORC2 activity. This blocks growth factor-driven activation of AKT and the potential for development of chemoresistance.

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. More information on NV-128 and on the Novogen group of companies can be found at www.novogen.com.

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Additional Information Re Novogen’s NV-128:

Yale Researchers Indicate That Novogen Compound NV-128 Induces Cell Death in Chemo-Resistant Ovarian Cancer Cells

“An abstract for an oral presentation to be given at the Annual Meeting of the American Association for Cancer Research, April 12 – 16, in San Diego, Calif., is now available (abstract number 4926) at http://www.aacr.org. The abstract, describing work undertaken by Professor Gil Mor and colleagues at the Yale University School of Medicine, indicates that the compound NV-128, developed by Novogen Limited (ASX: NRT) (NASDAQ: NVGN), may be useful for the maintenance of remission in chemo-resistant ovarian cancer.NV-128 is able to induce cell death through the inhibition of the mTOR pathway [mTOR pathway diagram] in cancer cells. NV-128 inhibition of the mTOR pathway results in caspase-independent apoptosis and autophagy. Only a few other compounds are in the mTOR antagonist class, providing an alternative to drug candidates reliant on caspase dependent cell death as their mechanism of action.

At the annual meeting of the Society for Gynecological Oncology in Tampa, earlier this month, several key speakers addressed the significance of mTOR antagonists in cancer therapeutics.

mTOR is a key intracellular kinase, integrating proliferation and survival pathways. In cancer cells, mTOR signals enhance tumour growth and may be associated with resistance to conventional therapy. Inhibition of mTOR may shut down many of these survival pathways, including the proteins protecting the mitochondria. It is believed that NV-128 affects the catalytic dynamics of mTOR in order to achieve apoptosis.

NV-128 works differently from therapies that are dependent on caspases to trigger apoptosis. Through the inhibition of mTOR, NV-128 is capable of triggering a cascade of events that leads to mitochondrial damage and cell death. Interestingly, since NV-128-induced cell death is completely caspase-independent, it could be effective on cancer cells characterised by high resistance to cell death and representative of late stage chemorefractory disease.”

Quoted Source: [ “Yale researchers to present data indicating that NV-128 uses mTOR pathway to induce cell death,” Novogen Limited News Release dated March 25, 2008.]

Comment: NV-128 represents a novel intracellular kinese inhibitor that disrupts chemo-resistant ovarian cancer cells. V-128 is an analogue of Novogen’s lead anti-cancer agents triphendiol (triphendiol), and phenoxodiol (NV-06). Phenoxodiol has demonstrated efficacy as a monotherapy and as a chemosensitizer against cancer cell lines representative of non-small cell lung carcinoma (NSCLC). Phenoxodiol is also currently being used in the OVArian TUmor REsponse (OVATURE) clinical trials for recurrent ovarian cancer being conducted in the U.S., Europe and Australia. Proof of concept xenograft studies have confirmed that orally delivered NV-128 retards NSCLC tumor proliferation. Efficacy studies are in progress in pre-clinical in vitro studies against late stage colorectal, breast, and gastric cancers and hepatocellular carcinoma, both as a monotherapy and in combination with current standard of care drugs.