“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.