Phenoxodiol, an investigational drug shows promise for ovarian cancer

A new study further supports the unique mechanism of action of phenoxodiol, an investigational drug being studied for the treatment of ovarian cancer.

The drug appears to work by targeting a certain tumor-specific protein, which triggers a series of events that selectively induce cancer cell death. Phenoxodiol is currently being studied in patients with resistant ovarian cancer, a disease that is estimated to kill more than 15,000 women this year in the U.S. alone.

In studies conducted thus far, phenoxodiol has exhibited an excellent safety profile, with few patients experiencing side effects attributed to the drug.

The new research was conducted by a team headed by Research Professor Michael Berridge Ph.D., at the Malaghan Institute of Medical Research - New Zealand's leading medical research facility focused on finding cures for cancer and other diseases.

Findings from the study, to be presented at the New Zealand Society of Oncology meeting to be held May 9-11, help explain the mechanism by which phenoxodiol induces cancer cell death. This new research supports previous findings by Professor James Morre, Ph.D. at Purdue University, which showed that phenoxodiol interacts with the tumor-specific protein, tNOX, to selectively block cancerous cells from dividing by switching off a variety of pro-survival signaling mechanisms within the cancer cell, causing it to die.

In cases of late-stage ovarian cancer, standard chemotherapy drugs often have a limited duration of use. The cancer can progressively lose its sensitivity to chemotherapy until cancer cells become unresponsive causing resistance, a major barrier to successful cancer treatment. In laboratory studies and Phase II clinical trials, phenoxodiol showed promise in restoring drug sensitivity to resistant cancer cells.

"Phenoxodiol has a unique mechanism of action not exhibited by other anticancer drugs in current use.," said Dr. Berridge. "By inhibiting plasma membrane electron transport selectively in cancer cells, phenoxodiol subjects these cells to stress that leads to cell death. This novel drug and its related analogues have the potential to enhance anticancer efficacy by a different mechanism, promising a new approach to management of solid tumors in a range of clinical settings. As the first compound to operate via this pathway, confirmatory evidence to validate the mechanism of action is very desirable."

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Evidence from this new study indicates that phenoxodiol inhibits proliferation of many cancer cell lines and some primary immune cells. Phenoxodiol induces the destruction of cancer cells by disrupting a stress pathway in the outer cell membrane, causing down regulation of the FLICE-inhibitory protein, FLIP, and resulting in caspase-dependent and independent degradation of the X-linked inhibitor of cell death, XIAP.

Phenoxodiol selectively limits plasma membrane electron transport in cancer cells, by binding to a cancer specific surface plasma membrane electron transport element on cancer cells thereby inhibiting their proliferation, whereas the compound has no such effect on normal healthy cells.

Phenoxodiol in combination with carboplatin is currently being studied in a multi-national Phase III clinical trial called OVATURE, following positive findings of previous trials conducted at Yale-New Haven Hospital. The OVATURE trial will take place in 60 sites in the United States, Europe, and Australia. Preliminary results from the trial are expected within 18 months.

Phenoxodiol is being developed as a therapy for late-stage, chemo-resistant prostate, ovarian and cervical cancers. Phenoxodiol is an investigational drug and, as such, is not commercially available. 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. Loss of activity of these proteins restores the ability of chemoresistant tumor cells to undergo apoptosis in response to chemotherapy. The putative molecular target for phenoxodiol is a tumor-specific protein, accounting for the highly selective nature of the drug.