for the Novogen followers

First, the background. Signal transduction inhibition (STI) in the late-1990s was heralded as the great white hope of anti-cancer therapy, in that it was the next logical step beyond the current blunderbuss approach to cancer therapy. That by directly targeting the functional 'error' in cancer cells and reversing that error, that it would reverse the cancer process both effectively and selectively.

Gleevec has been the champion of this argument. But the problem with Gleevec is that it is a purpose-built molecule designed for a specific mutation which is present in only two known cancers - chronic myeloid leukemia and a rare form of bowel cancer. Coincidentally, those two cancer types appear to be associated with that single mutation, meaning that blocking of that single mutant enzyme effectively switches off the ability of those cancer cells to survive.

Gleevec was the result of a process known as 'rational drug design'. This means that the drug is designed to interact with a specific target. In the case of Gleevec, the mutant gene was identified, allowing its product (a kinase enzyme) to be identified and a structure defined, and chemists then constructed a drug that attached specifically to the substrate binding site of this enzyme and blocked its ability to bind to the substrate.

STI drug design is overwhelmingly rational drug design - first identify the protein that is in error and then design a drug to hit that protein. The limitation of this dedicated approach is that almost every form of human cancer involves multiple mutations and multiple errors and that an attack on a single target therefore is unlikely to produce a profound anti-cancer effect.

This has meant that the great majority of STI drugs under development are single-target drugs whose contribution is limited to providing an additive anti-cancer effect when used in combination with standard chemotoxic drugs.

The short-sightedness of this approach was highlighted by the first wave of STI drugs – the anti-angiogenic drugs. These drugs were designed to block the development of abnormal blood vessels that a growing tumor needs to survive. Their value in human studies to date has been under-whelming.

The second wave of STI was the EGFR-antagonists, which brings us to the current saga. The rationale here was to block the ability of cancer cells to respond to growth signals. EGF, or epithelial growth factor, is a naturally occurring protein in the body that stimulates epithelial tissues (skin, breast, prostate, lungs, pancreas etc) to grow. That protein is present in blood and activates a specific receptor (EGFR) on the surface of cells. Activation of the EGFR sends a signal to the cell's nucleus to start dividing. Many forms of cancer (particularly non-small cell lung cancer and breast cancer) express abnormally large amounts of this receptor, meaning that they over-respond to normal amounts of EGF in the bloodstream. The theory was that if this growth receptor was blocked, then the cancer cell at the very least would stop growing - it may not necessarily die, but it would stop growing. Herceptin (Genentech), Iressa (AstraZenica), Tarceva (Genentech-Roche), Erbitux (ImClone) and the Abgenix drug are specifically-designed EGFR antagonists.

This approach has always seemed to have three deficiencies.

(a) It fails to take into account the fact that EGF is only one of a wide range of growth signals that a cell receives. Platelet-derived growth factor, fibroblast-growth factor, and insulin-like growth factor are just 3 of dozens of different growth factors that normal cells and cancer cells respond to, and cancer cells over-respond to a whole range of these growth signals. So, simply targeting a single growth factor is hardly blocking a growth response.

(b) Cancer cells change their nature over time. For example, most prostate cancer cells start off being responsive to testosterone, so that anti-testosterone therapy has a growth-retarding effect in the early stages. But then they lose this sensitivity, so that almost all late-stage prostate cancers fail to grow in the presence of large amounts of testosterone. The same thing appears to happen with the EGFR. Breast cancer expresses lots of EGFR in its early stages, but not in its later stages of development. That is why Herceptin only delivers about 9 months of extra survival.

(c) The third deficiency is that most cancers are likely to be polyclonal. That is, they are composed of several different populations cancer cells, each with different phenotypes and different genotypes. This means that they will behave differently in response to different drugs. STIs with specific targets of function are far less likely to be effective across all clones.

For these reasons, we should be unsurprised that EGFR antagonists have failed to deliver a potent anti-cancer effect.

For the same reason, other specifically-acting STIs are unlikely to be any more exciting.

So where does phenoxodiol stand in this matter?

We know that phenoxodiol blocks EGFR. It does this because it works in a similar manner to Tarceva, which means that it is inhibiting the activity of the protein tyrosine kinase that is associated with EGFR. That kinase has to become activated in order for EGFR to send its pro-growth signals.

However, unlike Tarceva that acts only against that one enzyme and that one receptor, phenoxodiol is blocking the response of all growth receptors. It does this because it inhibits another kinase enzyme – sphingosine kinase (SK). SK is associated with all the major growth receptors and probably in fact ALL growth receptors. The sequence of events appears to be this:


– Each receptor interacts with its specific growth factor present in the bloodstream.
– This in turn activates a protein tyrosine kinase enzyme that is specific for each receptor
– This in turn activates sphingosine kinase which is common to all receptors
– Sphingosine kinase produces sphingosine-1-phosphate which then activates the major pro-growth signaling mechanisms.

In this way, phenoxodiol is active against a broad range of growth signals, irrespective of which one is dysfunctional.

But the anti-growth effect of phenoxodiol goes beyond its ability to block the growth signals. Phenoxodiol inhibits the ability of the cell to divide, which means that it blocks cancer cells from dividing even in the absence of growth signals, something that drugs such as Iressa do not do.

But the action of phenoxodiol goes even beyond these effects. We now know that phenoxodiol has another major target, and that is the apoptotic mechanism. It is our belief that this is the primary mechanism of action of phenoxodiol.

This effect appears to be via a major signaling pathway known as Akt, which is a major force in regulating the balance between the pro-death and pro-survival mechanisms within the cell. Phenoxodiol tips this balance by up-regulating the pro-death and down-regulating the pro-survival messages in the cell. This work is the subject of future conference presentations and publications and cannot be detailed here.

So, in summary. phenoxodiol is not affected by the recent disappointment with STIs because:
1. it is not a 'designer drug' made for a single target;
2. it has multiple targets of action;
3. its primary mechanism of action appears to be to correct a fundamental imbalance in the cancer cell.

These characteristics make it far more likely that phenoxodiol
– will be active against a broad range of cancers (confirmed in vitro)
– will be active against distinctive clones within the one cancer
– will result in regression of tumors
– will act synergistically with other drugs.