Results of early tests on a novel experimental prostate cancer drug bring hope to men diagnosed with the most aggressive form of the disease that resists current treatments.

The findings of early phase I/II trials of the drug, dubbed MDV3100 and made by San Francisco-based Medivation Inc, are to be published later this week in the journal Science in a study led by Charles Sawyers of Memorial Sloan-Kettering Cancer Center in New York.

Sawyers is a co-inventor of the drug and consults for the drug company.

Ten per cent of men diagnosed with prostate cancer have the aggressive form and their prognosis is not good because while currrent treatments look like they are shrinking the tumors at first, later on the cancer cells that survive become resistant and start growing and spreading again.

These drug resistant forms of the disease account for nearly all the 29,000 deaths from prostate cancer among Americans every year.

In this study, Sawyers and his team showed that MDV3100 caused levels of prostate specific antigen (PSA, a biomarker for prostate tumor growth), fell by at least 50 per cent in 13 of 30 patients with advanced prostate cancer that had resisted other treatments.

Sawyers has previously researched drug resistance in leukemia, and in 2003 showed how prostate cancer cells become resistant to drugs.

He told ScienceNOW Daily News:

“For this group of patients, this is a very impressive result.”

The study also describes how Sawyers and his team first described how the drug shrank tumors in mice that had been implanted with human prostate tumors untreatable with current drugs.

Although more clinical studies are needed, the study has stirred interest among experts because it attacks the cancer in a new way.

“It’s possibly a new and better way of treating prostate cancer,” oncologist Philip Kantoff of the Dana-Farber Cancer Institute in Boston told ScienceNOW Daily News.

Prostate cancer tumors grow because the genes in prostate cells change in a way that allows male hormones called androgens (testosterone is one) to cause cells to grow out of control.

All cells have receptors on their surface. These are like doorways that need special keys to open them and allow various kinds of agents to get into the cell. Under ideal circumstances these agents are beneficial and carry out essential tasks for cell growth and repair. But in the case of prostate cancer, if too many androgen agents are allowed in, they play havoc and cause uncontrolled cell growth and proliferation.

There are two options for drug treatments, then, either reduce the number of receptors (the doorways into the cells), or reduce the number of androgen agents trying to get in through them. Most drugs address the latter: they try to limit the production of androgen in the body. That is the first course of treatment. If that fails, then other drugs are available that limit the number of receptors available to androgens by “blocking” these doorways: they behave like agents that are allowed in so they can chemically bind to the receptors and stop androgens getting access to them. However, these eventually stop working because the cancer cells develop a “work around”.

From their earlier work, Saywers and colleagues found out how they do this. The cancer cells produce even more androgen receptors than the normal cells, and they also become more sensitive to androgens so that even drugs that behaved like them (the ones that were designed to block the receptors) are able to stimulate the cancer cells to grow and spread.

So Sawyers and colleagues worked with chemist Michael Jung and his group at the University of California, Los Angeles, and made nearly 200 compounds that behave like androgens. Then they analysed each one, picking the ones that bound to the androgen receptor on the cancer cells but didn’t activate it. From these early candidates they developed two new potential experimental drugs.

As well as binding to the androgen receptor, the new drugs seemed to stop androgen getting into the cell’s DNA and triggering genes.

Cancer pharmacologist Donald McDonnell of Duke University in Durham, North Carolina said it was a “beautiful story”.

Sawyers and his team expect that eventually the cancer will become resistant to MDV3100; but hope that combining it with other new drugs undergoing testing (for instance one that stops cancer cells making their own androgen) it will be possible to come up with the right cocktail to stop a man’s prostate cancer ever reaching the drug resistant stage.

Science.

Sources: ScienceNOW Daily News.

Written by: Catharine Paddock, PhD