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Re-thinking the research model for future prostate cancer therapies

Posted Apr 23 2010 12:00am

In February this year Efstathiou and Logothetis published an article in Clinical Cancer Research stating that the traditional model of cancer drug development seeking agents that had some activity in very later stages of the cancer and then “working backwards” to explore the effects of these agents earlier in the disease had been ineffective in prostate cancer. They have expanded on their proposed new research model in a “Beyond the Abstract” commentary on the UroToday web site.

In the following, we have tried to explain their thinking for the layperson.

Efstathiou and Logothetis start by explaining the model that has been traditional to drug development for almost all cancer therapies for the past 30+ years. You go looking for drugs that can be shown to have some/any degree of activity in the treatment of patients who have highly advanced disease (e.g., metastatic, hormone-refractory prostate cancer patients). If you can show activity and get the drug approved for the treatment of patients like this, you can then start to test the activity of the drug earlier in the disease process, and maybe show activity and efficacy in (for example) non-metastatic, hormone-refractory prostate cancer.

This model of drug development has been highly successful in many forms of cancer: breast cancer, colorectal cancer, some blood cancers, etc. In all of these cases, it has been demonstrated that drugs that extend survival by small amounts in very late stage disease can also be used to extend survival more effectively in earlier stages of disease. Unfortunately, we have never been able to replicate this type of outcome in prostate cancer. Few drugs have ever been able to show a survival benefit in very late stages of prostate cancer, and earlier use of these therapies has not been shown, reliably, to extend survival by any significant amount either.

The most recent example of this is docetaxel-based chemotherapy. Yes, docetaxel did become the first chemotherapy ever shown to extend survival in patients who had failed hormone therapy (albeit by only a couple of months). There was considerable hope that by giving docetaxel-based therapy to high-risk patients earlier in their disease, that we might be able to transform the small benefit when used late in the disease process into a much larger benefit when docetaxel was given early. However, to quote the authors, “reported results of chemotherapy application in earlier disease state are to date, though not conclusive, disappointing, and chemotherapy isn’t expected to confer a significant survival benefit in earlier disease stages.”

So if the traditional model of drug development isn’t going to work for prostate cancer, or if it is only going to work in a limited way, how should we transform the research paradigm to look differently at the problem. There are still about 28,000 men dying from prostate cancer in the USA each year, and they need better options soon.

Efstathiou and Logothetis put forward the suggestion that the answer may, in fact, lie in the problem itself. They point out that the available clinical data and most specifically the data relating to the way prostate cancer preferentially metastasizes to a patients bones suggests that the so-called “tumor microenvironment” (the precise biological environment in which a particular prostate cancer cell that has escaped from the prostate selects to try to grow into a metastatic tumor) is critical to the spread of prostate cancer through a patient’s body and the progression of the disease. This thinking has certainly help to bring new agents through the research pipeline for other forms of cancer, so it may have value in prostate cancer too.

The new research model that this pair of authors propose is based on their assumption that prostate cancer progression actually has two fundamental stages. The first is a microevironment-dependent or “paracrine” phase. (“Paracrine” is a term that is used in biology to describe activities that primarily affect cells that neighbor the cells of origin of active effect, and this term is commonly used in describing glandular and hormonal actions.) The second is an “autocrine” or self-impacting effect of a hormone or other biochemical on the actual cells that produce it. An example of such an autocrine effect would be the way in which a cell is stimulated to grow and divide into two “daughter” cells through the process known as mitosis.

Understanding this two-compartment model of prostate cancer initiation, development, progression, and then acquired resistance to treatment requires a detailed understanding of the biology and biochemistry of the prostate cancer cell and its life-cycle. The early stages of prostate cancer development and its initial spread to distant sites in the body should be thought of as microenvironment dependent. The later stages, in which prostate cancer gradually acquires characteristics that make it unresponsive to therapy are “epitheliocentric” which means that they are dependent on the ways in which prostate cancer cells interact with the epithelial cells and structures that come together to form all our organs, from bones to lungs and others. Efstathiou and Logothetis argue that if their hypothesis is correct, then the limited clinical activity observed when targeted therapies have been tested in far-advanced disease settings may be explained by the disease stage, and might therefore be reversed in earlier stages of prostate cancer.

The proposed hypothesis leads to the idea that combinations of targeted agents and particularly those agents that affect the interactions between cancer cells and bone development should be prioritized in thinking about new and better treatments for potentially metastatic prostate cancer. A significant range of agents of this type is currently in clinical development. If the authors are correct, then such combinations of targeted agents need to be tested not just in castrate-resistant disease but also in much earlier stages, e.g., high-risk locally progressive disease.

Whether such a strategy will really help to accelerate the development of new drugs that offer better therapeutic outcomes for men with high-risk and progressive forms of prostate cancer, we don’t yet know. However, what is very clear is that the model of drug development followed for prostate cancer over the past 30 years has brought us few products with any noticeable impact on patient survival. It is most certainly time to try some other models!

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