Intelligent Cancers: Cancer is deadly, but is it also smart?

James Stark, MD, of Stark Oncology

James Stark, MD, of Stark Oncology

Recent cancer research has opened a window into a new world of biology: intelligent cancers.

Oncologists have known for decades that men with metastatic (e.g., spread to bones) prostate cancer will show clinical improvement if the level of testosterone in their blood is lowered. The tumor cells require male hormones (testosterone, made in the testis, or less powerful androgens made in the adrenal glands) to grow. Lowering testosterone used to be accomplished by removing the testicles; more recently it has been achieved by drugs.

Unfortunately the benefit of this intervention lasts only a year or two, after which prostate cancer starts to grow again throughout the body. The reason for this phenomenon was thought to be that the tumor cells remaining after initial hormone manipulation lacked the ability to respond to hormone withdrawal because they had undergone a genetic mutation and had lost a receptor on their surface which recognizes male hormones.  This concept is in keeping with conventional wisdom in oncology that acquired drug resistance is a function of spontaneous mutation which occurs randomly over time.  New research has forced the cancer research community to question this paradigm.

Investigators in several laboratories around the world have studied prostate tumor tissue from men whose tumors started to grow despite having been deprived of testosterone and have learned a startling fact: these tumors begin to make their own testosterone! How do the tumors know to do this? What survival instinct compels them?  Making testosterone is complicated. It requires a series of enzymes (proteins) which convert cholesterol to progesterone, then to testosterone. Creating these enzymes requires a coordinated effort on the part of the genetic material of the tumor.  This process is so complex that it is unlikely to occur by chance alone.

Montgomery et al Cancer Research 2008 68:4447

Montgomery et al Cancer Research 2008 68:4447

What is the evidence for this and how does it happen?
Investigators have looked at testosterone levels inside tumors and normal prostate tissue. Their graph (seen at right) shows a striking elevation in testosterone levels found inside prostate tumors from men whose own testosterone had been eliminated either through drugs or removal of the testicles. This phenomenon may explain why prostate tumors can start to grow again after shrinking when male hormones are taken away.

What can be done about this?
Researchers have developed a new drug, Abiraterone, which targets the production of testosterone inside prostate tumors. It has been shown to work in men whose tumors have started to spread after initial control was achieved by removal of testosterone from their blood stream. It will be released for general use by the FDA shortly and will be available to the general public thereafter.

Bacteria become resistant to antibiotics faster than one would predict based on random mutations. They learn to resist antibiotics. There is a powerful lesson to be learned from prostate cancer cells that similarly learn to make the enzymes necessary for their survival. If we understood how they did this we would know something important.

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