Photo caption: HHMI investigators (left to right) Todd R. Golub and Charles L. Sawyers have recently turned their attention from other cancers to prostate cancer.

Unsatisfied with the sensitivity of commercial CTC detection kits, Haber collaborated with Mehmet Toner, a biomedical engineer at Massachusetts General Hospital, to develop and test a new kind of detection device. While the commercial technology can detect only one or a few cells per teaspoon of blood, Haber and Toner's technology can force that same teaspoon of blood through a centimeter-wide silicon chamber that has 80,000 microscopic pillars in it, each coated with antibodies that can bind to cells. The pillars can sort through billions of blood cells per teaspoon of blood: the antibodies grab the rare cells that originate from tumors while blood cells flow right on by.

Once he's gathered these circulating cells, Haber can analyze them to identify which, if any, possess particular pieces of genetic information. For example, he can track whether circulating prostate cancer cells have Chinnaiyan's fusion gene.

“This could really add to PSA in terms of being able to identify which cases of cancer may be more likely to spread,” says Haber. The technology is still in early days though, Haber says it's raising as many questions as it's answering. Do only certain types of cancer cells enter the bloodstream? When during early cancer development are these cells first detectable? What makes circulating cells more likely to lodge in a new place and cause a metastatic cancer?

In 2001, Foley went through the first course of treatment for his prostate cancer: radiation, which kills cancerous cells wherever it's directed, and two common anti-hormone drugs—Lupron and Casodex. Both aim to block testosterone in the prostate. Physicians had known since the late 19th century that thwarting male hormones from acting on cells was one way to treat prostate cancer. The ETS fusion gene discovered by Chinnaiyan now explains why this works (in the cancers that it causes)—testosterone turns on the cancer-causing fusion gene; blocking testosterone turns off the rogue fusion gene.

Lupron directly decreases the amount of circulating testosterone, while Casodex works by binding to testosterone receptors, so that the hormone itself cannot. Used in conjunction, the drugs lowered Foley's PSA to less than one.

The problem with Lupron and Casodex is that enterprising cancer cells eventually evolve resistance to them. In 2006, almost five years to the day after Foley finished radiation treatment and hormone therapy, his PSA started rising. By July 2006, it was 13, higher than when he'd first been diagnosed. His doctor put him back on the anti-hormone drugs, but the PSA dropped only slightly and then started rising again.

“Essentially 100 percent of men who go on these drugs eventually develop resistance to them,” says Sawyers, who turned his attention from drug-resistant leukemias to drug-resistant prostate cancers after developing a drug that overcame resistance to the successful drug Gleevec in leukemia patients. What happens in prostate cancers, Sawyers found in mouse models, is that cancer cells start overproducing testosterone receptors. There are still trace amounts of testosterone in the prostate, even when patients are being treated with Lupron. If the number of receptors begins to increase, those tiny amounts of testosterone eventually find free receptors and once again turn on cancer-causing genes.

Sawyers' drug-hunting mind went to work. “What we needed was a new drug that's not perturbed by higher levels of the receptor.” So Sawyers' lab made a cell line overexpressing the receptor and screened it for compounds that would still block the receptor. One compound emerged: MDV3100, a drug that blocks testosterone receptors, like Casodex, but blocks them earlier in their activity cycle—before they transition from being free in the watery interior of a cell to being inside a cell's nucleus and able to bind DNA.

Photos: Golub: Paul Fetters; Sawyers: Liz Baylen / PR Newswire ©HHMI

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