Noninvasive assay monitors treatment response in patients with metastatic prostate cancer

Certain analyses of cancer cells isolated from the blood could guide decisions about the ideal treatment for a patient with metastatic prostate cancer who has stopped responding to initial therapy. This method involves isolating cancer cells from the blood of patients and measuring readouts of androgen receptor signaling in each of the individual cancer cells in the blood.

“The growth and survival of prostate cancer cells are very dependent on signals that the cancer cells receive through a protein called the androgen receptor,” said Daniel A. Haber, MD, PhD, director of the Massachusetts General Hospital Cancer Center in Boston and project leader of the Stand Up To Cancer Bioengineering and Clinical Applications of Circulating Tumor Cell Chip Dream Team. “Treatments that deprive the androgen receptor of its signals are initially highly effective in most patients with metastatic prostate cancer. Unfortunately, prostate cancer, like all cancers, undergoes evolution during therapy, and this can confer resistance to treatment.”

Before androgen-deprivation therapy is initiated, the androgen receptor signaling pathway was turned on in most of the cancer cells in the blood of patients with newly diagnosed metastatic prostate cancer. After androgen-deprivation therapy is initiated, the pathway is turned off in the circulating tumor cells.

However, in those patients whose prostate cancer had progressed after initially responding to androgen-deprivation therapy, the cancer cells in the blood were highly variable. The androgen receptor signaling pathway was turned on in some cells, off in others, and mixed with both on and off in some other cells. The presence of cells with a mixed androgen receptor signaling pattern was associated with an adverse treatment outcome.

Further, decreased overall survival was associated with an increased percentage of circulating tumor cells with the androgen receptor turned on despite abiraterone treatment. Abiraterone is a new drug that achieves more complete androgen deprivation than earlier treatments.

“This study is a proof of principle that it is possible to monitor, in patients with metastatic prostate cancer, the androgen receptor signaling pathway in real time, repeatedly and noninvasively,” Haber said. “Our approach allowed us to monitor whether initial androgen-deprivation therapy was keeping the androgen signaling pathway shut down or whether the tumor was becoming resistant, and if so, by what mechanism.”

“As more drugs are developed that target the different pathways that drive the recurrence of metastatic prostate cancer in different patients, it will become essential to know which drug and which pathway is relevant in each patient,” he said. “Our assay will be an effective way to interrogate the tumor and follow it during the course of treatment to monitor therapy response and the emergence of drug resistance.”

This study was reported in Cancer Discovery (2012; doi:10.1158/2159-8290.CD-12-0222).
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