PHILADELPHIA -- Deciding the ideal treatment for patients with metastatic prostate cancer that stops responding to initial therapy could be guided by certain analyses of cancer cells isolated from the patients' blood, according to data published in Cancer Discovery, a journal of the American Association for Cancer Research.
"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, M.D., Ph.D., 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."
Haber and his colleagues established a way to isolate cancer cells from the blood of patients with prostate cancer and to measure readouts of androgen receptor signaling in each of the individual cancer cells in the blood.
Prior to the initiation of androgen-deprivation therapy, 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 the initiation of androgen-deprivation therapy, the pathway turned off in the circulating tumor cells.
However, in patients whose prostate cancer had progressed after initially responding to androgen-deprivation therapy, the cancer cells in the blood were highly variable. Some cells had the androgen receptor signaling pathway turned on while other cells had it turned off. Yet other cells had characteristics of the signaling pathway being both on and off. The presence of cells with a mixed androgen receptor signaling pattern was associated with an adverse treatment outcome.
In addition, in patients treated with a new drug, abiraterone, which achieves more complete androgen deprivation than earlier treatments, an increased percentage of circulating tumor cells with androgen receptor signaling turned on despite abiraterone treatment was associated with decreased overall survival.
"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 work was supported by the Evans Foundation, the Prostate Cancer Foundation and Stand Up To Cancer.
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About the American Association for Cancer Research
Founded in 1907, the American Association for Cancer Research (AACR) is the world's first and largest professional organization dedicated to advancing cancer research and its mission to prevent and cure cancer. AACR membership includes more than 34,000 laboratory, translational and clinical researchers; population scientists; other health care professionals; and cancer advocates residing in more than 90 countries. The AACR marshals the full spectrum of expertise of the cancer community to accelerate progress in the prevention, biology, diagnosis and treatment of cancer by annually convening more than 20 conferences and educational workshops, the largest of which is the AACR Annual Meeting with more than 17,000 attendees. In addition, the AACR publishes seven peer-reviewed scientific journals and a magazine for cancer survivors, patients and their caregivers. The AACR funds meritorious research directly as well as in cooperation with numerous cancer organizations. As the scientific partner of Stand Up To Cancer, the AACR provides expert peer review, grants administration and scientific oversight of team science and individual grants in cancer research that have the potential for near-term patient benefit. The AACR actively communicates with legislators and policymakers about the value of cancer research and related biomedical science in saving lives from cancer.
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