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A Small Molecule Inhibitor of Jak2-Stat5 Signaling Pathway Stops Growth of Primary as well as Aggressive, Advanced Prostate Cancer


(PHILADELPHIA) An experimental drug targeting Jak2-Stat5 signaling blocks growth of both primary prostate cancer and prostate cancer that has become castrate-resistant, a state in which the cancer is typically aggressive and resistant to treatment, in animal models of prostate cancer say researchers at Thomas Jefferson University's Kimmel Cancer Center.

The researchers say their findings, posted online by Clinical Cancer Research, supports further clinical development of Jak2 inhibitors to treat advanced prostate cancer.

"Our experiments in human cancer samples in the laboratory and animal studies suggests that Jak2 inhibitors might provide a novel approach towards the treatment of primary and castrate-resistant prostate cancer," says the study's senior author, Marja Nevalainen, MD, PhD, associate professor of Cancer Biology, Medical Oncology, and Urology at Thomas Jefferson University.

AZD1480, discovered and produced by AstraZeneca, is an experimental drug that inhibits activation of STAT5 by blocking activity of the Jak2 kinase.

Stat5 is a transcription factor — a protein that can regulate expression of other genes, and in her research, Dr. Nevalainen has found that Stat5 is critical for the viability of prostate cancer cells and growth of prostate cancer. It is often over-expressed in high-grade prostate cancer and is associated with recurrence of prostate cancer and prostate cancer-related death in patients who had already been treated. Dr. Nevalainen has also discovered that amplification of the Stat5 gene locus, and associated increase in production of Stat5 protein production, increase as prostate cancer metastasizes and becomes treatment resistant. She has shown that blocking Stat5 in laboratory and animal models effectively destroyed prostate cancer.

This study is the first to find evidence of effectiveness in pharmacological targeting of Stat5 to inhibit prostate cancer. Dr. Nevalainen worked with collaborators from departments of Urology and Pathology and the Kimmel Cancer Center at Jefferson to test AZD1480 in prostate cancer tissue from patients that were grown in laboratory culture. "The vast majority of the prostate cancers from patients responded," she says. An equally successful response was also seen in mice growing human prostate tumors.

"The study provides mechanistic evidence that Jak kinase inhibition suppresses the molecular events leading to Stat5 activation, leading to destruction of prostate cancer cells," Dr. Nevalainen says.

"Of course, we won't know the effect of Jak2 inhibition in prostate cancer until it is tested in patients, and we hope that might happen in the near future," she says.

The study was supported by the National Cancer Institute (2RO1CA11358-06), AstraZeneca and Pennsylvania Department of Health.

Researchers from AstraZeneca also participated in the research.