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Pan-trk Inhibition Decreases Metastasis and Enhances Host Survival in Experimental Models as a Result of Its Selective Induction of Apoptosis of Prostate Cancer Cells¹

Johns Hopkins Oncology Center [A. T. W., S. L. D., J. C. L., S. R. D., J. T. I.], and James Buchanan Brady Urological Institute, Department of Urology [J. T. I.], Johns Hopkins School of Medicine, Baltimore Maryland 21231, and Cephalon Inc., West Chester, Pennsylvania 19380 [S. M., C. A. D.]

During the progression of prostate cancer, molecular changes occur resulting in the autocrine production of a series of neurotrophins by the malignant cells. This is coupled with expression of high-affinity cognate receptors for these ligands, termed trk receptors, by these cancer cells. The binding of the neurotrophins to their trk receptors activates the receptor’s latent tyrosine kinase activity inducing a series of signal transduction pathways within these prostate cancer cells. These molecular changes result in the acquisition by prostate cancer cells of a restricted requirement for these trk signaling pathways for optimal survival. CEP-701 is an indolocarbazole compound specifically designed as a potent inhibitor (IC₅₀, 4 nM) of the tyrosine kinase activity of the trk receptors required for initiation of these survival pathways. In the present studies, the consequences of CEP-701 inhibition of these trk signaling survival pathways were tested in vivo using both rat (R3327 AT 6.3 and H) and human (TSU-pr1 and CWR-22Rv1) prostatic cancer models.

These in vivo studies demonstrated that treatment with CEP-701 inhibits the growth of both rodent and human prostate cancers, without being toxic to the normal tissue including the host prostate. Because of this selective effect, CEP-701 inhibits metastasis and growth of both primary and metastatic sites of prostate cancer. Based upon this profile, long-term survival studies were performed using the slow-growing Dunning H rat prostate cancer model. For these latter studies, the dosing regimen was 10 mg CEP-701/kg/dose twice a day via gavage 5 days a week. This regimen maintains CEP-701 tumor tissue concentrations of 25–50 nM. Such chronic dosing increased (P < 0.001) the median survival of rats bearing the slow growing H prostate cancers from 408 days (395–432 days, 95% confidence interval) for the vehicle group (n = 18) to 566 days (497–598 days, 95% confidence interval) for the CEP-701-treated group (n = 24).

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