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 (IC(50), 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).