Preclinical Studies of Signaling Pathways in a Mutant Mouse Model of Hormone-Refractory Prostate Cancer

摘要

We have been investigating targeted therapies for the treatment of advanced prostate cancer using a genetically-engineered mouse model of the disease. Based on previous studies, we performed pre-clinical studies to examine the consequences of combinatorial inhibition of these signaling pathways for prostate tumorigenesis an androgen-independence. We found that combination therapy using Rapamycin, an inhibitor of mTOR, and PD0325901, a MEK inhibitor, is potently anti-tumorigenic in Nkx3.1; Pten mutant mice, particularly in contexts of limiting androgens. Furthermore, we find that these signaling pathways are coordinately de-regulated during prostate cancer progression in humans, as evident by our comprehensive analyses of their status in human tissue microarrays. Based on these pre-clinical studies in the mutant mice, and our supporting data from human prostate cancer, we propose that combination therapy targeting the Akt/mTOR kinase and Erk Map kinase signaling pathways may be effective for treatment of a broad spectrum of patients with advanced prostate cancer, particularly when used in conjunction with androgen deprivation therapy.