Efficacy of c-Met inhibitor for advanced prostate cancer

We tested two c-Met small molecule inhibitors, PHA-665752 and PF-2341066, for anti-proliferative activity by MTS assay and cell proliferation assay on human prostate cancer cell lines with different levels of androgen sensitivity. We also used renal subcapsular and castrated orthotopic xenograft mouse models to assess the effect of the inhibitors on prostate tumor formation and progression.We demonstrated a dose-dependent inhibitory effect of PHA-665752 and PF-2341066 on the proliferation of human prostate cancer cells and the phosphorylation of c-Met. The effect on cell proliferation was stronger in androgen insensitive cells. The c-Met inhibitor, PF-2341066, significantly reduced growth of prostate tumor cells in the renal subcapsular mouse model and the castrated orthotopic mouse model. The effect on cell proliferation was greater following castration.The c-Met inhibitors demonstrated anti-proliferative efficacy when combined with androgen ablation therapy for advanced prostate cancer.Prostate cancer is the most common malignancy in men in the United States [1]. While the mortality of prostate cancer has been slightly reduced recently, it still contributes to 30,000 deaths annually with the majority from castration resistant prostate cancer (CRPC) [2]. The androgen-signaling pathway, mediated mostly through the androgen receptor (AR), plays a critical role in the regulation of prostate cancer cell growth and survival [3,4]. Androgen deprivation is the standard therapy for advanced prostate cancer [5]. However, within two to three years after initiating therapy, most patients relapse with a more aggressive form of prostate cancer, termed CRPC, for which there is no effective treatment.The c-Met receptor tyrosine kinase (RTK) was originally discovered as an oncoprotein and has been implicated in the proliferation and progression of a wide variety of human malignancies, including prostate cancer [6-9]. High c-Met expression is observed in late stages and metastases