CDK5 as a Therapeutic Target in Prostate Cancer Metastasis; Annual rept. 1 Jan-31 Dec 2007

摘要

We have recently found that CDK5 is active in prostate cancer cell lines and in almost all human metastatic prostate cancers, and inhibition of CDK5 activity resulted in reduction of spontaneous metastases by 79%. This suggests that CDK5 is a novel potential therapeutic target to limit prostate cancer metastasis. Based on our finding that CDK5 activity is present in prostate cancer and is important for metastasis, we intend to develop CDK5 as a novel therapeutic target. We hypothesized that 1) pharmacological inhibitors of CDK5 can limit or block metastasis, and 2) in established skeletal metastases, inhibition of CDK5 may inhibit tumor growth and sensitize tumor cells to other therapies. Therefore, we proposed to characterize a series of small molecule CDK5 inhibitors for specificity in cell culture, and for their effect on xenograft models of prostate cancer. We also proposed to examine the role of CDK5 activity in growth of prostate cancer metastatic to bone, using PC3 based bioluminescent cell clones, and to explore the potential for CDK5 inhibition to sensitize prostate cancer cells to chemotherapy.