Novel Strategy to Inhibit Hedgehog Signaling and Control Growth of Androgen-Independent Prostate Cancer Cells.

摘要

The original hypothesis was that a novel proprietary compound we identified in a screen named LS122, would be a potent inhibitor of the kinase STK36 which had been proposed to play a role in hedgehog signaling. This pathway was been hypothesized to contribute to progression of castrate resistant prostate cancer (CRPCa). The original proposal and statement of work proposed that inhibition of STK36 would prevent nuclear translocation of Gli, the transcription factor important in this signaling pathway. The proposal also described in Task 2 the use of a high content screen to identify additional STK36 inhibitors using an available kit. We initiated these proposed experiments and to our disappointment, LS122 did NOT affect the Hedgehog pathway at all and furthermore, no kit existed that would allow us to screen for additional STK36 inhibitors. Fortunately, we confirmed that LS122 was a potent NFKB inhibitor most likely by targeting the kinase RIP2K which is active upstream of NF-B. Since NF-kB is an important signaling pathway implicated in CRPCa progression, our new SOW focusing on this pathways, is still is in line with the overarching mission of developing agents to treat CRPCa. Details of our findings will be presented in the final report. As a positive achievement, we were able to execute a patent of LS122 in the U.S. and Europe.