The majority of
cancers are caused by mutations of a few signal transducers such as the
GTPase RAS, the
kinase Src and the
tumor suppressor p53. Thus, a group of specific chemical compounds called 'signal
therapeutics', that block or reverse selectively these abnormally activated signaling pathways would be very useful for the treatment of these signally disordered
cancers. More than 90% of human
pancreatic cancers are associated with oncogenic mutations of RAS, in particular K-RAS at
codon 12. We have previously shown that, PAK1, the Rac/CDC42-dependent Ser/Thr
kinase, is essential for RAS/
estrogen-induced transformation and
neurofibromatosis (NF). Furthermore, we and others have demonstrated that the growth of mouse RAS-induced
sarcomas allografts in mice is almost completely suppressed by either
FK228 or a combination of two complimentary Tyr-
kinase inhibitors, PP1 and
AG 879, all of which block the RAS-induced activation of PAK1. Since, so far no effective therapeutic is available for the treatment of
pancreatic cancer patients, we have examined the therapeutic potential of either
FK228, the combination of these two Tyr-
kinase inhibitors or
GL-2003, a water-soluble derivative of
AG 879, on human
pancreatic cancer (Capan-1) xenograft in mice. Among these PAK1-blocking approaches, the PP1/GL-2003 combination is the most effective in the
therapy of this
cancer xenograft model. Its therapeutic potential is equivalent to those of
gemcitabine and
kigamicin D which suppress by 70-80% the growth of a similar human
pancreatic cancer xenograft model. Also, this PP1/GL-2003 combination
therapy has been proven to be very effective to suppress the
estrogen-independent growth of an NF1-deficient multidrug/
FK228-resistant human
breast cancer (MDA-MB-231) xenograft in mice.