Wednesday, July 20, 2011

Signaling in CLL: opportunities for treatment

Can anything be done at this stage of signaling to block it like Gleevec blocks bcr/abl? Two selective Lyn inhibitors, PP2 and SU6656, block Lyn kinase activity and induce apoptosis, but I know of no trials of these in clinical practice.

Elevated Syk expression by CLL cells results in activation of its downstream targets including Plc2, Erk and Akt. Selective Syk inhibitors BAY-61-3606 and R406 induce apoptosis of CLL cells. siRNA knockdown suggested that constitutively-active Syk maintains high levels of antiapoptotic Mcl-1 via protein kinase C (PKC) δ, which blocks proteasomal degradation of Mcl-1. Downregulation of Mcl-1 in CLL cells treated with Syk inhibitors is consistent with this hypothesis. The susceptibility of CLL cells to apoptosis induction by Syk inhibitors correlated with levels of Syk expression.

In other words Syk signal increase Mcl-1 levels and this seems to be the major agent that stops CLL cells dying. Syk inhibitors might well be effective in treating CLL.

Syk has also been implicated in signalling by chemokines and by integrins. Syk inhibition by R406 or siRNA-mediated knockdown of this PTK abrogated the protective effects of these signals.

Fostamatinib disodium (R788), an orally bioavailable prodrug of R406, blocked BCR signalling in vivo in malignant cells of the Eμ-TCL1 mouse model of CLL, decreased proliferation and survival of malignant cells and prolonged survival of the animals. The drug did not affect the generation of normal B cells. Six of eleven CLL patients treated with fostamatinib showed objective responses in one small clinical trial.

So Fostamatinib shows early promise in treatment. Perhaps in combination with other agents it might be useful.

Imatinib and dasatinib are selective inhibitors of the Abl PTK. Abl expression levels correlated positively with tumour burden and negatively with IGHV mutation levels. Imatinib induced apoptosis of CLL cells that express high levels of Abl. Dasatinib also induced CLL apoptosis in vitro. Dasatinib is a dual inhibitor of Abl and Src PTKs and its critical target with respect to apoptosis induction in CLL cells is not clear at present.

Comment: I think I have already written about Gleevec in CLL.


Dr. La Verne said...

Dear Dr. Hamblin:
What is your view on the BTK inhibitor pci-32765?

La Verne Abe Harris

Terry Hamblin said...

Looks encouraging. Search the blog, I have written a piece on it a few weeks ago.