Pharma Strategy Blog

Well, that was an attention grabbing headline for those of us interested in CML.
 
 
Whilst the majority of patients do well on treatment with imatinib (Gleevec), a small number will not respond to the drug initially (primary resistance), and a few will develop secondary resistance as new mutations occur.  Other tyrosine kinase inhibitors such as dasatinib (Sprycel) and nilotinib (Tasigna) are now available that cover most mutations except for  T315i.  There are also kinase inhibitors in develop for blocking the activity of T315i.

One theory that has been proposed for the development of resistance is that Gleevec does not eradicate cancer stem cells in this group.  Without a doubt, those that achieve a complete cytogenetic or molecular response do very well.

Zhao et al., looked at the stem cell issue in a letter to Nature.  They suggested that Hedgehog (Hh) signalling might well play an important part in CML because it is a critical regulator of oncogenesis.  They tested this idea in mice in whom smoothened (SMO), a protein necessary for Hh signal transduction, had been conditionally deleted in hematopoeitic cells and found that the loss of SMO impaired hematapoeitic stem cell renewal. 

They also found something very interesting.  Namely, that transplantation of Smo cells transduced with the BCR-ABL oncoprotein that causes CML into irradiated mice significantly reduced the frequency of cancer stem cells compared to controls.  Transgenic expression of Smo, hwoever, increased the frequency of cancer stems cells, leading to disease progression.

Blocking the Hh pathway chemically with cyclopamine produced different results in the experimental group compared to the controls.  Overall, the results suggest that Hh signalling inhibitors might possibly be useful in both normal and imatinib-resistant CML.  Some of these small molecules are already in phase I development, including one from Genentech, but it should be noted that none of them appear to target the Hh proteins themselves.

Zhao, C., Chen, A., Jamieson, C., Fereshteh, M., Abrahamsson, A., Blum, J., Kwon, H., Kim, J., Chute, J., Rizzieri, D., Munchhof, M., VanArsdale, T., Beachy, P., & Reya, T. (2009). Hedgehog signalling is essential for maintenance of cancer stem cells in myeloid leukaemia Nature DOI: 10.1038/nature07737