Pain often accompanies
cancer and most current
therapies for treating
cancer pain have significant unwanted side effects. Targeting
nerve growth factor (
NGF) or its cognate receptor
tropomyosin receptor
kinase A (TrkA) has become an attractive target for attenuating
chronic pain. In the present report, we use a mouse model of
bone cancer pain and examine whether
oral administration of a selective small molecule Trk inhibitor (ARRY-470, which blocks TrkA, TrkB and TrkC
kinase activity at low nm concentrations) has a significant effect on
cancer-induced
pain behaviors,
tumor-induced remodeling of sensory nerve fibers,
tumor growth and
tumor-induced bone remodeling. Early/sustained (initiated day 6 post
cancer cell injection), but not late/acute (initiated day 18 post
cancer cell injection) administration of
ARRY-470 markedly attenuated
bone cancer pain and significantly blocked the ectopic sprouting of sensory nerve fibers and the formation of
neuroma-like structures in the
tumor bearing bone, but did not have a significant effect on
tumor growth or bone remodeling. These data suggest that, like
therapies that target the
cancer itself, the earlier that the blockade of TrkA occurs, the more effective the control of
cancer pain and the
tumor-induced remodeling of sensory nerve fibers. Developing targeted
therapies that relieve
cancer pain without the side effects of current
analgesics has the potential to significantly improve the quality of life and functional status of
cancer patients.