Administration of a tropomyosin receptor kinase inhibitor attenuates sarcoma-induced nerve sprouting, neuroma formation and bone cancer pain.
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.
Research Service, VA Medical Center, One Veterans Drive, Minneapolis, MN 55417, USA.
Joseph R
JR
Ghilardi
Katie T
KT
Freeman
Juan M
JM
Jimenez-Andrade
William G
WG
Mantyh
Aaron P
AP
Bloom
Michael A
MA
Kuskowski
Patrick W
PW
Mantyh
D000818:Animals; D016723:Bone Remodeling / Q000187:drug effects; D004195:Disease Models, Animal; D051379:Mice; D009463:Neuroma / Q000188:drug therapy* / Q000517:prevention & control; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000494:pharmacology* / Q000627:therapeutic use; D011720:Pyrazoles / Q000008:administration & dosage* / Q000494:pharmacology* / Q000627:therapeutic use; D011743:Pyrimidines / Q000008:administration & dosage* / Q000494:pharmacology* / Q000627:therapeutic use; D020917:Receptor, trkA / Q000037:antagonists & inhibitors*; D012509:Sarcoma / Q000188:drug therapy* / Q000473:pathology; D011984:Sensory Receptor Cells / Q000187:drug effects; D013997:Time Factors; D016896:Treatment Outcome; D047368:Tumor Burden / Q000187:drug effects
D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D020917:Receptor, trkA; C000609083:larotrectinib