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Cabozantinib Resolves Bone Scans in Tumor-Naive Mice Harboring Skeletal Injuries

Doran, Michael G.; Spratt, Daniel E.; Wongvipat, John; Ulmert, David LU ; Carver, Brett S.; Sawyers, Charles L. and Evans, Michael J. (2014) In Molecular Imaging 13.
Abstract
The receptor tyrosine kinase inhibitor cabozantinib (XL184, BMS-907351 Cometriq) has displayed impressive clinical activity against several indications, culminating in its recent approval for medullary thyroid cancer. Among malignancies with tropism for the bone (prostate, breast), one striking feature of early clinical reports about this drug has been the rapid and complete resolution of bone scans, a phenomenon almost never observed even among therapies already shown to confer survival benefit. In castration-resistant prostate cancer, not all conventional response indicators change as dramatically posttreatment, raising the possibility that cabozantinib may impair the ability of bone-seeking radionuclides to integrate within the... (More)
The receptor tyrosine kinase inhibitor cabozantinib (XL184, BMS-907351 Cometriq) has displayed impressive clinical activity against several indications, culminating in its recent approval for medullary thyroid cancer. Among malignancies with tropism for the bone (prostate, breast), one striking feature of early clinical reports about this drug has been the rapid and complete resolution of bone scans, a phenomenon almost never observed even among therapies already shown to confer survival benefit. In castration-resistant prostate cancer, not all conventional response indicators change as dramatically posttreatment, raising the possibility that cabozantinib may impair the ability of bone-seeking radionuclides to integrate within the remodeling bone. To test this hypothesis, we surgically induced bone remodeling via physical insult in non-tumor-bearing mice and performed F-18-sodium fluoride (F-18-NaF) positron emission tomographic (PET) and technetium 99m-methylene diphosphonate (Tc-99m-MDP) single-photon emission computed tomographic (SPECT) scans pre- and posttreatment with cabozantinib and related inhibitors. A consistent reduction in the accumulation of either radiotracer at the site of bone remodeling was observed in animals treated with cabozantinib. Given that cabozantinib is known to inhibit several receptor tyrosine kinases, we drugged animals with various permutations of more selective inhibitors to attempt to refine the molecular basis of bone scan resolution. Neither the vascular endothelial growth factor receptor (VEGFR) inhibitor axitinib, the MET inhibitor crizotinib, nor the combination was capable of inhibiting F-18-NaF accumulation at known bioactive doses. In summary, although the mechanism by which cabozantinib suppresses radionuclide incorporation into foci undergoing bone remodeling remains unknown, that this phenomenon occurs in tumor-naive models indicates that caution should be exercised in interpreting the clinical significance of this event. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Molecular Imaging
volume
13
publisher
BC Decker
external identifiers
  • wos:000344215900005
  • scopus:84907695265
ISSN
1535-3508
DOI
10.2310/7290.2014.00026
language
English
LU publication?
yes
id
43b4e561-80cc-4f43-bc82-7c6c3f90f0b5 (old id 4875832)
date added to LUP
2015-01-07 10:27:50
date last changed
2017-01-01 04:16:59
@article{43b4e561-80cc-4f43-bc82-7c6c3f90f0b5,
  abstract     = {The receptor tyrosine kinase inhibitor cabozantinib (XL184, BMS-907351 Cometriq) has displayed impressive clinical activity against several indications, culminating in its recent approval for medullary thyroid cancer. Among malignancies with tropism for the bone (prostate, breast), one striking feature of early clinical reports about this drug has been the rapid and complete resolution of bone scans, a phenomenon almost never observed even among therapies already shown to confer survival benefit. In castration-resistant prostate cancer, not all conventional response indicators change as dramatically posttreatment, raising the possibility that cabozantinib may impair the ability of bone-seeking radionuclides to integrate within the remodeling bone. To test this hypothesis, we surgically induced bone remodeling via physical insult in non-tumor-bearing mice and performed F-18-sodium fluoride (F-18-NaF) positron emission tomographic (PET) and technetium 99m-methylene diphosphonate (Tc-99m-MDP) single-photon emission computed tomographic (SPECT) scans pre- and posttreatment with cabozantinib and related inhibitors. A consistent reduction in the accumulation of either radiotracer at the site of bone remodeling was observed in animals treated with cabozantinib. Given that cabozantinib is known to inhibit several receptor tyrosine kinases, we drugged animals with various permutations of more selective inhibitors to attempt to refine the molecular basis of bone scan resolution. Neither the vascular endothelial growth factor receptor (VEGFR) inhibitor axitinib, the MET inhibitor crizotinib, nor the combination was capable of inhibiting F-18-NaF accumulation at known bioactive doses. In summary, although the mechanism by which cabozantinib suppresses radionuclide incorporation into foci undergoing bone remodeling remains unknown, that this phenomenon occurs in tumor-naive models indicates that caution should be exercised in interpreting the clinical significance of this event.},
  author       = {Doran, Michael G. and Spratt, Daniel E. and Wongvipat, John and Ulmert, David and Carver, Brett S. and Sawyers, Charles L. and Evans, Michael J.},
  issn         = {1535-3508},
  language     = {eng},
  publisher    = {BC Decker},
  series       = {Molecular Imaging},
  title        = {Cabozantinib Resolves Bone Scans in Tumor-Naive Mice Harboring Skeletal Injuries},
  url          = {http://dx.doi.org/10.2310/7290.2014.00026},
  volume       = {13},
  year         = {2014},
}