Bone-specific growth inhibition of prostate cancer metastasis by atrasentan

Justin M. Drake, Joshua R. Danke, Michael D. Henry

Research output: Contribution to journalArticlepeer-review

21 Scopus citations

Abstract

Advanced prostate cancer frequently metastasizes to bone and remains an incurable disease. One recent experimental therapy involves endothelin receptor A (ETA) antagonists (e.g., atrasentan). Clinical results to date have been mixed, with atrasentan not meeting its primary endpoints in a Phase III trial. It remains an open question whether some patients might benefit from this therapy, while others may not. Preclinical data supports the concept that the endothelin signaling axis may be particularly important for tumor growth in bone, but the extent to which it is involved in metastatic colonization of other organ sites in prostate cancer remains unclear. Here we evaluate the efficacy of atrasentan in a mouse model of prostate cancer metastatic colonization. Using bioluminescence imaging, we show that atrasentan does inhibit tumor growth in, but not the initial colonization of, bony sites in intracardially-injected 22Rv1 prostate cancer cells. however, atrasentan shows little efficacy in soft tissues such as adrenal gland or liver. Our studies show that whether atrasentan exhibits significant overall anti-tumor efficacy and survival benefit depends on the presence of bone metastasis evident in that animal. Though in contrast to previous findings, efficacy is apparent in a prostate tumor model that elicits mixed osteoblastic/osteolytic lesions. These data confirm the notion that atrasentan may exhibit selective activity against prostate cancer bone metastasis, mirroring clinical findings, and suggest that the role of endothelin signaling in bone metastasis may be more complex than previously appreciated. The model described here may provide a valuable tool for unraveling this complexity.

Original languageEnglish (US)
Pages (from-to)607-614
Number of pages8
JournalCancer Biology and Therapy
Volume9
Issue number8
DOIs
StatePublished - Apr 15 2010
Externally publishedYes

Bibliographical note

Funding Information:
We would like to thank Abbott Labs for atrasentan, Dr. Brian Smith for advice on statistical analyses and members of the Henry laboratory for comments on the manuscript. This work was supported by an NIH Predoctoral Training Grant (T32 GM067795) to J.M.D. and an American Heart Association grant-in-aid (0750196Z) to M.D.H.

Keywords

  • Atrasentan
  • Bioluminescence imaging
  • Bone
  • Endothelin-1
  • Metastasis
  • Prostate cancer

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