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 antitumor 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.