Bone-specific growth inhibition of prostate cancer metastasis by atrasentan.
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.
Drake
Justin M
JM
Department of Molecular Physiology and Biophysics, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, IA, USA.
Danke
Joshua R
JR
Henry
Michael D
MD
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000473:pathology / Q000556:secondary*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000077868:Atrasentan; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000556:secondary*; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D006801:Humans; D008297:Male; D051379:Mice; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011759:Pyrrolidines / Q000494:pharmacology*; D011897:Random Allocation; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D011759:Pyrrolidines; D000077868:Atrasentan