TY - JOUR
TI - Hedgehog signaling inhibition by the small molecule smoothened inhibitor
GDC-0449 in the bone forming prostate cancer xenograft MDA PCa 118b
AU - Karlou, Maria
AU - Lu, Jing-Fang
AU - Wu, Guanglin
AU - Maity, Sankar and
AU - Tzelepi, Vassiliki
AU - Navone, Nora M.
AU - Hoang, Anh
AU - Logothetis,
AU - Christopher J.
AU - Efstathiou, Eleni
JO - Prostate Cancer and Prostatic Diseases
PY - 2012
VL - 72
TODO - 15
SP - 1638-1647
PB - Wiley-Blackwell
SN - 1365-7852, 1476-5608
TODO - 10.1002/pros.22517
TODO - Hh signaling; prostate cancer; MDA PCa 118b
TODO - BACKGROUND Hedgehog signaling is a stromal-mesenchymal pathway central
to the development and homeostasis of both the prostate and the bone.
Aberrant Hedgehog signaling activation has been associated with prostate
cancer aggressiveness. We hypothesize that Hedgehog pathway is a
candidate therapeutic target in advanced prostate cancer. We confirm
increased Hedgehog signaling in advanced and bone metastatic castrate
resistant prostate cancer and examine the pharmacodynamic effect of
Smoothened inhibition by the novel reagent GDC-0449 in an experimental
prostate cancer model. METHODS Hedgehog signaling component expression
was assessed in tissue microarrays of high grade locally advanced and
bone metastatic disease. Male SCID mice subcutaneously injected with the
bone forming xenograft MDA PCa 118b were treated with GDC-0449. Hedgehog
signaling in the tumor microenvironment was assessed by proteomic and
species specific RNA expression and compared between GDC-0449 treated
and untreated animals. RESULTS We observe Hedgehog signaling in high
grade locally advanced and bone marrow infiltrating disease. Evidence of
paracrine activation of Hedgehog signaling in the tumor xenograft, was
provided by increased Sonic Hedgehog expression in human tumor
epithelial cells, coupled with increased Gli1 and Patched1 expression in
the murine stromal compartment, while normal murine stroma did not
exhibit Hh signaling expression. GDC-0449 treatment attenuated Hh
signaling as evidenced by reduced expression of Gli1 and Ptch1.
Reduction in proliferation (Ki67) was observed with no change in tumor
volume. CONCLUSIONS GDC-0449 treatment is pharmacodynamically effective
as evidenced by paracrine Hedgehog signaling inhibition and results in
tumor cell proliferation reduction. Understanding these observations
will inform the clinical development of therapy based on Hedgehog
signaling inhibition. Prostate 72:16381647, 2012. (c) 2012 Wiley
Periodicals, Inc.
ER -