TY - JOUR
T1 - Enhancing Radium 223 treatment efficacy by anti-beta 1 integrin targeting
AU - Paindelli, Claudia
AU - Casarin, Stefano
AU - Wang, Feng
AU - Diaz-Gomez, Luis
AU - Zhang, Jianhua
AU - Mikos, Antonios G.
AU - Logothetis, Christopher J.
AU - Friedl, Peter
AU - Dondossola, Eleonora
N1 - Publisher Copyright:
© 2022 Society of Nuclear Medicine Inc.. All rights reserved.
PY - 2022/7/1
Y1 - 2022/7/1
N2 - Radium 223 (223Ra) is an α-emitter approved for the treatment of bone metastatic prostate cancer (PCa), which exerts direct cytotoxicity towards PCa cells near the bone interface, whereas cells positioned in the core respond poorly, due to short α-particle penetrance. β1 integrin (β1I) interference has been shown to increase radiosensitivity and significantly enhance external beam radiation efficiency. We hypothesized that targeting β1I would improve 223Ra outcome. We tested the effect of combining 223Ra and anti-β1I antibody treatment in PC3 and C4-2B PCa cell models expressing high and low β1I levels, respectively. In vivo tumor growth was evaluated through bioluminescence. Cellular and molecular determinants of response were analyzed by ex vivo three-dimensional imaging of bone lesions, proteomic analysis and further confirmed by computational modeling and in vitro functional analysis in tissue-engineered bone mimetic systems. Interference with β1I combined with 223Ra reduced PC3 cell growth in bone and significantly improved overall mouse survival, while no change was achieved in C4-2B tumors. Anti-β1I treatment decreased PC3 tumor cell mitosis index and spatially expanded 223Ra lethal effects two-fold, in vivo and in silico. Regression was paralleled by decreased expression of radio-resistance mediators. Targeting β1I significantly improves 223Ra outcome and points towards combinatorial application in PCa tumors with high β1I expression.
AB - Radium 223 (223Ra) is an α-emitter approved for the treatment of bone metastatic prostate cancer (PCa), which exerts direct cytotoxicity towards PCa cells near the bone interface, whereas cells positioned in the core respond poorly, due to short α-particle penetrance. β1 integrin (β1I) interference has been shown to increase radiosensitivity and significantly enhance external beam radiation efficiency. We hypothesized that targeting β1I would improve 223Ra outcome. We tested the effect of combining 223Ra and anti-β1I antibody treatment in PC3 and C4-2B PCa cell models expressing high and low β1I levels, respectively. In vivo tumor growth was evaluated through bioluminescence. Cellular and molecular determinants of response were analyzed by ex vivo three-dimensional imaging of bone lesions, proteomic analysis and further confirmed by computational modeling and in vitro functional analysis in tissue-engineered bone mimetic systems. Interference with β1I combined with 223Ra reduced PC3 cell growth in bone and significantly improved overall mouse survival, while no change was achieved in C4-2B tumors. Anti-β1I treatment decreased PC3 tumor cell mitosis index and spatially expanded 223Ra lethal effects two-fold, in vivo and in silico. Regression was paralleled by decreased expression of radio-resistance mediators. Targeting β1I significantly improves 223Ra outcome and points towards combinatorial application in PCa tumors with high β1I expression.
KW - bone metastasis
KW - integrin beta 1 Running Title: Enhancing Radium 223 efficacy
KW - prostate cancer
KW - Radium 223
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U2 - 10.2967/jnumed.121.262743
DO - 10.2967/jnumed.121.262743
M3 - Article
C2 - 34711616
AN - SCOPUS:85125059340
SN - 0161-5505
VL - 63
JO - Journal of Nuclear Medicine
JF - Journal of Nuclear Medicine
IS - 7
ER -