Claudia Paindelli1,2, Stefano Casarin3, Feng Wang4, Luis Diaz-Gomez5, Jianhua Zhang4, Antonios G Mikos5, Christopher J Logothetis1, Peter Friedl1,2,6, Eleonora Dondossola7. 1. Department of Genitourinary Medical Oncology and David H. Koch Center for Applied Research of Genitourinary Cancers, University of Texas M.D. Anderson Cancer Center, Houston, Texas. 2. Department of Cell Biology, Radboud University Medical Center, Nijmegen, The Netherlands. 3. Center for Computational Surgery, Department of Surgery and Houston Methodist Academic Institute, Houston Methodist Research Institute, Houston, Texas. 4. Department of Genomic Medicine, University of Texas M.D. Anderson Cancer Center, Houston, Texas. 5. Department of Bioengineering, Rice University, Houston, Texas; and. 6. Cancer Genomics Centre, Utrecht, The Netherlands. 7. Department of Genitourinary Medical Oncology and David H. Koch Center for Applied Research of Genitourinary Cancers, University of Texas M.D. Anderson Cancer Center, Houston, Texas; edondossola@mdanderson.org.
Abstract
223Ra is an α-emitter approved for the treatment of bone metastatic prostate cancer (PCa), which exerts direct cytotoxicity toward PCa cells near the bone interface, whereas cells positioned in the core respond poorly because of 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. Methods: 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 3-dimensional imaging of bone lesions and by proteomic analysis and were further confirmed by computational modeling and in vitro functional analysis in tissue-engineered bone mimetic systems. Results: Interference with β1I combined with 223Ra reduced PC3 cell growth in bone and significantly improved overall mouse survival, whereas no change was achieved in C4-2B tumors. Anti-β1I treatment decreased the PC3 tumor cell mitosis index and spatially expanded 223Ra lethal effects 2-fold, in vivo and in silico. Regression was paralleled by decreased expression of radioresistance mediators. Conclusion: Targeting β1I significantly improves 223Ra outcome and points toward combinatorial application in PCa tumors with high β1I expression.
223Ra is an α-emitter approved for the treatment of bone metastatic prostate cancer (PCa), which exerts direct cytotoxicity toward PCa cells near the bone interface, whereas cells positioned in the core respond poorly because of 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. Methods: 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 3-dimensional imaging of bone lesions and by proteomic analysis and were further confirmed by computational modeling and in vitro functional analysis in tissue-engineered bone mimetic systems. Results: Interference with β1I combined with 223Ra reduced PC3 cell growth in bone and significantly improved overall mouse survival, whereas no change was achieved in C4-2B tumors. Anti-β1I treatment decreased the PC3 tumor cell mitosis index and spatially expanded 223Ra lethal effects 2-fold, in vivo and in silico. Regression was paralleled by decreased expression of radioresistance mediators. Conclusion: Targeting β1I significantly improves 223Ra outcome and points toward combinatorial application in PCa tumors with high β1I expression.
Authors: P Gasperin; M Gozy; O Pauwels; J Frühling; P Van Houtte; J L Pasteels; R Kiss Journal: Int J Radiat Oncol Biol Phys Date: 1992 Impact factor: 7.038
Authors: Anna Haeger; Stephanie Alexander; Manon Vullings; Fabian M P Kaiser; Cornelia Veelken; Uta Flucke; Gudrun E Koehl; Markus Hirschberg; Michael Flentje; Robert M Hoffman; Edward K Geissler; Stephan Kissler; Peter Friedl Journal: J Exp Med Date: 2020-01-06 Impact factor: 14.307