TY - JOUR
T1 - Towards a transcriptome-based theranostic platform for unfavorable breast cancer phenotypes
AU - Dobroff, Andrey S.
AU - D'Angelo, Sara
AU - Eckhardt, Bedrich L.
AU - Ferrara, Fortunato
AU - Staquicini, Daniela I.
AU - Cardó-Vila, Marina
AU - Staquicini, Fernanda I.
AU - Nunes, Diana N.
AU - Kim, Kisu
AU - Driessen, Wouter H.P.
AU - Hajitou, Amin
AU - Lomo, Lesley C.
AU - Barry, Marc
AU - Krishnamurthy, Savitri
AU - Sahin, Aysegul
AU - Woodward, Wendy A.
AU - Prossnitz, Eric R.
AU - Anderson, Robin L.
AU - Dias-Neto, Emmanuel
AU - Brown-Glaberman, Ursa A.
AU - Royce, Melanie E.
AU - Ueno, Naoto T.
AU - Cristofanilli, Massimo
AU - Hortobagyi, Gabriel N.
AU - Marchiò, Serena
AU - Gelovani, Juri G.
AU - Sidman, Richard L.
AU - Arap, Wadih
AU - Pasqualini, Renata
N1 - Funding Information:
We thank Dr. Andrew R. Bradbury of Los Alamos National Laboratory for critical reading of the manuscript, Dr. Helen Pickersgill of Life Science Editors for editorial services, and Dr. Kelly Davis Orcutt of inviCRO for imaging services. This work received funding from Department of Defense IMPACT Grant W81XWH-09-1-0224 and award funding from AngelWorks and the Gillson-Longenbaugh Foundation (all toW.A. and R.P.) and was supported in part by National Cancer Institute Cancer Center Support Grants P30 CA016672 to the MDACC and P30 CA118100 to the UNMCCC.
PY - 2016/11/8
Y1 - 2016/11/8
N2 - Inflammatory breast carcinoma (IBC) is one of the most lethal forms of human breast cancer, and effective treatment for IBC is an unmet clinical need in contemporary oncology. Tumor-targeted theranostic approaches are emerging in precision medicine, but only a few specific biomarkers are available. Here we report up-regulation of the 78-kDa glucose-regulated protein (GRP78) in two independent discovery and validation sets of specimens derived from IBC patients, suggesting translational promise for clinical applications. We show that a GRP78-binding motif displayed on either bacteriophage or adeno-associated virus/phage (AAVP) particles or loop-grafted onto a human antibody fragment specifically targets orthotopic IBC and other aggressive breast cancer models in vivo. To evaluate the theranostic value, we used GRP78-targeting AAVP particles to deliver the human Herpes simplex virus thymidine kinase type-1 (HSVtk) transgene, obtaining simultaneous in vivo diagnosis through PET imaging and tumor treatment by selective activation of the prodrug ganciclovir at tumor sites. Translation of this AAVP system is expected simultaneously to image, monitor, and treat the IBC phenotype and possibly other aggressive (e.g., invasive and/or metastatic) subtypes of breast cancer, based on the inducible cell-surface expression of the stress-response chaperone GRP78, and possibily other cell-surface receptors in human tumors.
AB - Inflammatory breast carcinoma (IBC) is one of the most lethal forms of human breast cancer, and effective treatment for IBC is an unmet clinical need in contemporary oncology. Tumor-targeted theranostic approaches are emerging in precision medicine, but only a few specific biomarkers are available. Here we report up-regulation of the 78-kDa glucose-regulated protein (GRP78) in two independent discovery and validation sets of specimens derived from IBC patients, suggesting translational promise for clinical applications. We show that a GRP78-binding motif displayed on either bacteriophage or adeno-associated virus/phage (AAVP) particles or loop-grafted onto a human antibody fragment specifically targets orthotopic IBC and other aggressive breast cancer models in vivo. To evaluate the theranostic value, we used GRP78-targeting AAVP particles to deliver the human Herpes simplex virus thymidine kinase type-1 (HSVtk) transgene, obtaining simultaneous in vivo diagnosis through PET imaging and tumor treatment by selective activation of the prodrug ganciclovir at tumor sites. Translation of this AAVP system is expected simultaneously to image, monitor, and treat the IBC phenotype and possibly other aggressive (e.g., invasive and/or metastatic) subtypes of breast cancer, based on the inducible cell-surface expression of the stress-response chaperone GRP78, and possibily other cell-surface receptors in human tumors.
KW - AAVP
KW - Gene therapy
KW - Inflammatory breast cancer
KW - Ligand-directed theranostics
KW - Molecular imaging
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U2 - 10.1073/pnas.1615288113
DO - 10.1073/pnas.1615288113
M3 - Article
C2 - 27791177
AN - SCOPUS:84994509949
SN - 0027-8424
VL - 113
SP - 12780
EP - 12785
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 45
ER -
