Towards a transcriptome-based theranostic platform for unfavorable breast cancer phenotypes

Andrey S. Dobroff, Sara D'Angelo, Bedrich L. Eckhardt, Fortunato Ferrara, Daniela I. Staquicini, Marina Cardó-Vila, Fernanda I. Staquicini, Diana N. Nunes, Kisu Kim, Wouter H.P. Driessen, Amin Hajitou, Lesley C. Lomo, Marc Barry, Savitri Krishnamurthy, Aysegul Sahin, Wendy A. Woodward, Eric R. Prossnitz, Robin L. Anderson, Emmanuel Dias-Neto, Ursa A. Brown-GlabermanMelanie E. Royce, Naoto T. Ueno, Massimo Cristofanilli, Gabriel N. Hortobagyi, Serena Marchiò, Juri G. Gelovani, Richard L. Sidman, Wadih Arap, Renata Pasqualini

Research output: Contribution to journalArticle

16 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)12780-12785
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume113
Issue number45
DOIs
StatePublished - Nov 8 2016
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • General

Keywords

  • AAVP
  • Gene therapy
  • Inflammatory breast cancer
  • Ligand-directed theranostics
  • Molecular imaging

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  • Cite this

    Dobroff, A. S., D'Angelo, S., Eckhardt, B. L., Ferrara, F., Staquicini, D. I., Cardó-Vila, M., Staquicini, F. I., Nunes, D. N., Kim, K., Driessen, W. H. P., Hajitou, A., Lomo, L. C., Barry, M., Krishnamurthy, S., Sahin, A., Woodward, W. A., Prossnitz, E. R., Anderson, R. L., Dias-Neto, E., ... Pasqualini, R. (2016). Towards a transcriptome-based theranostic platform for unfavorable breast cancer phenotypes. Proceedings of the National Academy of Sciences of the United States of America, 113(45), 12780-12785. https://doi.org/10.1073/pnas.1615288113