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Contributed by Richard L. Sidman, September 16, 2016 (sent for review July 11, 2016; reviewed by Otis W. Brawley, Sanjiv S. Gambhir, and Amy S. Lee)
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Significance
Inflammatory breast cancer (IBC) is defined clinically and pathologically. Dermal lymphatic invasion is typical but is neither necessary nor sufficient for diagnosis; sentinel lymph node biopsy is contraindicated, challenging multidisciplinary management with upfront chemotherapy, surgery, and postoperative radiotherapy. Here we applied a ligand-directed “theranostic” (a combination of therapeutic and diagnostic) enabling platform to target IBC based on adeno-associated virus/phage (AAVP)-Herpes simplex virus thymidine kinase type-1 (HSVtk) particles displaying ligands to cell surface-associated 78-kD glucose-regulated protein (GRP78). In a suite of preclinical models and human tumor samples, we show simultaneous noninvasive molecular serial PET/CT imaging and targeted suicide transgene therapy. This study shows that a tumor-specific promoter, human GRP78 (hGRP78), can drive the expression of an imaging/suicide transgene in IBC and aggressive breast cancer in vivo.
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.
Footnotes
↵1A.S.D., S.D., and B.L.E. contributed equally to this work.
- ↵2To whom correspondence may be addressed. Email: richard_sidman{at}hms.harvard.edu, rpasqual{at}salud.unm.edu, or warap{at}salud.unm.edu.
↵3W.A. and R.P. contributed equally to this work.
Author contributions: A.S.D., S.D., B.L.E., F.F., D.I.S., M.C.-V., F.I.S., D.N.N., K.K., A.H., E.D.-N., R.L.S., W.A., and R.P. designed research; A.S.D., S.D., B.L.E., F.F., D.I.S., M.C.-V., F.I.S., D.N.N., K.K., W.H.P.D., A.H., L.C.L., M.B., S.K., A.S., and E.D.-N. performed research; A.S.D., S.D., B.L.E., F.F., D.I.S., M.C.-V., F.I.S., D.N.N., K.K., W.H.P.D., A.H., L.C.L., M.B., S.K., A.S., W.A.W., E.R.P., R.L.A., E.D.-N., U.A.B.-G., M.E.R., N.T.U., M.C., G.N.H., S.M., J.G.G., R.L.S., W.A., and R.P. analyzed data; and A.S.D., S.D., F.F., U.A.B.-G., M.E.R., N.T.U., M.C., S.M., J.G.G., R.L.S., W.A., and R.P. wrote the paper.
Reviewers: O.W.B., Emory University and the American Cancer Society; S.S.G., Stanford University School of Medicine; and A.S.L., University of Southern California/Norris Comprehensive Cancer Center.
Conflict of interest statement: W.A. and R.P. are founders of AAVP BioSystems, which has licensed intellectual property related to the AAVP technology. A.H., W.A., and R.P. are named as inventors on patent applications and are entitled to standard royalties if commercialization occurs. The M. D. Anderson Cancer Center and the University of New Mexico Comprehensive Cancer Center manage these arrangements according to their established institutional conflict-of-interest policies.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1615288113/-/DCSupplemental.
Freely available online through the PNAS open access option.
Theranostic targeting aggressive breast cancer
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