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Research Article

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, View ORCID ProfileRobin L. Anderson, Emmanuel Dias-Neto, Ursa A. Brown-Glaberman, Melanie E. Royce, Naoto T. Ueno, Massimo Cristofanilli, Gabriel N. Hortobagyi, Serena Marchiò, Juri G. Gelovani, Richard L. Sidman, Wadih Arap, and Renata Pasqualini
PNAS first published October 24, 2016; https://doi.org/10.1073/pnas.1615288113
Andrey S. Dobroff
aUniversity of New Mexico Comprehensive Cancer Center, Albuquerque, NM 87131;
bDivision of Molecular Medicine, Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, NM 87131;
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Sara D’Angelo
aUniversity of New Mexico Comprehensive Cancer Center, Albuquerque, NM 87131;
bDivision of Molecular Medicine, Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, NM 87131;
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Bedrich L. Eckhardt
cDepartment of Breast Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030;
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Fortunato Ferrara
aUniversity of New Mexico Comprehensive Cancer Center, Albuquerque, NM 87131;
bDivision of Molecular Medicine, Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, NM 87131;
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Daniela I. Staquicini
aUniversity of New Mexico Comprehensive Cancer Center, Albuquerque, NM 87131;
bDivision of Molecular Medicine, Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, NM 87131;
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Marina Cardó-Vila
aUniversity of New Mexico Comprehensive Cancer Center, Albuquerque, NM 87131;
bDivision of Molecular Medicine, Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, NM 87131;
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Fernanda I. Staquicini
aUniversity of New Mexico Comprehensive Cancer Center, Albuquerque, NM 87131;
bDivision of Molecular Medicine, Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, NM 87131;
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Diana N. Nunes
dInternational Research Center, A. C. Camargo Cancer Center, Sao Paulo 01508-010, Brazil;
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Kisu Kim
eMOGAM Biotechnology Institute, Yongin, Gyeonggi-do 16924, Korea;
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Wouter H. P. Driessen
fDavid H. Koch Center, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030;
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Amin Hajitou
gHammersmith Hospital Campus, Imperial College London, London W12 0NN, United Kingdom;
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Lesley C. Lomo
aUniversity of New Mexico Comprehensive Cancer Center, Albuquerque, NM 87131;
hDepartment of Pathology, University of New Mexico School of Medicine, Albuquerque, NM 87131;
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Marc Barry
aUniversity of New Mexico Comprehensive Cancer Center, Albuquerque, NM 87131;
hDepartment of Pathology, University of New Mexico School of Medicine, Albuquerque, NM 87131;
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Savitri Krishnamurthy
iDepartment of Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030;
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Aysegul Sahin
iDepartment of Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030;
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Wendy A. Woodward
jDepartment of Radiation Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030;
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Eric R. Prossnitz
aUniversity of New Mexico Comprehensive Cancer Center, Albuquerque, NM 87131;
bDivision of Molecular Medicine, Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, NM 87131;
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Robin L. Anderson
kDepartment of Oncology, Sir Peter MacCallum Cancer Centre, The University of Melbourne, Parkville, VIC 3010, Australia;
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  • ORCID record for Robin L. Anderson
Emmanuel Dias-Neto
dInternational Research Center, A. C. Camargo Cancer Center, Sao Paulo 01508-010, Brazil;
lInstitute of Psychiatry, University of São Paulo Medical School, Sao Paulo 01060-970, Brazil;
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Ursa A. Brown-Glaberman
aUniversity of New Mexico Comprehensive Cancer Center, Albuquerque, NM 87131;
mDivision of Hematology/Oncology, Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, NM 87131;
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Melanie E. Royce
aUniversity of New Mexico Comprehensive Cancer Center, Albuquerque, NM 87131;
mDivision of Hematology/Oncology, Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, NM 87131;
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Naoto T. Ueno
cDepartment of Breast Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030;
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Massimo Cristofanilli
nRobert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611;
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Gabriel N. Hortobagyi
cDepartment of Breast Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030;
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Serena Marchiò
aUniversity of New Mexico Comprehensive Cancer Center, Albuquerque, NM 87131;
bDivision of Molecular Medicine, Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, NM 87131;
oCandiolo Cancer Institute-Fondazione del Piemonte per l’Oncologia, Istituto di Ricovero e Cura a Carattere Scientifico, Candiolo, Turin 10060, Italy;
pDepartment of Oncology, University of Turin, Candiolo, Turin 10060, Italy;
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Juri G. Gelovani
qDepartment of Biomedical Engineering, Wayne State University, Detroit, MI 48201;
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Richard L. Sidman
rDepartment of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215
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  • For correspondence: richard_sidman@hms.harvard.edu rpasqual@salud.unm.edu warap@salud.unm.edu
Wadih Arap
aUniversity of New Mexico Comprehensive Cancer Center, Albuquerque, NM 87131;
mDivision of Hematology/Oncology, Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, NM 87131;
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  • For correspondence: richard_sidman@hms.harvard.edu rpasqual@salud.unm.edu warap@salud.unm.edu
Renata Pasqualini
aUniversity of New Mexico Comprehensive Cancer Center, Albuquerque, NM 87131;
bDivision of Molecular Medicine, Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, NM 87131;
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  • For correspondence: richard_sidman@hms.harvard.edu rpasqual@salud.unm.edu warap@salud.unm.edu
  1. 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.

  • inflammatory breast cancer
  • ligand-directed theranostics
  • molecular imaging
  • gene therapy
  • AAVP

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.

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Theranostic targeting aggressive breast cancer
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-Glaberman, Melanie E. Royce, Naoto T. Ueno, Massimo Cristofanilli, Gabriel N. Hortobagyi, Serena Marchiò, Juri G. Gelovani, Richard L. Sidman, Wadih Arap, Renata Pasqualini
Proceedings of the National Academy of Sciences Oct 2016, 201615288; DOI: 10.1073/pnas.1615288113

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Theranostic targeting aggressive breast cancer
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-Glaberman, Melanie E. Royce, Naoto T. Ueno, Massimo Cristofanilli, Gabriel N. Hortobagyi, Serena Marchiò, Juri G. Gelovani, Richard L. Sidman, Wadih Arap, Renata Pasqualini
Proceedings of the National Academy of Sciences Oct 2016, 201615288; DOI: 10.1073/pnas.1615288113
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