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

15 Citations (Scopus)

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

Fingerprint

Inflammatory Breast Neoplasms
Transcriptome
Bacteriophages
Dependovirus
Breast Neoplasms
Phenotype
Virion
Neoplasms
Immunoglobulin Fragments
Precision Medicine
Ganciclovir
Prodrugs
Cell Surface Receptors
Simplexvirus
Transgenes
Up-Regulation
Biomarkers
Theranostic Nanomedicine
Therapeutics

All Science Journal Classification (ASJC) codes

  • General

Keywords

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

Cite this

Dobroff, Andrey S. ; D'Angelo, Sara ; Eckhardt, Bedrich L. ; Ferrara, Fortunato ; Staquicini, Daniela I. ; Cardó-Vila, Marina ; Staquicini, Fernanda I. ; Nunes, Diana N. ; Kim, Kisu ; Driessen, Wouter H.P. ; Hajitou, Amin ; Lomo, Lesley C. ; Barry, Marc ; Krishnamurthy, Savitri ; Sahin, Aysegul ; Woodward, Wendy A. ; Prossnitz, Eric R. ; Anderson, Robin L. ; Dias-Neto, Emmanuel ; Brown-Glaberman, Ursa A. ; Royce, Melanie E. ; Ueno, Naoto T. ; Cristofanilli, Massimo ; Hortobagyi, Gabriel N. ; Marchiò, Serena ; Gelovani, Juri G. ; Sidman, Richard L. ; Arap, Wadih ; Pasqualini, Renata. / Towards a transcriptome-based theranostic platform for unfavorable breast cancer phenotypes. In: Proceedings of the National Academy of Sciences of the United States of America. 2016 ; Vol. 113, No. 45. pp. 12780-12785.
@article{41d1252ab37046e1bc94cd3c97a2621f,
title = "Towards a transcriptome-based theranostic platform for unfavorable breast cancer phenotypes",
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.",
keywords = "AAVP, Gene therapy, Inflammatory breast cancer, Ligand-directed theranostics, Molecular imaging",
author = "Dobroff, {Andrey S.} and Sara D'Angelo and Eckhardt, {Bedrich L.} and Fortunato Ferrara and Staquicini, {Daniela I.} and Marina Card{\'o}-Vila and Staquicini, {Fernanda I.} and Nunes, {Diana N.} and Kisu Kim and Driessen, {Wouter H.P.} and Amin Hajitou and Lomo, {Lesley C.} and Marc Barry and Savitri Krishnamurthy and Aysegul Sahin and Woodward, {Wendy A.} and Prossnitz, {Eric R.} and Anderson, {Robin L.} and Emmanuel Dias-Neto and Brown-Glaberman, {Ursa A.} and Royce, {Melanie E.} and Ueno, {Naoto T.} and Massimo Cristofanilli and Hortobagyi, {Gabriel N.} and Serena Marchi{\`o} and Gelovani, {Juri G.} and Sidman, {Richard L.} and Wadih Arap and Renata Pasqualini",
year = "2016",
month = "11",
day = "8",
doi = "10.1073/pnas.1615288113",
language = "English (US)",
volume = "113",
pages = "12780--12785",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "45",

}

Dobroff, AS, D'Angelo, S, Eckhardt, BL, Ferrara, F, Staquicini, DI, Cardó-Vila, M, Staquicini, FI, Nunes, DN, Kim, K, Driessen, WHP, Hajitou, A, Lomo, LC, Barry, M, Krishnamurthy, S, Sahin, A, Woodward, WA, Prossnitz, ER, Anderson, RL, Dias-Neto, E, Brown-Glaberman, UA, Royce, ME, Ueno, NT, Cristofanilli, M, Hortobagyi, GN, Marchiò, S, Gelovani, JG, Sidman, RL, Arap, W & 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, vol. 113, no. 45, pp. 12780-12785. https://doi.org/10.1073/pnas.1615288113

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

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 113, No. 45, 08.11.2016, p. 12780-12785.

Research output: Contribution to journalArticle

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

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

UR - http://www.scopus.com/inward/record.url?scp=84994509949&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84994509949&partnerID=8YFLogxK

U2 - 10.1073/pnas.1615288113

DO - 10.1073/pnas.1615288113

M3 - Article

AN - SCOPUS:84994509949

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

SN - 0027-8424

IS - 45

ER -