Towards a transcriptome-based theranostic platform for unfavorable breast cancer phenotypes
File(s)
Accepted version
Supporting information
Author(s)
Type
Journal Article
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.
Date Issued
2016-11-08
Date Acceptance
2016-10-01
Citation
Proceedings of the National Academy of Sciences of the United States of America, 2016, 113 (45), pp.12780-12785
ISSN
0027-8424
Publisher
National Academy of Sciences
Start Page
12780
End Page
12785
Journal / Book Title
Proceedings of the National Academy of Sciences of the United States of America
Volume
113
Issue
45
Copyright Statement
© 2018 National Academy of Sciences. Freely available online through the PNAS open access option under a CC-BY-NC-ND
Sponsor
Medical Research Council (MRC)
Identifier
http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000388073300069&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
Grant Number
G0701159
Subjects
Science & Technology
Multidisciplinary Sciences
Science & Technology - Other Topics
inflammatory breast cancer
ligand-directed theranostics
molecular imaging
gene therapy
AAVP
UNFOLDED PROTEIN RESPONSE
ENDOTHELIAL GROWTH-FACTOR
ENDOPLASMIC-RETICULUM
PROSTATE-CANCER
TARGETING GRP78
PHAGE DISPLAY
GENE-THERAPY
IN-VIVO
EXPRESSION
CHAPERONE
Publication Status
Published
Date Publish Online
2016-10-24