Aggressive variant prostate cancers (AVPC) are a clinically defined group of tumors of heterogeneous morphologies, characterized by poor patient survival and for which limited diagnostic and treatment options are currently available. We show that the cell surface 78-kDa glucose-regulated protein (GRP78), a receptor that binds to phage-display-selected ligands, such as the SNTRVAP motif, is a candidate target in AVPC. We report the presence and accessibility of this receptor in clinical specimens from index patients. We also demonstrate that human AVPC cells displaying GRP78 on their surface could be effectively targeted both in vitro and in vivo by SNTRVAP, which also enabled specific delivery of siRNA species to tumor xenografts in mice. Finally, we evaluated ligand-directed strategies based on SNTRVAP-displaying adeno-associated virus/phage (AAVP) particles in mice bearing MDA-PCa-118b, a patient-derived xenograft (PDX) of castration-resistant prostate cancer bone metastasis that we exploited as a model of AVPC. For theranostic (a merging of the terms therapeutic and diagnostic) studies, GRP78-targeting AAVP particles served to deliver the human Herpes simplex virus thymidine kinase type-1 (HSVtk) gene, which has a dual function as a molecular-genetic sensor/reporter and a cell suicide-inducing transgene. We observed specific and simultaneous PET imaging and treatment of tumors in this preclinical model of AVPC. Our findings demonstrate the feasibility of GPR78-targeting, ligand-directed theranostics for translational applications in AVPC.
Proceedings of the National Academy of Sciences of the United States of America. 2016 Oct 24 [Epub ahead of print]
Fortunato Ferrara, Daniela I Staquicini, Wouter H P Driessen, Sara D'Angelo, Andrey S Dobroff, Marc Barry, Lesley C Lomo, Fernanda I Staquicini, Marina Cardó-Vila, Suren Soghomonyan, Mian M Alauddin, Leo G Flores, Marco A Arap, Richard C Lauer, Paul Mathew, Eleni Efstathiou, Ana M Aparicio, Patricia Troncoso, Nora M Navone, Christopher J Logothetis, Serena Marchiò, Juri G Gelovani, Richard L Sidman, Renata Pasqualini, Wadih Arap
University of New Mexico Comprehensive Cancer Center, Albuquerque, NM 87131; Division of Molecular Medicine, Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, NM 87131., David H. Koch Center, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030., University of New Mexico Comprehensive Cancer Center, Albuquerque, NM 87131; Department of Pathology, University of New Mexico School of Medicine, Albuquerque, NM 87131., Department of Biomedical Engineering, Wayne State University, Detroit, MI 48201., Department of Cancer Systems Imaging, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030., Department of Urology, University of São Paulo Medical School, Sao Paulo 04604-006, Brazil., University of New Mexico Comprehensive Cancer Center, Albuquerque, NM 87131; Division of Hematology/Oncology, Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, NM 87131., Department of Hematology and Oncology, Tufts Medical Center, Boston, MA 02111., Department of Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030., University of New Mexico Comprehensive Cancer Center, Albuquerque, NM 87131; Division of Molecular Medicine, Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, NM 87131; Candiolo Cancer Institute-Fondazione del Piemonte per l'Oncologia, Istituto di Ricovero e Cura a Carattere Scientifico, Candiolo, Turin 10060, Italy; Department of Oncology, University of Turin, Candiolo, Turin 10060, Italy., Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215 ., University of New Mexico Comprehensive Cancer Center, Albuquerque, NM 87131; Division of Molecular Medicine, Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, NM 87131; ., University of New Mexico Comprehensive Cancer Center, Albuquerque, NM 87131; Division of Hematology/Oncology, Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, NM 87131; .