title: Targeted molecular-genetic imaging and ligand-directed therapy in aggressive variant prostate cancer.
abstract: 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 humanHerpes simplexvirus 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.
authors: 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.
authors: Fortunato
authors: F
authors: Ferrara
authors: 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.
authors: Daniela I
authors: DI
authors: Staquicini
authors: David H. Koch Center, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030.
authors: Wouter H P
authors: WHP
authors: Driessen
authors: 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.
authors: Sara
authors: S
authors: D'Angelo
authors: 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.
authors: Andrey S
authors: AS
authors: Dobroff
authors: University of New Mexico Comprehensive Cancer Center, Albuquerque, NM 87131.|Department of Pathology, University of New Mexico School of Medicine, Albuquerque, NM 87131.
authors: Marc
authors: M
authors: Barry
authors: University of New Mexico Comprehensive Cancer Center, Albuquerque, NM 87131.|Department of Pathology, University of New Mexico School of Medicine, Albuquerque, NM 87131.
authors: Lesley C
authors: LC
authors: Lomo
authors: 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.
authors: Fernanda I
authors: FI
authors: Staquicini
authors: 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.
authors: Marina
authors: M
authors: Cardó-Vila
authors: Department of Biomedical Engineering, Wayne State University, Detroit, MI 48201.
authors: Suren
authors: S
authors: Soghomonyan
authors: Department of Cancer Systems Imaging, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030.
authors: Mian M
authors: MM
authors: Alauddin
authors: Department of Cancer Systems Imaging, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030.
authors: Leo G
authors: LG
authors: Flores
authors: Department of Urology, University of São Paulo Medical School, Sao Paulo 04604-006, Brazil.
authors: Marco A
authors: MA
authors: Arap
authors: 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.
authors: Richard C
authors: RC
authors: Lauer
authors: Department of Hematology and Oncology, Tufts Medical Center, Boston, MA 02111.
authors: Paul
authors: P
authors: Mathew
authors: David H. Koch Center, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030.
authors: Eleni
authors: E
authors: Efstathiou
authors: David H. Koch Center, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030.
authors: Ana M
authors: AM
authors: Aparicio
authors: Department of Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030.
authors: Patricia
authors: P
authors: Troncoso
authors: David H. Koch Center, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030.
authors: Nora M
authors: NM
authors: Navone
authors: David H. Koch Center, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030.
authors: Christopher J
authors: CJ
authors: Logothetis
authors: 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.
authors: Serena
authors: S
authors: Marchiò
authors: Department of Biomedical Engineering, Wayne State University, Detroit, MI 48201.
authors: Juri G
authors: JG
authors: Gelovani
authors: Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215 richard_sidman@hms.harvard.edu rpasqual@salud.unm.edu warap@salud.unm.edu.
authors: Richard L
authors: RL
authors: Sidman
authors: University of New Mexico Comprehensive Cancer Center, Albuquerque, NM 87131; richard_sidman@hms.harvard.edu rpasqual@salud.unm.edu warap@salud.unm.edu.|Division of Molecular Medicine, Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, NM 87131.
authors: Renata
authors: R
authors: Pasqualini
authors: University of New Mexico Comprehensive Cancer Center, Albuquerque, NM 87131; richard_sidman@hms.harvard.edu rpasqual@salud.unm.edu warap@salud.unm.edu.|Division of Hematology/Oncology, Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, NM 87131.
authors: Wadih
authors: W
authors: Arap
keywords: AAVP; aggressive variant prostate cancer; gene therapy; ligand-directed theranostics; molecular imaging