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.