Targeted molecular-genetic imaging and liganddirected therapy in aggressive variant prostate cancer

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. LogothetisSerena Marchiò, Juri G. Gelovani, Richard L. Sidman, Renata Pasqualini, Wadih Arap

Research output: Contribution to journalArticlepeer-review

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 patientderived 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 suicideinducing 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, liganddirected theranostics for translational applications in AVPC.

Original languageEnglish
Pages (from-to)12786-12791
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume113
Issue number45
DOIs
Publication statusPublished - Nov 8 2016

Keywords

  • AAVP
  • Aggressive variant prostate cancer
  • Gene therapy
  • Ligand-directed theranostics
  • Molecular imaging

ASJC Scopus subject areas

  • General

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