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

被引：32

作者：

Ferrara, Fortunato ^{[1
,2
]}

Staquicini, Daniela I. ^{[1
,2
]}

Driessen, Wouter H. P. ^{[3
]}

D'Angelo, Sara ^{[1
,2
]}

Dobroff, Andrey S. ^{[1
,2
]}

Barry, Marc ^{[1
,4
]}

Lomo, Lesley C. ^{[1
,4
]}

Staquicini, Fernanda I. ^{[1
,2
]}

Cardo-Vila, Marina ^{[1
,2
]}

Soghomonyan, Suren ^{[5
]}

Alauddin, Mian M. ^{[6
]}

Flores, Leo G., II ^{[6
]}

Arap, Marco A. ^{[7
]}

Lauer, Richard C. ^{[1
,8
]}

Mathew, Paul ^{[9
]}

Efstathiou, Eleni ^{[3
]}

Aparicio, Ana M. ^{[3
]}

Troncoso, Patricia ^{[10
]}

Navone, Nora M. ^{[3
]}

Logothetis, Christopher J. ^{[3
]}

Marchio, Serena ^{[1
,2
,11
,12
]}

Gelovani, Juri G. ^{[5
]}

Sidman, Richard L. ^{[13
]}

Pasqualini, Renata ^{[1
,2
]}

Arap, Wadih ^{[1
,8
]}

机构：

[1] Univ New Mexico, Ctr Comprehens Canc, Albuquerque, NM 87131 USA

[2] Univ New Mexico, Sch Med, Dept Internal Med, Div Mol Med, Albuquerque, NM 87131 USA

[3] Univ Texas MD Anderson Canc Ctr, David H Koch Ctr, Houston, TX 77030 USA

[4] Univ New Mexico, Sch Med, Dept Pathol, Albuquerque, NM 87131 USA

[5] Wayne State Univ, Dept Biomed Engn, Detroit, MI 48201 USA

[6] Univ Texas MD Anderson Canc Ctr, Dept Canc Syst Imaging, Houston, TX 77030 USA

[7] Univ Sao Paulo, Sch Med, Dept Urol, BR-04604006 Sao Paulo, Brazil

[8] Univ New Mexico, Sch Med, Dept Internal Med, Div Hematol Oncol, Albuquerque, NM 87131 USA

[9] Tufts Med Ctr, Dept Hematol & Oncol, Boston, MA 02111 USA

[10] Univ Texas MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA

[11] Ist Ricovero & Cura Carattere Sci, Fdn Piemonte Oncol, Candiolo Canc Inst, I-10060 Turin, Italy

[12] Univ Turin, Dept Oncol, I-10060 Turin, Italy

[13] Harvard Med Sch, Beth Israel Deaconess Med Ctr, Dept Neurol, Boston, MA 02215 USA

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2016年 / 113卷 / 45期

关键词：

aggressive variant prostate cancer; ligand-directed theranostics; molecular imaging; gene therapy; AAVP; GLUCOSE-REGULATED PROTEIN; REPORTER GENE; GRP78; RECEPTOR; EXPRESSION; PEPTIDES; DELIVERY; TUMORS; MODEL; BACTERIOPHAGE;

D O I：

10.1073/pnas.1615400113

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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, GRP78targeting 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.

引用

页码：12786 / 12791

页数：6

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