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 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.aggressive variant prostate cancer | ligand-directed theranostics | molecular imaging | gene therapy | AAVP P rostate cancer, the most common carcinoma in men and a major cause of morbidity and mortality (1), is a clinically heterogenous disease. Although a majority of prostate cancers are highly responsive to androgen receptor (AR)-directed therapies, a subset is relatively resistant to these therapies and carries a dismal prognosis (2-5). At the extreme of this spectrum are the small-cell or neuroendocrine carcinomas, a predominantly AR-negative histological variant of the disease that is associated with atypical clinical features (such as visceral metastases, predominantly lytic bone metastases, low levels of prostate-specific antigen relative to tumor burden, bulky primary tumors, and high levels of lactic dehydrongenase and carcinoembryonic antigen) and responds to platinum-based chemotherapies (6). Although small-cell or neuorendocrine carcinomas of the prostate are rare at initial diagnosis, they are increasingly recognized in the castration-resistant phases of disease progression. Moreover, a larger group of morphologically heterogeneous prostate cancers share the clinical features of the small-cell neuroendocrine carcinomas and, likely, their underlying biology (7, 8); these have been grouped under the term aggressive variant prostate carcinomas (AVPC). The molecular underpinnings of the AVPC are likely shared with subsets of other Significance Aggressive variant prost...

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“…Attesting to its inherent versatility, ligand-directed AAVPbased delivery of transgenes in preclinical settings has been demonstrated successfully in xenograft and transgenic models of soft-tissue sarcomas (10), glioblastomas (11), and neuroendocrine pancreatic tumors (12), in addition to the original new technology report in breast and prostate cancer in tumor-bearing mice a decade ago (9,19). Notably, one also could speculate that the described ligand-directed theranostic approach introduced here could also be used to determine the precise location of a lesion intraoperatively and/or to integrate the administration of tumor-directed treatments based on the recent report of an enabling AAVP-based nanotechnology platform (46). (See SI Discussion for a further discussion of the potential for AAVP in the clinical setting.…”

“…Gene therapy has been recognized as a great promise for the treatment of cancer, but the lack of a robust system to deliver reporter and/ or therapeutic transgene(s) effectively and specifically is a serious limiting factor. The AAVP-based strategy reported here has its maximum diagnostic and therapeutic efficacy targeted at the tumor site, making it a promising candidate for the development of first in-human clinical trials for tumors such as IBC and aggressive variant prostate cancer (46), which are in the advanced planning stage. Finally, in the future other tumor-specific ligandreceptor systems and/or inducible promoters may be integrated easily into the AAVP-based platform.…”

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“…The other recent therapeutic model utilized a phage, displaying a ligand specific to GRP78, to deliver the herpes simplex virus thymidine kinase type-1 suicide inducing transgene to mice with MDA-PCa-118b patient derived tumor xenografts. After treatment with the antiviral drug ganciclovir, tumors were reduced by an average of 50%[33]. It is curious to speculate whether ionizing radiation could be employed prior to treatment with the viral phage to upregulate expression of GRP78 to increase the effectiveness of phage targeting of cancer cells.…”

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“…The aim of gene therapy is to transfect a target gene into host cells to be specifically expressed, thus killing tumor cells. Currently, suicide gene therapy has become a promising strategy for gene therapy, especially the herpes simplex virus thymidine kinase ( HSVtk )/ganciclovir (GCV) system (10). Previous studies have demonstrated the use of a pro-drug sensitive gene as a suicide gene, to convert a non-toxic pro-drug into a toxic product, to block the extension of DNA chains and inhibit the activation of DNA polymerase, finally leading to cell apoptosis (11–13).…”