Radioiodine therapy for castration-resistant prostate cancer following prostate-specific membrane antigen promoter-mediated transfer of the human sodium iodide symporter

Abstract

Radioiodine therapy, the most effective form of systemic radiotherapy available, is currently useful only for thyroid cancer because of the thyroid-specific expression of the human sodium iodide symporter (hNIS). Here, we explore the efficacy of a novel form of gene therapy using prostate-specific membrane antigen (PSMA) promoter-mediated hNIS gene transfer followed by radioiodine administration for the treatment of castration-resistant prostate cancer (CRPC). The androgen-dependent C33 LNCaP cell line and the androgen-independent C81 LNCaP cell line were transfected by adenovirus. PSMA promoter-hNIS (Ad.PSMApro-hNIS) or adenovirus.cytomegalovirus–hNIS containing the cytomegalovirus promoter (Ad.CMV-hNIS) or a control virus. The iodide uptake was measured in vitro. The in vivo iodide uptake by C81 cell xenografts in nude mice injected with an adenovirus carrying the hNIS gene linked to PSMA and the corresponding tumor volume fluctuation were assessed. Iodide accumulation was shown in different LNCaP cell lines after Ad.PSMApro-hNIS and Ad.CMV-hNIS infection, but not in different LNCaP cell lines after adenovirus.cytomegalovirus (Ad.CMV) infection. At each time point, higher iodide uptake was shown in the C81 cells infected with Ad.PSMApro-hNIS than in the C33 cells (P < 0.05). An in vivo animal model showed a significant difference in 131I radioiodine uptake in the tumors infected with Ad.PSMApro-hNIS, Ad.CMV-hNIS and control virus (P < 0.05) and a maximum reduction of tumor volume in mice infected with Ad.PSMApro-hNIS. These results show prostate-specific expression of the hNIS gene delivered by the PSMA promoter and effective radioiodine therapy of CRPC by the PSMA promoter-driven hNIS transfection.

The five “W”s and “How” of Targeted Alpha Therapy: Why? Who? What? Where? When? and How?

“…For instance, the recombinant humanized IgG1 monoclonal antibody HuM195reactive with CD33 targeting acute myelogenous leukemia; the murine 9.2.27 mAb highly specific for the melanomaassociated chondroitin sulfate proteoglycan NG2; the anti-CD20 for lymphoma; MX35 F(ab′)2 (targeting a cell surface glycoprotein), and trastuzumab (targeting Her2) for ovarian cancer; the murine 81C6 IgG2b mAb targeting an extracellular matrix glycoprotein expressed in many tumors but not in healthy tissues; the human-mouse chimeric anti-tenascin 81C6 for brain tumors, the PAI2 against urokinase-type plasminogen activator, the C595 a murine mAb against MUC-1, and the folate receptor alpha for many solid tumors. Prostate-specific membrane antigen (PSMA), investigated for various diagnostic applications, especially in prostate cancer (Vallabhajosula et al 2004;Behe et al 20111;Gao et al 2014;Kiess et al 2015;Evans et al 2016;Hadaschik and Boegemann 2017), is one of the most promising theragnostic agents for TAT. Radium-223-dichloride, due to its natural affinity for bone, is applied in bone cancers and skeletal metastases (Allen 2012;Dekempeneer et al 2016).…”

“…Therefore, the possibility to deliver cytotoxic radiation to a specific target makes PSMA a suitable and attractive molecule for RIT. RIT with PSMA radiolabeled with beta emitters ( 125/131 I, 177 Lu, and 90 Y) determined a reduction of tumor volume or a delayed tumor growth in preclinical PCa animal models (Vallabhajosula et al 2004;Behe et al 2011;Gao et al 2014;Kiess et al 2015;Evans et al 2016;Hadaschik and Boegemann 2017). In men, RIT with PSMA radiolabeled with beta emitters showed biochemical or radiological response associated with clinical benefit (e.g., pain relief) in the majority of cases (Bander et al 2005;Vallabhajosula et al 2005;Tagawa et al 2013;Zechmann et al 2014;Ahmadzadehfar et al 2015Ahmadzadehfar et al , 2017Kratochwil et al 2015;Rahbar et al 2017), even if about one-third of treated patients did not respond despite the in vivo demonstration of PSMA overexpression by 68 Ga-PSMA PET/CT (Hadaschik and Boegemann 2017).…”

Targeting strategies of adenovirus-mediated gene therapy and virotherapy for prostate cancer

“…PSMA is primarily expressed in PCa cells and is highly expressed in PCa and during metastasis ( 31 – 37 ). Gao et al ( 38 ) constructed a recombinant adenovirus that expressed human sodium iodide symporter (hNIS) driven by the PSMA promoter (Ad.PSMApro-hNIS). Compared with the recombinant adenovirus containing a cytomegalovirus (CMV) promoter (Ad.CMV-hNIS), expression of the hNIS gene induced by the PSMA promoter was highly prostate-specific in different LNCaP cell lines, particularly in the androgen-independent C81 LNCaP cell line.…”

Usefulness of the MRP2 promoter to overcome the chemoresistance of gastrointestinal and liver tumors by enhancing the expression of the drug transporter OATP1B1

“…This has been assayed in several types of cancer including hepatocellular carcinoma [ 29 ]. Tissue specificity has been further improved by using promoters of cell-specific genes such as alpha-fetoprotein in hepatocellular carcinoma [ 29 ], prostate-specific membrane antigen in prostate cancer [ 30 ], and glial fibrillary acidic protein in glioma [ 31 ].…”