AEG-1 Promoter–Mediated Imaging of Prostate Cancer

Abstract

We describe a new imaging method for detecting prostate cancer, whether localized or disseminated and metastatic to soft tissues and bone. The method relies on the use of imaging reporter genes under the control of the promoter of AEG-1 (MTDH), which is selectively active only in malignant cells. Through systemic, nanoparticle-based delivery of the imaging construct, lesions can be identified through bioluminescence imaging and single photon emission-computed tomography in the PC3-ML murine model of prostate cancer at high sensitivity. This approach is applicable for the detection of prostate cancer metastases, including bone lesions for which there is no current reliable agent for non-invasive clinical imaging. Further, the approach compares favorably to accepted and emerging clinical standards, including positron emission tomography with [18F]fluorodeoxyglucose and [18F]sodium fluoride. Our results offer a preclinical proof of concept that rationalizes clinical evaluation in patients with advanced prostate cancer.

Critical Length of PEG Grafts on lPEI/DNA Nanoparticles for Efficient in Vivo Delivery

“…54 For this experiment, the nanoparticles were used to deliver a plasmid DNA encoding firefly luciferase capable of tumor-specific imaging under transcriptional control of the progression-elevated gene-3 promoter ( peg -Prom). 69,70 The peg -Prom constructs have demonstrated tumor-specific gene expression in several experimental cancer models, including breast cancer, melanoma, glioma, and prostate cancer.…”

“…54 Briefly, 4 to 6-week old male NOG (NOD/Shi- scid /IL-2Rγ null ) mice were obtained from the Sidney Kimmel Comprehensive Cancer Center Animal Core Facility (Johns Hopkins School of Medicine). PC3-ML cells were expanded over 3 to 5 passages, harvested, and diluted to a concentration of 2 × 10 7 cells/mL in sterile RPMI-1640 media supplemented with 1% FBS (Life Technologies, Carlsbad, CA).…”

Detecting Tumor Metastases

“…Several gene promoters that are selectively active in cancer cells have been identified and utilized for molecular-genetic imaging approaches (Minn et al, 2014). Some of these promoters include the PEG-3 promoter (Su, Shi, & Fisher, 1997), the AEG-1 (astrocyte-elevated gene-1) promoter (Bhatnagar et al, 2014; Kang et al, 2005), the hTERT (human telomerase reverse transcriptase) promoter (Majumdar et al, 2001), a truncated tCCN1 (Cysteine-rich protein 61) promoter (Sarkar et al, 2015), and the survivin promoter (Chen et al, 2004). These promoters that are selectively active in tumor cells can be combined with different reporters and different gene delivery methods in order to visualize tumors and metastatic lesions in vivo.…”

“…2). Similarly, the tumor-specific AEG-1 promoter was combined with the firefly luciferase reporter and HSV1-tk reporter and delivered using nanoparticles to detect metastases in soft tissues and bone in a mouse model of prostate cancer (Bhatnagar et al, 2014) (Fig. 2).…”

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“…These studies clearly show the importance of AEG-1/MTDH/LYRIC in regulating cancer progression and metastasis, which is reflected in the admittance of AEG-1/MTDH/LYRIC in mamma print. The first FDA-approved individualized metastasis prospect assessment assay for mamma cancer that includes a unique 70-gene signature 7 . Notable thing is that AEG-1/MTDH/LYRIC associates with multiple biological phenomena and upcoming research will absolutely identify a broad spectrum of progresses dovetailed with and potentially regulated with the help of AEG-1/MTDH/LYRIC.…”