A targeted theranostic agent for aggressive prostate cancer has been described in Proceedings of the National Academy of Sciences. GRP-78 — a glucose-regulated cell surface protein — can be effectively targeted for imaging and therapy delivery and could be translated into clinical applications for patients with this disease.

Credit: P. Morgan/NPG

Renata Pasqualini, one of the corresponding authors, told Nature Reviews Urology “In essence, we use combinatorial library selection to discover, validate, and exploit the biochemical diversity of tumour and endothelial cells for developing targeted pharmacology.” She explained “In this proof-of-concept endeavour, our criteria included finding the optimal signal-to-background attributes and determining the best correlation between the imaging signal and GRP-78 expression levels for the detection of prostate cancer.”

The investigators first characterized GRP-78 expression in tumour samples from patients with prostate cancer. They then mapped the interaction of the ligand SNTRVAP with GRP-78, observing that all residues are required for complete binding and that the interaction is specific.

In vivo, phage particles displaying the SNTRVAP motif specifically targeted GRP-78-expressing, DU145-derived xenografts. Moreover, coupling of SNTRVAP with a small interfering RNA for GRP-78 effectively downregulated GRP-78 expression.

...phage particles displaying the SNTRVAP motif specifically targeted GRP-78-expressing, DU145-derived xenografts

The theranostic capacity of HSVtk, which can be used for noninvasive imaging in the presence of a radiolabel substrate and a cell-suicide-inducing transgene in the presence of ganciclovir (GCV), was analysed in vivo using patient-derived xenografts. PET imaging using 18F-FDG or 18F-FEAU showed that HSVtk-containing targeted particles specifically localized at metabolically active tumour sites. Furthermore, 18F-FEAU–PET–CT imaging revealed that delivery of HSVtk plus GVC significantly inhibited tumour growth in these mice.

Wadih Arap, another corresponding author, explained “This work substantially accelerates plans for the translation of molecular–genetic imaging and therapy for advanced prostate cancer into the clinic. Our long-term goals are to change the management of patients with prostate cancer by enabling noninvasive, systemic, targeted monitoring through imaging of reporter genes. The much-heralded era of precision medicine has the potential to bring therapeutic and molecular-genetic imaging strategies together.” He concluded “Translational clinical trials will ultimately determine the value of this strategy.”