Prostate-specific membrane antigen-based imaging

Abstract

Prostate cancer (CaP) is the most common noncutaneous malignancy affecting men in North America. Despite significant efforts, conventional imaging of CaP does not contribute to patient management as much as imaging performed for other common cancers. Given the lack of specificity in conventional imaging techniques, one possible solution is to screen for CaP-specific antigenic targets and generate agents able to specifically bind. Prostate-specific membrane antigen (PSMA) is overexpressed in CaP tissue, with low levels of expression in the small intestine, renal tubular cells, and salivary gland. The first clinical agent for targeting PSMA was ¹¹¹In-capromab, involving an antibody recognizing the internal domain of PSMA. The second- and third-generation humanized PSMA binding antibodies have the potential to overcome some of the limitations inherent to capromab penditide (i.e., inability to bind to live CaP cells). One example is the humanized monoclonal antibody J591 (Hu mAb J591) that was developed primarily for therapeutic purposes but also has interesting imaging characteristics, including the identification of bone metastases in CaP. The major disadvantage of use of mAb for imaging is slow target recognition and background clearance in an appropriate time frame for diagnostic imaging. Urea-based compounds, such as small molecule inhibitors may also present promising agents for CaP imaging with single-photon emission computed tomography (SPECT) and positron emission tomography (PET). Two such small-molecule inhibitors targeting PSMA, MIP-1072, and MIP-1095 have exhibited high affinity for PSMA. The uptake of ¹²³I-MIP-1072 and ¹²³I-MIP-1095 in CaP xenografts have imaged successfully with favorable properties amenable to human trials. While advances in conventional imaging will continue, Ab and small molecule imaging exemplified by PSMA targeting have the greatest potential to improve diagnostic sensitivity and specificity.

Introduction

Prostate cancer (CaP) is the most common noncutaneous malignancy affecting men in North America. In 2011, approximately 240,890 patients were diagnosed with CaP and 33,720 died of the disease in the USA [1]. The large majority of CaP cases have clinically localized low-risk disease and high cure rates. The remaining patients present with advanced disease that is not completely characterized by standard-of-care clinical algorithms or conventional imaging. There is a considerable interest in developing an accurate noninvasive imaging biomarker that will ideally quantify aggressiveness, extent, and burden of disease.

The role of imaging in CaP is divided into detection of recurrent and/or metastatic disease and lesion localization [2]. Despite significant efforts, conventional imaging of CaP does not contribute to patient management as much as imaging performed for other common cancers. In addition, these imaging tests yield little information to differentiate aggressive from indolent disease. The first postdiagnostic imaging test is often an extent-of-disease evaluation with magnetic resonance imaging (eMRI-endorectal coil) or computed tomography (CT) to evaluate the prostate and/or prostate bed, locoregional lymphadenopathy, solid organ, or bony involvement in high-risk patients. Bone scintigraphy with ^99mTc-MDP or more recently, ¹⁸F-NaF is widely used as an adjunct for the detection of bone metastases. Positron emission tomography (PET) with fluorodeoxyglucose (FDG) has no role in early diagnosis of CaP because of low and heterogeneous utilization of glucose by CaP, and it has a limited role in late stage cancers [3]. Other nonspecific PET agents, such as acetate and choline (¹¹C and ¹⁸F-labeled) or MR-based nanoparticles, diffusion weighted imaging, and spectroscopy may have a future role; however, the performance of these agents remains to be determined in randomized controlled clinical trials.