Will GRPR Compete with PSMA as a Target in Prostate Cancer?

Imaging of prostate cancer (PCa) plays an important role in guiding biopsy at initial diagnosis, in accurately evaluating the extent of disease, in assessing sites of recurrent disease, and in monitoring response to treatment. A variety of PET radiopharmaceuticals for PCa are in clinical trials or available commercially. Prostate-specific membrane antigen (PSMA) is a transmembrane protein that is highly overexpressed on almost all PCas (1). Only 5%– 10% of primary PCa lesions have been shown to be PSMA-negative (2), making this class of radiopharmaceutical suitable for diagnosis of primary PCa and for initial staging (3,4). Use for noninvasive tumor grading has also been reported (3). High accuracy has been reported for use in detecting biochemical recurrence, even at very low prostate-specific antigen levels (5,6). However, these promising agents do not detect all recurrences (5,7), and other types of cancer also express PSMA (8,9). False-positive findings have also been reported using PSMA agents (10–12). Given the widespread adoption of PSMA radiopharmaceuticals and their excellent performance at all stages of PCa, is there a need or a role for another class of PET radiopharmaceutical targeting other biologic processes in PCa? Gastrin-releasing peptide receptor (GRPR) is a G-protein–coupled receptor overexpressed in many types of cancer, such as PCa, breast cancer, and small cell lung cancer (13). It belongs to the bombesin receptor family. Bombesin is a 14-mer peptide (Pyr-Gln-Arg-LeuGly-Asn-Gln-Trp-Ala-Val-Gly-His-Leu-Met-NH2) that binds with high affinity to the GRPR (14). Clinically translated GRPR antagonist PET radiopharmaceuticals include 68Ga-RM2, 68GaSB3, 68Ga-NeoBOMB1, 18F-BAY-864367, and 64Cu-CB-TE2AAR06. They have a stable biodistribution in healthy volunteers (15) and mean effective doses comparable to those of other radiopharmaceuticals (16,17). Data are encouraging regarding their potential for the initial diagnosis of PCa (15–19), for the assessment of biochemical recurrence (15,16,18–23), and for the theranostic approach (24). The lack of salivary or lacrimal gland uptake and the low hepatobiliary clearance give them an advantage. The high pancreatic uptake may be of concern to some; however, although initial uptake is high, it decreases rapidly whereas tumor radioactivity is retained longer (24). A comparison of 68Ga-RM2 PET scans before and after treatment is shown in Figure 1, and comparisons of paired 68Ga-PSMA-11 and 68Ga-RM2 scans are shown in Figure 2. Although the overexpression of PSMA is ubiquitous in PCa, it is not universal and there will be lesions not detected by PSMAtargeted imaging in different risk classes or stages of disease. The influence of GRPR expression on cancer grade and stage is not clear. Nagasaki et al. (25) found that GRPR expression was positively correlated with Gleason score, but another study found that GRPR expression was inversely correlated with Gleason score, preoperative prostate-specific antigen concentration, and tumor size (26). Therefore, the indication (i.e., lowvs. intermediatevs high-risk, and early vs. late stage of disease) for the use of PSMAvs. GRPR-targeted imaging or both is an active focus of research. Another unsettled question is whether the uptake is specific for (prostate) cancer. High uptake was reported in primary PCa lesions and metastases (16,18,23), but benign prostate hypertrophy resulted in false-positive findings in some cases (16). This may be avoided by the development of appropriate metrics of image interpretation. In our experience with 68Ga-RM2, all 7 biopsied lesions (prostate, lymph nodes, liver, and lung nodule) were confirmed PCa (22). As GRPR-targeting radiopharmaceuticals are evaluated in more patients, it is likely that more reports of non–cancer-specific uptake will emerge, as with any new class of radiopharmaceutical.