Gastrin-releasing peptide receptor (GRPR) as a novel biomarker and therapeutic target in prostate cancer

Abstract

Aim: This comprehensive review aims to explore the potential applications of Gastrin-releasing peptide receptor (GRPR) in the diagnosis and treatment of prostate cancer. Additionally, the study investigates the role of GRPR in prognostic assessment for individuals afflicted with prostate cancer.Methods: The review encompasses a thorough examination of existing literature and research studies related to the upregulation of GRPR in various tumor types, with a specific focus on prostate. The review also evaluates the utility of GRPR as a molecular target in prostate cancer research, comparing its significance to the well-established Prostate-specific membrane antigen (PSMA). The integration of radionuclide-targeted therapy with GRPR antagonists is explored as an innovative therapeutic approach for individuals with prostate cancer.Results: Research findings suggest that GRPR serves as a promising molecular target for visualizing low-grade prostate cancer. Furthermore, it is demonstrated to complement the detection of lesions that may be negative for PSMA. The integration of radionuclide-targeted therapy with GRPR antagonists presents a novel therapeutic paradigm, offering potential benefits for individuals undergoing treatment for prostate cancer.Conclusions: In conclusion, this review highlights the emerging role of GRPR in prostate cancer diagnosis and treatment. Moreover, the integration of radionuclide-targeted therapy with GRPR antagonists introduces an innovative therapeutic approach that holds promise for improving outcomes in individuals dealing with prostate cancer. The potential prognostic value of GRPR in assessing the disease’s progression adds another dimension to its clinical significance in the realm of urology.

Keywords:

• PET
• Gastrin-releasing peptide receptor(GRPR)
• prostate cancer
• radiomics
• radionuclide-targeted therapy
• diagnosis

Introduction

Prostate cancer (PCa) ranks among the most prevalent malignant tumors affecting men, with approximately 1.4 million new cases reported in 2020. In a quarter of the world’s nations, PCa stands as the leading cause of cancer-related deaths among men, contributing to an estimated 375,000 deaths in 2020 [1]. Early detection and diagnosis of prostate cancer pose intricate challenges in clinical practice. Although prostate-specific antigen (PSA) screening has undoubtedly increased the identification of low-grade prostate cancer cases, it has also led to a dilemma of overdiagnosis and overtreatment. This predicament not only results in treatment-related adverse events but also imposes a substantial economic burden on our healthcare system [2].

The Prostate-specific membrane antigen (PSMA), a membrane glycoprotein, exhibits expression levels on prostate cancer cells that are 100–1000 times higher than those on normal prostate tissue. Due to its outstanding affinity and precision in the repeated targeting of diagnosis, staging, and detection of PCa biochemical recurrence, the radiolabeled PSMA-PET(positron emission tomography) imaging has gained widespread acceptance [3]. The use of ⁶⁸Ga-PSMA PET/CT has become a common practice for initial staging and detection of biochemical recurrence in high-risk patients. However, its ability to detect low-grade tumor lesions is not ideal; it may miss approximately 15% of lesions [4]. Furthermore, PSMA expression is not limited to benign and inflammatory tissues; it is also expressed in other malignancies, including thyroid, kidney, and breast tumors, leading to potential false-positive findings [5–8]. Moreover, some prostate adenocarcinomas and neuroendocrine differentiated prostate cancer cells do not express PSMA [9–15]. To develop a more comprehensive imaging approach for prostate cancer, it is necessary to target other cellular markers besides PSMA. In this regard, GRPR has emerged as a significant and promising target [16].

Gastrin-releasing peptide receptor (GRPR), a member of the bombesin G-protein-coupled receptor family is overexpressed in various malignant tumors across anatomical sites such as the breast, prostate, lung, and gastrointestinal tract [17]. GRPR plays roles in human physiological mechanisms, including regulating gastrointestinal motility, gastric emptying, and smooth muscle contractions. It is highly expressed in the pancreas, inducing the release of endogenous gastric hormones and regulating the secretion of pancreatic enzymes [18]. Elevated GRPR expression has been observed in lower-grade PCa cases [19,20]. Thus, GRPR holds significant diagnostic and therapeutic potential, particularly in PSMA-negative and low-grade prostate malignancies. This review aims to explore the current role of GRPR-based imaging in prostate cancer.

Diagnostic role of GRPR in PCA

In the realm of prostate cancer diagnosis and treatment, transrectal ultrasound-guided prostate biopsy (TRUS-biopsy) has been endorsed as a standardized method by organizations such as the AUA and EAU. It holds significant value in diagnosing, treating, and prognostically evaluating prostate cancer. TRUS biopsy is widely utilized for tasks such as tumor detection, localization, staging, invasiveness assessment, and guiding adjuvant therapeutic decisions [21–23]. Despite its widespread use, studies have highlighted substantial misdiagnosis rates and associated procedural risks, including bleeding, pain, and infection. In one study involving 740 men, inaccuracies were noted in 18% of clinically significant carcinomas (csPca) and 32% of non-clinically significant carcinomas (ncsPca). Severe adverse events, including sepsis, were reported in 44 participants, including sepsis in eight cases [23]. Multiparametric magnetic resonance imaging (mpMRI) exhibits high sensitivity for clinically significant prostate cancer, enhancing detection while minimizing unnecessary biopsies. However, mpMRI faces challenges in detecting small lesions within prostate cancer, and interpretation variability among radiologists has led to misdiagnosis rates of up to 35% for clinically significant prostate cancer (csPca) [24,25].

The potential of PET MRI/CT imaging in cancer detection, staging, and functional characterization is promising [26]. Prostate-specific antigen (PSMA), serves as an ideal target for ⁶⁸Ga-labeled PSMA in PET/CT and PET/MRI. This approach exhibits high sensitivity and specificity, valuable for diagnosing and staging prostate cancer. Compared to multiparametric magnetic resonance imaging (mpMRI),⁶⁸Ga-PSMA PET/CT exhibits execellent performance in pinpointing lesion locations and extents, enhancing diagnostic outcomes. However, it exhibits a higher underdiagnosis rate in low-grade prostate cancer.

In recent years, attention has shifted towards GRPR targeting in prostate cancer imaging due to limitations observed in established These limitations include challenges such as PSMA-negative lesions, false-positive scans, and resistance to PSMA-targeted radionuclide therapy (TRT) [7,27,28].

Gastrin-releasing peptide receptor (GRPR), a subtype of the bombesin (BBN) G protein-coupled receptor family, is overexpressed in prostate cancer, particularly in low-grade and smaller tumors [16,29]. RM2 is one of the extensively applied synthetic GRPR antagonists. Studies employing ⁶⁸Ga-RM2 PET/CT demonstrated a high positivity rate of 98% for newly diagnosed prostate cancer (PCa) patients [30].¹⁸F-labeled bombesin analogs, such as ¹⁸F-FB-[Lys3]BBN, have proved effective for in vivo detection of GRPR-positive prostate cancer using PET [31]. Another experiment utilizing ¹⁸F, ¹⁸F-BAY 864367, a bombesin analog, exhibited specific tumor and rapid renal and hepatobiliary excretion in a mouse model [32]. These analogs have been applied successfully in human clinical trials for prostate cancer (PCa) and have shown good dosimetric properties [33]. Different tracers exhibit varying imaging effects on prostate tumors. In previous studies, two BBN peptides, AMBA and RM1, have been compared using imaging PCa xenograft models [34]. ¹⁸F-AlF-NODAGA-RM1 demonstrated high stability, efficient tumor uptake, and optimal pharmacokinetic properties, indicating significant potential in prostate cancer PET imaging [34]. Selecting an appropriate tracer is paramount in prostate cancer PET imaging. Furthermore, the use of the same GRPR antagonist with different radioactive labels may yield different results. We can leverage these differences in results and apply them in various situations. In a comparative experiment between ⁶⁸Ga-NeoBOMB1 and ¹⁷⁷Lu-NeoBOMB1, both effectively displayed the tumor, but ¹⁷⁷Lu-NeoBOMB1 exhibited a higher tumor uptake rate and lower pancreatic tissue uptake [35].

Of note, the outcomes for patients with advanced prostate cancer or those who have undergone multiple treatments are often unsatisfactory. This discrepancy can be attributed to the interplay between GRPR expression and androgens, as hormone therapy may impact GRPR expression in prostate cancer [36]. Moreover, GRPR expression extends beyond prostate cancer cells to include benign prostate tissue and prostate hyperplastic tissue. This broad expression could potentially result in false-positive outcomes when using GRPR for prostate cancer diagnosis. A study found that GRPR exhibited 27% positive staining in samples from 34 cases of normal prostate tissue and benign prostatic hyperplasia [29]. In clinical studies, the sensitivity of detecting prostate tumors using ⁶⁸Ga-RM2 and ⁶⁸Ga-PSMA 11 PET was close, at 98% and 95%, respectively, surpassing that of mpMRI (77%). However, mpMRI showed the highest specificity at 75%, followed by 68Ga-PSMA11 (67%) and 68Ga-RM2 (65%) [37]. Another study using RM2, a GRPR antagonist, demonstrated a slightly lower uptake rate in patients with a Gleason score >7 compared to those with benign prostatic hyperplasia (BPH) [38].

Integrating GRPR and PSMA dual-tracer PET/CT for patient evaluation significantly reduced unnecessary biopsies by 52.67% and achieved a higher dual-tracer detection rate (77.36%) without misdiagnosing clinically significant prostate cancer (csPCa) [22]. Additionally, ⁶⁸Ga-RM2 PET/CT proved promising in detecting and localizing primary prostate cancer, complementing multiparametric magnetic resonance imaging (mpMRI). Importantly, GRPR expression appears independent of PSMA expression, indicating that GRPR and PSMA-targeted PET imaging can complement each other [39]. An in vivo trial further substantiated that tracers targeting both GRPR and PSMA provide superior delineation of the total tumor volume for prostate cancer patients [40].

While GRPR imaging alone holds significant diagnostic value, particularly for low-grade prostate cancer or cases without hormonal treatment, PSMA imaging tends to yield superior results in high-grade prostate cancer and post-hormone therapy cases. GRPR imaging serves as a valuable complementary tool, especially for lesions that are PSMA-negative or yield false-positive findings [18]. However, the occurrence of false-positive results in GRPR-based prostate cancer imaging should be considered.

The role of GRPR in prostate cancer management

Current treatment options for prostate cancer include surgery, endocrine therapy, chemotherapy, and more. The evolving landscape of nuclear medicine in prostate cancer research garnered significant attention. Tracer-based nuclear medicine enhances the precise localization of tumor cells, crucial for targeted therapy. Accurate assessment of lesion aggressiveness and localization plays a vital role in guiding treatment decisions.

GRPR exhibits high expression, especially in early-stage prostate cancers, primarily within tumor cells [16,41]. Radiolabeled GRPR, particularly antagonists, offers precise localization of tumor cell localization, improving therapeutic outcomes. Radiolabeled GRPR agents include both antagonists and agonists, but the current consensus among scholars favors antagonists for several reasons [42,43]. This preference may stem from potential side effects associated with GRPR agonists, such as pronounced gastrointestinal reactions. Additionally, GRPR antagonists can bypass GRPR activation, which might otherwise stimulate tumor cell proliferation and growth. Furthermore, GRPR antagonists are small in size, allowing rapid tissue penetration and swift blood clearance [16,44–48]. GRPR radio antagonists, including but not limited to ⁶⁸Ga-RM2, ⁶⁸Ga-NeoBOMB1, ⁶⁸Ga- ProBOMB2, ¹⁷⁷Lu-ProBOMB2, ⁶⁸Ga-HZ220, ⁶⁸Ga-SB3, [⁶⁸Ga]Ga-DOTA-Ava-BBN2, [99^mTc]Tc-DB15, [44^gSc]Sc-DOTA-Ava-BBN2, ⁶⁸Ga-JMV4168/¹⁷⁷Lu-JMV4168, ⁶⁸Ga-AMBA/¹⁷⁷Lu-AMBA, and [99^mTc]Tc-maSSS-PEG2-RM26, have demonstrated promising outcomes in both prostate cancer imaging and treatment [49–59]. Recent studies on GRPR antagonists in prostate cancer and their conclusions are shown in Table 1.

Table 1. Recent studies on GRPR antagonists in prostate cancer and their conclusions.

Radiolabeled antagonist	Purpose	Conclude	Author	Year
^177Lu-AMTG	treatments	Compared to ^177Lu-RM2, ^177Lu-AMTG demonstrates a slightly increased affinity for GRPR, similar internalization rates, a slight improvement in lipophilicity, and significantly enhanced stability both in vivo and in vitro.	Günther, T	2022
[(68)Ga]Ga-RM2	imaging	[(68)Ga]Ga-RM2 is considered a promising PET tracer, particularly suitable for prostate cancer patients at intermediate risk. Imaging methods based on GRPr can complement other PET/CT imaging approaches in certain patients, offering improved characterization of prostate cancer and guidance for biopsies.	Beheshti, M	2023
(68)Ga-SB3	imaging	(68)Ga-SB3 PET/CT is a safe imaging method and a promising tool for early PCa imaging.	Bakker, I.L	2021
[(99m)Tc]Tc-maSSS-PEG(2)-RM26	imaging	maSSS-PEG(2)-RM26 is a promising GRPR antagonist: This substance is considered a potential GRPR (Gastrin-Releasing Peptide Receptor) antagonist, demonstrating targeting capabilities towards prostate cancer with GRPR expression.	Abouzayed, A.	2021
[(68)Ga]Ga-DOTA-Ava-BBN2/[(44g)Sc]Sc-DOTA-Ava-BBN2	imaging	It exhibits similar tumor uptake and retention characteristics, as well as rapid blood and kidney clearance features.	Ferguson, S	2020
[(99m)Tc]Tc-DB15	imaging	It exhibits high and sustained GRPR-specific uptake in mouse PC-3 tumors, while being rapidly cleared.	Nock, B.A	2021
[(68)Ga]Ga-AMBA	imaging	PET imaging using [(68)Ga]Ga-AMBA reveals that GRPRcould represent a feasible alternative target for diagnosis or treatment in PCa with limited PSMA expression levels.	Zhang-Yin, J	2020
(177)Lu-JMV4168	treatments	Radioisotope therapy using (177) Lu-JMV4168 leads to a significant reduction in the size of PC-3 tumors.	Chatalic, K.L	2016
(68)Ga-ProBOMB2/(177)Lu-ProBOMB2	–	(68)Ga-ProBOMB2 and (177) Lu-ProBOMB2 are considered promising tracers suitable for imaging and treating tumors expressing GRPR. Additionally, they exhibit low uptake in pancreatic tissue.	Bratanovic, I.J	2022
(68)Ga-JMV5132/(68)Ga-JMV4168	imaging	Both (68) Ga-JMV5132 and (68) Ga-JMV4168 demonstrate significantly high and specific accumulation in GRP-positive PC-3 tumors. These novel PET tracers are promising candidates for future clinical translation.	Chatalic, K.L	2014

RM2 is one of the extensively applied synthetic GRPR antagonists [60,61]. Specifically, ⁶⁸Ga-RM2 exhibits remarkable selective binding affinity for GRPR, coupled with metabolic stability and prolonged retention time within lesions [60]. ⁶⁸Ga-RM2 is primarily excreted through the urinary tract and does not bind to the renal cortex [62,63]. Notable uptake of ⁶⁸Ga-RM2 is observed in the pancreas due to GRPR’s role in regulating enteropancreatic hormone release. Dosimetry studies have revealed the highest uptake in the bladder wall and pancreas, followed by the kidneys. Multiple studies have confirmed the favorable pharmacokinetics, biosafety, and selectivity of ⁶⁸Ga-RM2, which exhibits high binding affinity to GRPR and rapid clearance in organs and blood. These characteristics position it as a promising candidate for therapeutic applications [2,48,61].

An in vivo experiment involving 35 patients with metastatic castration-resistant prostate cancer (mCRPC) who exhibited insufficient PSMA expression or lower PSMA accumulation following [¹⁷⁷Lu]Lu-PSMA-617 therapy, yielded promising results with ¹⁷⁷Lu-RM2. This alternative treatment demonstrated a higher tumor uptake rate and swift clearance from normal organs [64]. In a murine study, ¹⁷⁷Lu-RM2 and rapamycin were used alone and in combination to treat PC-3 prostate cancer cells. The results showed that high doses of ¹⁷⁷Lu-RM2 monotherapy effectively induced complete tumor remission in 60% of the treated mice. Combining ¹⁷⁷Lu-RM2 with rapamycin significantly extended survival compared to using either drug alone, suggesting that ¹⁷⁷Lu-labeled GRPR antagonist alone or in combination with paclitaxel-based therapy can effectively inhibit tumor growth in vivo, offering a promising strategy for prostate cancer treatment [65].

Different targeted tracers for GRPR may demonstrate varying effectiveness, ¹⁷⁷Lu-AMTG was compared with ¹⁷⁷Lu-RM2, showing a slightly higher affinity for GRPR and significantly improved in vitro and in vivo stability. Small-animal SPECT/CT imaging demonstrated slower clearance of ¹⁷⁷Lu-AMTG from tumor tissue [49]. A preclinical study also confirmed that AMTG possesses favorable pharmacokinetic properties [66]. In mice with prostate cancer, ⁶⁸Ga-AMBA exhibited higher tumor uptake while maintaining lower overall background activity compared to what was observed with ¹⁸F-FCH. This suggests that targeting PC using AMBA may be more effective than metabolism-based choline targeting for prostate cancer treatment [67].

In conclusion, targeted radiopharmaceutical therapy based on GRPR offers a promising and innovative treatment option that can improve outcomes in prostate cancer patients. Among radioligands targeting GRPR, antagonists often exhibit superiority. However, the diverse selection of available radioligands necessitates extensive experimental validation. Thus, determining the optimal GRPR radioligands for both diagnosing and treating prostate cancer patients remains a subject that warrants further investigation.

The relationship between GRPR and CRPC

Prostate cancer, a hormone-dependent malignancy, relies heavily on amplified androgen receptor (AR) signaling for tumor cell growth. Consequently, androgen deprivation therapy (ADT) serves as a pivotal initial systemic treatment for metastatic and recurrent prostate cancer [68,69]. In most PCa patients, ADT leads to initial disease regression and a significant reduction in serum PSA levels. Despite the initial success of ADT, including the use of next-generation anti-androgens such as abiraterone acetate or enzalutamide, nearly all patients eventually progress to castration-resistant prostate cancer (CRPC). Emerging research indicates that androgen receptor variants (ARVs) play a pivotal role in CRPC development [70–72]. Prolonged androgen deprivation therapy (ADT) upregulates the expression of gastrin-releasing peptide (GRP) and its receptor (GRPR) in prostate cancer cells. The activation of GRP/GRPR signaling, mediated by NF-κB signaling, results in increased ARV expression, facilitating cancer progression to CRPC [73].

As a cell surface protein, GRPR represents a readily targetable molecule for drug intervention to block GRP/GRPR signal transduction. The use of selective GRPR antagonists, like RC-3095, offers the potential to inhibit NF-κB activity and suppress ARV expression in CRPC [73,74]. In a clinical study, 35 metastatic castration-resistant prostate cancer (mCRPC) patients underwent PET/CT scans using ⁶⁸Ga-RM2; among them, four received ¹⁷⁷Lu-RM2 treatment. The scans revealed high tumor uptake and rapid clearance from normal organs, suggesting the potential suitability of ¹⁷⁷Lu-RM2 for radioisotope therapy in mCRPC patients. Blocking GRP/GRP-R signaling by targeting GRPR sensitizes CRPC cells to androgen deprivation therapy [64]. Moreover, targeted GRPR inhibition may sufficiently suppress ARV expression, effectively controlling CRPC tumor progression [47]. This presents a novel therapeutic approach for advanced-stage CRPC treatment.

The relationship between GRPR and NEPC

Neuroendocrine differentiation (NED) enables prostate cancer cells to undergo differentiation, allowing them to evade androgen deprivation therapy (ADT) [75–78]. In certain individuals with advanced CRPC, a specific subgroup of prostate adenocarcinoma cells may transform, acquiring neuroendocrine characteristics during the later stages of CRPC progression. This transformation ultimately culminates in the emergence of a distinct clinical entity known as Neuroendocrine Prostate Cancer (NEPC) [47,79,80]. De novo NEPC development occurs in only a small fraction of patients [81]. Nevertheless, an ongoing debate persists regarding whether de novo NEPC and treatment-induced NEPC are indeed manifestations of the same disease. NEPC, classified as a rare yet highly aggressive subtype of prostate cancer, typically demonstrates resistance to hormone-based therapies, such as castration therapy. NEPC is characterized by the presence of cancer cells that exhibit distinct neuroendocrine features and produce neuroendocrine markers, including neuron-specific enolase (NSE) and insulin-like growth factor (IGF), among others.

Currently, the mainstay treatment for Neuroendocrine Prostate Cancer (NEPC) involves platinum-based chemotherapy, typically using agents like cisplatin or carboplatin, often administered in combination with etoposide [82,83]. Furthermore, emerging treatment strategies, encompassing the utilization of PARP inhibitors, checkpoint inhibitors, and tyrosine kinase inhibitors, either as monotherapy or in combination, are currently under investigation [80]. However, the majority of these emerging treatment strategies are still in the experimental phase.

GRPR exhibits high expression levels in NEPC, and the utilization of GRPR antagonists holds the potential to reduce the expression of ARVs, although it may not provide complete control over the levels and activity of both AR-FL and ARVs [73]. In a specific study, inhibiting GRPR with a GRPR antagonist, when combined with anti-androgen therapy, successfully suppressed tNEPC tumor growth [47], presenting a promising emerging treatment approach for NEPC. Nevertheless, extensive clinical trials are imperative to validate these findings.

The relationship between GRPR and biochemical recurrence in prostate cancer

Biochemical Recurrence (BCR) in prostate cancer is characterized by the reemergence of the disease, as indicated by the elevated prostate-specific antigen (PSA) levels in the bloodstream following the initial treatment. This recurrence can occur within five years after the initial treatment [84]. BCR definitions vary depending on treatment type. Following radical prostatectomy (RP), BCR is typically characterized as an increase in PSA level exceeding 0.4 ng/mL [85], whereas after primary radiotherapy (RT), any PSA increase exceeding 2 ng/mL above the nadir value signifies BCR [86–88]. Numerous studies consistently demonstrate a significant time lag between the detection of BCR and its impact on mortality [89–91]. Hence, timely and precise interventions are crucial for managing patients following BCR.

Although PSA is used for detecting biochemical recurrence of prostate cancer with good results, its ability to precisely localize the lesion site, a critical factor in disease management, is limited. Early identification of the lesion site, prognostic assessment, and timely intervention significantly benefit prostate cancer management. Traditional imaging modalities like transrectal ultrasound, CT, or MRI lack sufficient diagnostic accuracy and reliability for detecting primary or recurrent PCa [92]. Improved imaging techniques are needed to predict biochemical recurrence. PET imaging, renowned for accurately pinpointing lesion locations, has demonstrated its value. In a prospective study involving 32 patients with BCR, who had previously received negative results in routine imaging such as CT scans and bone scans, ⁶⁸Ga-RM2 PET scans exhibited an impressive 71% detection rate for recurrent disease, whereas simultaneously conducted MRI achieved only a 34% detection rate [93]. Another study involving 100 patients with biochemical recurrence (BCR) showed a positivity rate of 69% with ⁶⁸Ga-RM2 scans [30]. A negative ⁶⁸Ga-RM2 scan can have significant prognostic implications in prostate cancer. Targeted radiopharmaceuticals like ⁶⁸Ga-PSMA 11 and ¹⁸F-DCFPyL, used for assessing BCR, exhibit superior sensitivity and specificity compared to conventional imaging modalities. A study involving 50 patients who underwent both ⁶⁸Ga-RM2 PET/MRI and ⁶⁸Ga-PSMA 11 or ¹⁸F-DCFPyL PET/CT scans demonstrated similar positivity rates but distinct uptake areas, suggesting complementary roles [94]. Results from another study indicated different biodistributions of ⁶⁸Ga-RM2 and ⁶⁸Ga-PSMA in prostate tumors with biochemical recurrence [95], further emphasizing their potential complementary functions.

[¹⁸F] Fluoroethylcholine (¹⁸FECH) has proven valuable as a positron emission tomography (PET) tracer for recurrent prostate cancer (PCa) [96], though its accuracy is limited. In an experiment involving 16 patients with biochemical recurrence (BCR), ¹⁸F-Fluoroethylcholine (¹⁸FECH) PET/CT scans showed no positive results in 14 cases and uncertain results in 2 cases. Subsequent ⁶⁸Ga-RM2 PET/CT scans revealed positive results in 10 of these patients (63%), including the. 2 cases with uncertain results from ¹⁸FECH-PET/CT, highlighting the superiority of ⁶⁸Ga-RM2-PET/CT scans [92].

In summary, ⁶⁸Ga-RM2 PET emerges as a valuable tool for patients experiencing BCR of prostate cancer, particularly when other molecular imaging results are negative or raise suspicion. Furthermore, the combination of ⁶⁸Ga-RM2 with PSMA imaging holds promise in expanding lesion site coverage [97]. However, determining the optimal restaging radiopharmaceutical can be challenging due to the potential influence of hormone or chemotherapy treatments on GRPR expression and the highly variable treatment histories of BCR patients. Consequently, extensive research is warranted to validate the effectiveness of such radiopharmaceuticals for specific patient populations, ultimately advancing the realm of personalized medicine.

Discussion

GRPR-based PET/CT imaging has higher sensitivity and specificity compared to conventional imaging techniques. Although GRPR is less sensitive relative to PSMA for high-grade prostate malignancies or CRPC, it outperforms PSMA in cases of low-grade prostate cancer. Consequently, GRPR serves as a valuable complementary marker to PSMA in nuclear medicine imaging for prostate cancer, with the potential to enhance diagnostic accuracy and reduce missed diagnoses.

TRT utilizing various GRPR antagonists has proven effective in mouse models of prostate cancer. However, most experiments involving GRPR antagonists against prostate cancer have remained at the in vitro stage.

Blocking the GRPR receptor pathway with GRPR antagonists can effectively inhibit the growth of CRPC tumor cells and sensitize them to androgen deprivation therapy. In neuroendocrine prostate cancer (NEPC) originating from CRPC, combining GRPR antagonism with anti-androgen therapy significantly suppresses AR-negative tNEPC tumor cells. Consequently, GRPR antagonists offer a promising emerging treatment approach for both CRPC and tNEPC.

⁶⁸Ga-RM2 PET emerges as a valuable tool for patients experiencing biochemical recurrence (BCR) of prostate cancer, particularly when other molecular imaging results are inconclusive or suspicious. The combination of ⁶⁸Ga-RM2 with PSMA imaging shows potential in expanding lesion site coverage. However, due to the potential influences of hormones or chemotherapy on GRPR expression and the evolving treatment histories of BCR patients, selecting the optimal radiopharmaceutical can be challenging.

Conclusion

GRPR plays a pivotal role in the diagnosis, targeted therapy with radiopharmaceuticals, and prognostic prediction of prostate cancer patients. The combination of GRPR imaging with PSMA imaging for diagnosis or targeted treatment in prostate cancer holds great promise for advancing nuclear medicine-based approaches in prostate cancer. However, GRPR expression can be influenced by various factors, such as disease stage and prior hormone therapy. Moreover, careful consideration of potential false positives associated with GRPR is essential. Therefore, judicious selection of GRPR PET and GRPR antagonists in prostate cancer patients, coupled with PSMA imaging for diagnosis or TRT, necessitates thorough experimental validation regarding safety and efficacy. This validation is crucial in advancing personalized precision medicine.

Authors contributions

YC and XG designed and supervised the review. HZ searched the literature and wrote the manuscript. LQ, XG, and YC reviewed the manuscript. All authors contributed to the article and approved the submitted version.

Disclosure statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Data availability statement

Data sharing is not applicable to this article, given that no new data were created or analysed in this study.

Additional information

Funding

This research was supported by the Key Research and Development Program of Hunan Province of China (2021SK2014), National Natural Science Foundation of China (82272907, 81974397) and the clinical research foundation of the National Clinical Research Center for Geriatric Diseases (XIANGYA) (2022LNJJ13).