High Prostate-specific Membrane Antigen Research Articles

Novel technetium-99m-labeled bivalent PSMA-targeting probe based on hydroxamamide chelate for diagnosis of prostate cancer.

Prostate-specific membrane antigen (PSMA) is a well-known biomarker of prostate cancer. Previously, our group reported that the succinimidyl-cystatin-urea-glutamate (SCUE) moiety has a high affinity for PSMA. In this study, we developed the novel technetium-99m-labeled PSMA-targeting probe "[99mTc]Tc-(Ham-SCUE)2" based on a hydroxamamide chelate with a bivalent SCUE and evaluated its potential as a SPECT imaging probe for the diagnosis of PSMA-expressing prostate cancer. Ham-SCUE was synthesized by a one-step reaction with Ham-Mal and cysteine-urea-glutamine. Then, Ham-SCUE was reacted with [99mTc]NaTcO4 for 10min at room temperature to obtain [99mTc]Tc-(Ham-SCUE)2. [99mTc]Tc-(Ham-SCUE)2 was added to LNCaP (high PSMA expression) cells or PC3 (low PSMA expression) cells, and their radioactivity was measured 60min after administration. The blocking study was performed by co-incubation of LNCaP cells with various concentrations of 2-PMPA (a PSMA inhibitor) for 15min before adding [99mTc]Tc-(Ham-SCUE)2. The biodistribution of [99mTc]Tc-(Ham-SCUE)2 in LNCaP/PC3 dual xenografted C.B.-17/Icr scid/scid Jcl mice was evaluated for 120min after intravenous injection. The blocking study was performed by pretreatment of mice with 2-PMPA (10mg/kg weight). [99mTc]Tc-(Ham-SCUE)2 was acquired at radiochemical yields of 56% with a radiochemical purity of over 95%. The cellular uptake level of [99mTc]Tc-(Ham-SCUE)2 by LNCaP cells was significantly higher than that by PC3 cells (LNCaP: 11.12 ± 0.71 vs. PC3: 1.40 ± 0.13%uptake/mg protein, p < 0.01), and the uptake was significantly suppressed by pretreatment with 2-PMPA (2.56 ± 0.37%uptake/mg protein, p < 0.05). IC50 of 2-PMPA was 245 ± 47nM. In the in vivo study, the radioactivity of LNCaP tumor tissue was significantly higher than that of PC3 tumor tissue at 120min after the administration of [99mTc]Tc-(Ham-SCUE)2 (LNCaP: 9.97 ± 2.79, PC3: 1.16 ± 0.23%ID/g, p < 0.01), and was suppressed by pretreatment with 2-PMPA (2.50 ± 0.45%ID/g, p < 0.01). [99mTc]Tc-(Ham-SCUE)2 has the potential to be a SPECT imaging agent for diagnosing high PSMA-expressing prostate cancer.

Evaluation of gastrin-releasing peptide receptor, prostate-specific membrane antigen, and neurotensin receptor 1 as potential biomarkers for accurate prostate cancer stratified diagnosis

BackgroundStudies on single-target PET imaging of gastrin-releasing peptide receptor (GRPR), prostate-specific membrane antigen (PSMA), or neurotensin receptor 1(NTR1) have been reported. However, the performance of these three targets in the progression of PCa remains unclear. Our study aims to compare the expression of GRPR, PSMA, and NTR1 in patients with prostatic intraepithelial neoplasia (PIN), prostate cancer (PCa), and lymph node metastasis. We synthesized molecular probes targeting the markers to achieve a non-invasive precise detection of PCa patients with PET/CT imaging.MethodsIn this study, the expression of GRPR, PSMA, and NTR1 was evaluated by immunohistochemistry in 34 PIN, 171 PCa, and 22 lymph node metastasis tissues of patients. The correlation between their expression and the clinicopathological parameters of PCa patients was assessed. Sixteen PCa patients with different Gleason scores (GS) underwent dual-tracer (68Ga-NOTA-RM26 and 68Ga-NOTA-PSMA617) PET/CT.ResultsIn the PIN stage, the expression of GRPR was significantly higher than that of PSMA and NTR1 (P < 0.001), while NTR1 expression was significantly higher than PSMA and GRPR expression in primary PCa (P = 0.001). High PSMA expression in PCa patients was associated with shorter progression-free survival (P = 0.037) and overall survival (P = 0.035). PCa patients with high GS had higher tumor uptake of 68Ga-NOTA-PSMA617 than those with low GS (P = 0.001), while PCa patients with low GS had higher tumor uptake of 68Ga-NOTA-RM26 than those with high GS (P = 0.001).ConclusionsThis study presents three novel biomarkers (PSMA, GRPR, and NTR1) as imaging agents for PET/CT, and may offer a promising approach for non-invasive precise detection and Gleason grade prediction of PCa patients.

Intramuscular Granular Cell Tumor Detected on 68 Ga-PSMA PET/CT.

Finding of the prostate-specific membrane antigen (PSMA) is highly expressed in prostate cancer (PC) cells that have made it possible to evaluate the patients with PC with a single imaging method. 68 Ga-PSMA PET/CT is now part of the routine in patients with PC. After several years of clinical experience with PSMA tracers, the specificity is satisfactory; however, concerns about the specificity are raising day by day due to the newly laid out nonprostatic malignant and benign lesions with high PSMA expression. Herein, we present an incidental 68 Ga-PSMA uptake in an intramuscular granular cell tumor.

Preparation, Biological Evaluation, and First-in-Human Single-Photon Emission Computed Tomography (SPECT) Study of 99mTc-Labeled Prostate-Specific Membrane Antigen (PSMA)-Targeted Radiotracers Containing Triazole with Reduced Kidneys Accumulation.

Prostate-specific membrane antigen (PSMA), a well-established biological marker for prostate cancer (PCa) imaging and therapy, is overexpressed on the surface of prostate cancer lesions. In this study, a triazole ring was introduced into the linker by click chemistry to generate a HYNIC-derived ligand (T), which exhibited good PSMA affinity (Ki = 2.23 nM). Eight stable 99mTc-labeled complexes, [99mTc]Tc-T-Mn (n = 1-8), with hydrophilic properties were synthesized by incorporating different coligands at high radiochemical yields and purities without purification. The radioligands were concentrated in the kidneys of healthy Kunming male mice and were significantly blocked by the PSMA inhibitor ZJ-43. The uptake of the optimized complex [99mTc]Tc-T-M2 was correlated with PSMA, and it had good PSMA affinity (Kd = 5.42 nM). [99mTc]Tc-T-M2 accumulated on LNCaP (PSMA++) tumors and was significantly blocked by ZJ-43 at 2 h p.i., indicating high PSMA specificity. Relatively suitable kidney uptake was beneficial for reducing kidneys exposure in patients. SPECT/CT imaging of [99mTc]Tc-T-M2 in LNCaP (PSMA++) or 22Rv1 (PSMA+) tumor-bearing mice revealed high tumor uptake, low background uptake (especially low kidney uptake (49.06 ± 9.20 %ID/g) at 2 h p.i.), and obvious inhibition by ZJ-43, whereas PC-3 (PSMA-) tumors were undetectable. A freeze-dried [99mTc]Tc-T-M2 kit was successfully developed (T-M2 kit). Preliminary clinical trials showed that [99mTc]Tc-T-M2 clearly identified small prostate cancer lesions and has potential for clinical application.

Impact of Circulating Tumor Cell-Expressed Prostate-Specific Membrane Antigen and Prostate-Specific Antigen Transcripts in Different Stages of Prostate Cancer.

Prostate-specific membrane antigen (PSMA)-based images, which visually quantify PSMA expression, are used to determine prostate cancer micrometastases. This study evaluated whether a circulating tumor cell (CTC)-based transcript platform, including PSMA mRNA, could help identify potential prognostic markers in prostate cancer. We prospectively enrolled 21 healthy individuals and 247 patients with prostate cancer [localized prostate cancer (LPCa), n = 94; metastatic hormone-sensitive prostate cancer (mHSPC), n = 44; and metastatic castration-resistant prostate cancer (mCRPC), n = 109]. The mRNA expression of six transcripts [PSMA, prostate-specific antigen (PSA), AR, AR-V7, EpCAM, and KRT 19] from CTCs was measured, and their relationship with biochemical recurrence (BCR) in LPCa and mCRPC progression-free survival (PFS) rate in mHSPC was assessed. PSA-PFS and radiological-PFS were also calculated to identify potential biomarkers for predicting androgen receptor signaling inhibitor (ARSI) and taxane-based chemotherapy resistance in mCRPC. CTC detection rates were 75.5%, 95.3%, and 98.0% for LPCa, mHSPC, and mCRPC, respectively. In LPCa, PSMA [hazard ratio (HR), 3.35; P = 0.028) and PSA mRNA (HR, 1.42; P = 0.047] expressions were associated with BCR. Patients with mHSPC with high PSMA (HR, 4.26; P = 0.020) and PSA mRNA (HR, 3.52; P = 0.042) expressions showed significantly worse mCRPC-PFS rates than those with low expression. Increased PSA and PSMA mRNA expressions were significantly associated with shorter PSA-PFS and radiological PFS in mCPRC, indicating an association with drug resistance. PSMA and PSA mRNA expressions are associated with BCR in LPCa. In advanced prostate cancer, PSMA and PSA mRNA can also predict rapid progression from mHSPC to mCRPC and ARSI or taxane-based chemotherapy resistance.

Enhancing the anticancer effect of androgen deprivation therapy by monocarboxylate transporter 1 inhibitor in prostate cancer cells.

Tumor initiation and progression necessitate a metabolic shift in cancer cells. Consequently, the progression of prostate cancer (PCa), a leading cause of cancer-related deaths in males globally, involves a shift from lipogenic to glycolytic metabolism. Androgen deprivation therapy (ADT) serves as the standard treatment for advanced-stage PCa. However, despite initial patient responses, castrate resistance emerges ultimately, necessitating novel therapeutic approaches. Therefore, in this study, we aimed to investigate the role of monocarboxylate transporters (MCTs) in PCa post-ADT and evaluate their potential as therapeutic targets. PCa cells (LNCaP and C4-2 cell line), which has high prostate-specific membrane antigen (PSMA) and androgen receptor (AR) expression among PCa cell lines, was used in this study. We assessed the expression of MCT1 in PCa cells subjected to ADT using charcoal-stripped bovine serum (CSS)-containing medium or enzalutamide (ENZ). Furthermore, we evaluated the synergistic anticancer effects of combined treatment with ENZ and SR13800, an MCT1 inhibitor. Short-term ADT led to a significant upregulation in folate hydrolase 1 (FOLH1) and solute carrier family 16 member 1 (SLC16A1) gene levels, with elevated PSMA and MCT1 protein levels. Long-term ADT induced notable changes in cell morphology with further upregulation of FOLH1/PSMA and SLC16A1/MCT1 levels. Treatment with ENZ, a nonsteroidal anti-androgen, also increased PSMA and MCT1 expression. However, combined therapy with ENZ and SR13800 led to reduced PSMA level, decreased cell viability, and suppressed expression of cancer stem cell markers and migration indicators. Additionally, analysis of human PCa tissues revealed a positive correlation between PSMA and MCT1 expression in tumor regions. Our results demonstrate that ADT led to a significant upregulation in MCT1 levels. However, the combination of ENZ and SR13800 demonstrated a promising synergistic anticancer effect, highlighting a potential therapeutic significance for patients with PCa undergoing ADT.

Abstract A010: Prostate-specific membrane antigen use in glioma management: past, present, and future

Abstract Introduction: Prostate-Specific Membrane Antigen (PSMA) is a type II membrane-bound zinc metallopeptidase expressed in various tissues, including the prostate, renal tubular epithelium, small and large intestinal mucosa, and brain. It plays a role in cell proliferation pathways and folate and glutamate metabolism. PSMA has been utilized for imaging and treatment of prostate cancer and is also expressed in solid tumor neovasculature of other cancers. Gliomas, which are central nervous system neoplasms of glial tissue, represent a challenging group of tumors with limited treatment options due to their invasive nature. PSMA's ability to internalize and location makes it a promising diagnostic and therapeutic target for gliomas. This review synthesizes the literature surrounding the use of PSMA in gliomas to inform current and future directions of study. Methods: A review of the literature was conducted using PubMed and Scopus databases in June 2023. Seventy-one relevant studies, including histopathological, imaging, and therapeutic investigations, were identified. These publications were categorized by year of publication to analyze the evolution of PSMA research in glioma management. Additionally, clinicaltrials.gov was searched for ongoing clinical trials involving PSMA and gliomas. Results: Histopathological studies have demonstrated PSMA's high expression in glioma vasculature, particularly in glioblastoma (GBM), a high-grade glioma (HGG). Studies have investigated PSMA's role in tumor metabolism and its interplay with other tumor markers. Some research suggests that high PSMA expression in GBM endothelium may promote angiogenesis and correlates with poor prognosis. PSMA PET imaging has shown promise in diagnosing and differentiating HGGs and low-grade gliomas (LGGs). Studies have reported high sensitivity and diagnostic accuracy of PSMA PET for HGGs, making it a potentially useful screening tool for radioligand therapy patient selection. Mouse models have also been employed to evaluate the utility of PSMA PET imaging in GBM, with some studies suggesting its application in defining non-enhancing portions of tumors and recurrence volume. PSMA-targeted therapies, particularly PSMA-targeted radiotherapy using radionuclide agents like 177Lu-PSMA-617, have been explored for the treatment of gliomas. Case reports and preliminary studies have demonstrated potential efficacy and tumor response to such therapies, warranting further investigation. Conclusion: The evolving literature indicates that PSMA holds promise as a valuable tool in the diagnosis, prognosis, and treatment of gliomas. Studies have highlighted PSMA PET imaging's high diagnostic accuracy and its potential in patient selection for targeted therapies. However, more research is needed to fully understand the role of PSMA in glioma behavior and to optimize treatment strategies. Ongoing clinical trials and future investigations will further our knowledge of PSMA's potential in managing gliomas and improving patient outcomes. Citation Format: Joshua D. McBriar, Neeva Shafiian, Steven Scharf, A. Gabriella Wernicke. Prostate-specific membrane antigen use in glioma management: past, present, and future [abstract]. In: Proceedings of the AACR Special Conference on Brain Cancer; 2023 Oct 19-22; Minneapolis, Minnesota. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_1):Abstract nr A010.

Abstract C090: High GLUT1 membrane expression and low PSMA membrane expression in ductal adenocarcinoma and intraductal carcinoma of the prostate

Abstract Background: Both Ductal Adenocarcinoma (DAC) and Intraductal Carcinoma (IDC) of the prostate are generally associated with aggressive clinical behavior and poor prognosis and can be lethal. Furthermore, previous studies linked aggressive clinical behavior and poor prognosis with discordant FDG positivity and low Prostate-specific membrane antigen (PSMA) expression. A recent study only cited a DAC patient with low 68Ga-PSMA-11 PET/CT uptake but high 18F-FDG PET/CT uptake, however, there is lack of directly compared articles nor large data sets. IDC-P has similar cribriform pattern in the pathological structure as a mean differential diagnosis for DAC. Hence, the objective of this study was to investigate the expression of PSMA and GLUT1 in DAC and IDC-P patients. Methods: The study was conducted on 87 DAC or IDCP patients without any treatment and 97 PAC patients with a Gleason score ≥ 8 of prostate biopsies and prostatectomy samples between August 2017 and August 2022. We performed immunohistochemical staining and scoring of various cancer component samples from the patients to reflect the protein expression levels of PSMA and GLUT1. Results: PSMA expression in PAC tissues was significantly higher than in DAC/IDC-P tissues (141.2 vs 78.6, p &amp;lt; 0.001). There was no significant difference in PSMA membrane expression between DAC/IDC-P and adjacent acinar adenocarcinoma (78.6 vs 93.4, p = 0.166). GLUT1 expression was higher in DAC/IDC-P tissue than in acinar adenocarcinoma tissue adjacent to DAC/IDC-P (68.6 vs 51.3, p = 0.007), but was still lower than that in PAC tissue (68.6 vs 93.1, p = 0.0014). It is worth noting that GLUT1 membrane expression in DAC/IDC-P was significantly increased than in PAC (13.0 vs 6.6, p = 0.025), and in acinar adenocarcinoma adjacent to DAC/IDC-P (13.0 vs 2.0, p &amp;lt; 0.001). Conclusions: In DAC and IDC-P tissues, PSMA membrane expression is low, while GLUT1 expression, especially GLUT1 membrane expression is high. These findings imply that DAC and IDC-P cells may have higher glucose metabolic and raise interest in targeting membrane GLUT1 as a novel anticancer strategy for DAC/IDC-P and other prostate cancer with high glucose metabolism. Citation Format: Xingming Wang, Xiaomei Gao, Lin Qi, Ye Zhang, Hongling Yin, Yu Gan, Yi Cai. High GLUT1 membrane expression and low PSMA membrane expression in ductal adenocarcinoma and intraductal carcinoma of the prostate [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr C090.

Administering [177Lu]Lu-PSMA-617 Prior to Radical Prostatectomy in Men with High-risk Localised Prostate Cancer (LuTectomy): A Single-centre, Single-arm, Phase 1/2 Study

BackgroundHigh-risk localised prostate cancer (HRCaP) has high rates of biochemical recurrence; [177Lu]Lu-PSMA-617 is effective in men with advanced prostate cancer. ObjectiveTo investigate the dosimetry, safety, and efficacy of upfront [177Lu]Lu-PSMA-617 in men with HRCaP prior to robotic radical prostatectomy (RP). Design, setting, and participantsIn this single-arm, phase I/II trial, we recruited men with HRCaP (any of prostate-specific antigen [PSA] >20 ng/ml, International Society of Urological Pathology (ISUP) grade group [GG] 3–5, and ≥cT2c), with high tumour uptake on [68Ga]Ga-PSMA-11 positron emission tomography/computed tomography (PSMA PET/CT), and scheduled for RP. InterventionCohort A (n = 10) received one cycle and cohort B (n = 10) received two cycles of [177Lu]Lu-PSMA-617 (5 GBq) followed by surgery 6 weeks later. Outcome measurements and statistical analysisThe primary endpoint was tumour radiation absorbed dose. Adverse events (AEs; Common Terminology Criteria for Adverse Events (CTCAE) version 5.0), surgical safety (Clavien-Dindo), imaging, and biochemical responses were evaluated (ClinicalTrials.gov: NCT04430192). Results and limitationsBetween May 29, 2020 and April 28, 2022, 20 patients were enrolled. The median PSA was 18 ng/ml (interquartile range [IQR] 11–35), Eighteen (90%) had GG ≥3, and six (30%) had N1 disease. The median (IQR) highest tumour radiation absorbed dose after cycle 1 for all lesions was 35.5 Gy (19.5–50.1), with 19.6 Gy (11.3–48.4) delivered to the prostate. Five patients received radiation to lymph nodes. Nine (45%) patients achieved >50% PSA decline. The most common AEs related to [177Lu]Lu-PSMA-617 were grade 1 fatigue in eight (40%), nausea in seven (35%), dry mouth in six (30%), and thrombocytopenia in four (20%) patients. No grade 3/4 toxicities or Clavien 3–5 complications occurred. Limitations include small a sample size. ConclusionsIn men with HRCaP and high prostate-specific membrane antigen (PSMA) expression, [177Lu]Lu-PSMA-617 delivered high levels of targeted radiation doses with few toxicities and without compromising surgical safety. Further studies of [177Lu]Lu-PSMA-617 in this population are worthwhile to determine whether meaningful long-term oncological benefits can be demonstrated. Patient summaryIn this study, we demonstrate that up to two cycles of [177Lu]Lu-PSMA-617 given prior to radical prostatectomy in patients with high-risk localised prostate cancer are safe and deliver targeted doses of radiation to tumour-affected tissues. It is tolerated well with minimal treatment-related adverse events, and surgery is safe with a low rate of complications. Activity measured through PSA reduction, repeat PSMA PET/CT, and histological response is promising.

68Ga-PSMA-11 PET/CT Imaging in Brain Gliomas and Its Correlation With Clinicopathological Prognostic Parameters.

Gliomas are the most common primary central nervous system tumors, of which the malignant gliomas account for 60%-75%. The primary and secondary brain malignancies are highly treatment resistant, and their marked angiogenesis attracts interest as a potential therapeutic target. The grade of gliomas, Ki-67 index, and IDH mutation status are among the major prognostic markers in gliomas. Prostate-specific membrane antigen (PSMA) is a zinc-dependent peptidase that is not only expressed in prostate cancer cells but also in the tumor neovasculature. The initial PSMA PET studies in central nervous system tumors using 68Ga-HBED-CC-PSMA (68Ga-PSMA-11) PET tracer confirmed selective target expression in gliomas of different grades, with higher expression in high-grade glioma compared with low-grade glioma. The aim of the present study was to correlate and compare the 68Ga-PSMA-11 and 18F-FDG uptake in brain tumors with their clinicopathological prognostic parameters, so as to study their prognostic implications. In addition, the study also aimed to identify patients who are likely to benefit from potential PSMA-targeted therapies. This ongoing prospective study was approved by the institutional scientific and medical ethics committee. The patients with primary or recurrent glioma lesions on MRI underwent regional brain PET/CT scanning with 68Ga-PSMA-11 and 18F-FDG. The final histopathology of the brain lesions (glioma grade), Ki-67 index, and IDH mutation status were compared with SUVmax values of the 68Ga-PSMA-11 and 18F-FDG PET/CT. A total of 15 patients (13 males and 2 females; age range, 21-73 years; median age, 58 years) were included in this study analysis. Among the 15 patients, 10 were treatment naive and 2 were patients with recurrent glioma. Three patients turned out to be WHO grade I-II, 6 belonged to grade III, and 6 grade IV (glioblastoma multiforme) on final histopathology. The 68Ga-PSMA-11 PET/CT showed tracer uptake in all high-grade gliomas with good tumor-to-background ratio. It was PSMA nonavid in 2/3 low-grade gliomas, and it showed low-grade uptake in 1/3 patients. PSMA expression (as evaluated by SUVmax values) was significantly higher in higher-grade tumors, those with IDH mutation wildtype status, and higher Ki-67 indices. FDG PET SUVmax also showed significant correlation with these prognostic parameters. In these preliminary results, PSMA PET appears to be an important tool in the evaluation and prognosis of gliomas. PSMA-directed theranostics can be explored as a personalized approach in gliomas with high PSMA uptake. However, with the limitation of small sample size, larger clinical trials are warranted to draw conclusive evidence regarding the same.

Tumoral Ki67 and PSMA Expression in Fresh Pre-PSMA-RLT Biopsies and Its Relation With PSMA-PET Imaging and Outcomes of PSMA-RLT in Patients With mCRPC.

Prostate specific membrane antigen (PSMA) directed radioligand therapy (RLT) is a novel therapy for metastatic castration-resistant prostate cancer (mCRPC) patients. However, it is still poorly understood why approximately 40% of the patients does not respond to PSMA-RLT. The aims of this study were to evaluate the pretreatment PSMA expression on immunohistochemistry (IHC) and PSMA uptake on PET/CT imaging in mCRPC patients who underwent PSMA-RLT. We correlated these parameters and a cell proliferation marker (Ki67) to the therapeutic efficacy of PSMA-RLT. In this retrospective study, mCRPC patients who underwent PSMA-RLT were analyzed. Patients biopsies were scored for immunohistochemical Ki67 expression, PSMA staining intensity and percentage of cells with PSMA expression. Moreover, the PSMA tracer uptake of the tumor lesion(s) and healthy organs on PET/CT imaging was assessed. The primary outcome was to evaluate the association between histological PSMA protein expression of tumor in pre-PSMA-RLT biopsies and the PSMA uptake on PSMA PET/CT imaging of the biopsied lesion. Secondary outcomes were to assess the relationship between PSMA expression and Ki67 on IHC and the progression free survival (PFS) and overall survival (OS) following PSMA-RLT. In total, 22 mCRPC patients were included in this study. Nineteen (86%) patients showed a high and homogenous PSMA expression of >80% on IHC. Three (14%) patients had low PSMA expression on IHC. Although there was limited PSMA uptake on PET/CT imaging, these 3 patients had lower PSMA uptake on PET/CT imaging compared to the patients with high PSMA expression on IHC. Yet, no correlation was found between PSMA uptake on PET/CT imaging and PSMA expression on IHC (SUVmax: R2=0.046 and SUVavg: R2=0.036). The 3 patients had a shorter PFS compared to the patients with high PSMA expression on IHC (HR: 4.76, 95% CI: 1.14-19.99; P=.033). Patients with low Ki67 expression had a longer PFS and OS compared to patients with a high Ki67 expression (HR: 0.40, 95% CI: 0.15-1.06; P=.013) CONCLUSION: The PSMA uptake on PSMA-PET/CT generally followed the PSMA expression on IHC. However, heterogeneity may be missed on PSMA-PET/CT. Immunohistochemical PSMA and Ki67 expression in fresh tumor biopsies, may contribute to predict treatment efficacy of PSMA-RLT in mCRPC patients. This needs to be further explored in prospective cohorts.

The role of PSMA PET/CT to predict upgrading in patients undergoing radical prostatectomy for ISUP grade group 1 prostate cancer.

To investigate the additive role of prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) independent from multiparametric magnetic resonance imaging (mpMRI) and clinical-pathological parameters to predict pathological upgrading in patients with ISUP grade group (GG) 1 prostate cancer (PCa) at prostate biopsy. A total of 41 patients who underwent robotic radical prostatectomy (RP) for GG1 disease at prostate biopsy with preoperative PSMA PET/CT and mpMRI images available for central review were included in the study. Univariate and multivariate logistic regression analyses were performed to determine the independent predictors of pathological upgrading (GG ≥ 2). Final RP pathology revealed upgrading in 26 patients (65.9%); to GG 2 disease in 25 cases and GG 4 disease in one case. International Society of Urological Pathology (ISUP) upgrading rates for prostate imaging-reporting and data system (PIRADS)-5, PIRADS-4, and PIRADS ≤ 3 lesions were 78%, 74%, and 38%, respectively. Fourteen out of 15 (93.3%) patients with an SUVmax ≥ 5.6 and all patients with an SUVmax ≥ 6.5 (n = 10) had pathological upgrading. The upgrading rate in patients with SUV < 5.6 was 46.2% (12/26). Intraprostatic SUVmax ≥ 5.6 was found as the only independent predictor of pathological upgrading in multivariate analysis. High prostatic PSMA uptake was found to be a very reliable predictor of pathological upgrading, but low PSMA uptake cannot exclude pathological upgrading. Intraprostatic PSMA uptake along with previously known mpMRI and biopsy-related parameters should be considered when making a treatment decision in patients with GG1 PCa at prostate biopsy.

Development of [177Lu]Lu-LNC1003 for radioligand therapy of prostate cancer with a moderate level of PSMA expression.

Evans blue as an albumin binder has been widely used to improve pharmacokinetics and enhance tumor uptake of radioligands, including prostate-specific membrane antigen (PSMA) targeting agents. The goal of this study is to develop an optimal Evans blue-modified radiotherapeutic agent that could maximize the absolute tumor uptake and tumor absorbed dose thus the therapeutic efficacy to allow treatment of tumors even with moderate level of PSMA expression. [177Lu]Lu-LNC1003 was synthesized based on PSMA-targeting agent and Evans blue. Binding affinity and PSMA targeting specificity were verified through cell uptake and competition binding assay in 22Rv1tumor model that has moderate level of PSMA expression. SPECT/CT imaging and biodistribution studies in 22Rv1 tumor-bearing mice were performed to evaluate the preclinical pharmacokinetics. Radioligand therapy studies were conducted to systematically assess the therapeutic effect of [177Lu]Lu-LNC1003. LNC1003 showed high binding affinity (IC50 = 10.77nM) to PSMA in vitro, which was comparable with that of PSMA-617 (IC50 = 27.49nM) and EB-PSMA-617 (IC50 = 7.91nM). SPECT imaging of [177Lu]Lu-LNC1003 demonstrated significantly improved tumor uptake and retention as compared with [177Lu]Lu-EB-PSMA and [177Lu]Lu-PSMA-617, making it suitable for prostate cancer therapy. Biodistribution studies further confirmed the remarkably higher tumor uptake of [177Lu]Lu-LNC1003 (138.87 ± 26.53%ID/g) over [177Lu]Lu-EB-PSMA-617 (29.89 ± 8.86%ID/g) and [177Lu]Lu-PSMA-617 (4.28 ± 0.25%ID/g) at 24h post-injection. Targeted radioligand therapy results showed noteworthy inhibition of 22Rv1 tumor growth after administration of a single dose of 18.5MBq [177Lu]Lu-LNC1003. There was no obvious antitumor effect after [177Lu]Lu-PSMA-617 treatment under the same condition. In this study, [177Lu]Lu-LNC1003 was successfully synthesized with high radiochemical purity and stability. High binding affinity and PSMA targeting specificity were identified in vitro and in vivo. With greatly enhanced tumor uptake and retention, [177Lu]Lu-LNC1003 has the potential to improve therapeutic efficacy using significantly lower dosages and less cycles of 177Lu that promises clinical translation to treat prostate cancer with various levels of PSMA expression.

Dual probe difference specimen imaging for prostate cancer margin assessment.

Positive margin status due to incomplete removal of tumor tissue during radical prostatectomy for high-risk localized prostate cancer requires reoperation or adjuvant therapy, which increases morbidity and mortality. Adverse effects of prostate cancer treatments commonly include erectile dysfunction, urinary incontinence, and bowel dysfunction, making successful initial curative prostatectomy imperative. Current intraoperative tumor margin assessment is largely limited to frozen section analysis, which is a lengthy, labor-intensive process that is obtrusive to the clinical workflow within the operating room (OR). Therefore, a rapid method for prostate cancer margin assessment in the OR could improve outcomes for patients. Dual probe difference specimen imaging (DDSI), which uses paired antibody-based probes that are labeled with spectrally distinct fluorophores, was shown herein for prostate cancer margin assessment. The paired antibody-based probes consisted of a targeted probe to prostate-specific membrane antigen (PSMA) and an untargeted probe, which were used as a cocktail to stain resected murine tissue specimens including prostate tumor, adipose, muscle, and normal prostate. Ratiometric images (i.e., DDSI) of the difference between targeted and untargeted probe uptake were calculated and evaluated for accuracy using receiver operator characteristic curve analysis with area under the curve values used to evaluate the utility of the DDSI method to detect PSMA positive prostate cancer. Targeted and untargeted probe uptake was similar between the high and low PSMA expressing tumor due to nonspecific probe uptake after topical administration. The ratiometric DDSI approach showed substantial contrast difference between the PSMA positive tumors and their respective normal tissues (prostate, adipose, muscle). Furthermore, DDSI showed substantial contrast difference between the high PSMA expressing tumors and the minimally PSMA expressing tumors due to the ratiometric correction for the nonspecific uptake patterns in resected tissues. Previous work has shown that ratiometic imaging has strong predictive value for breast cancer margin status using topical administration. Translation of the ratiometric DDSI methodology herein from breast to prostate cancers demonstrates it as a robust, ratiometric technique that provides a molecularly specific imaging modality for intraoperative margin detection. Using the validated DDSI protocol on resected prostate cancers permitted rapid and accurate assessment of PSMA status as a surrogate for prostate cancer margin status. Future studies will further evaluate the utility of this technology to quantitatively characterize prostate margin status using PSMA as a biomarker.

Landscape of prostate-specific membrane antigen heterogeneity and regulation in AR-positive and AR-negative metastatic prostate cancer.

Tumor expression of prostate-specific membrane antigen (PSMA) is lost in 15-20% of men with castration-resistant prostate cancer (CRPC), yet the underlying mechanisms remain poorly defined. In androgen receptor (AR)-positive CRPC, we observed lower PSMA expression in liver lesions versus other sites, suggesting a role of the microenvironment in modulating PSMA. PSMA suppression was associated with promoter histone 3 lysine 27 methylation and higher levels of neutral amino acid transporters, correlating with 18F-fluciclovine uptake on positron emission tomography imaging. While PSMA is regulated by AR, we identified a subset of AR-negative CRPC with high PSMA. HOXB13 and AR co-occupancy at the PSMA enhancer and knockout models point to HOXB13 as an upstream regulator of PSMA in AR-positive and AR-negative prostate cancer. These data demonstrate how PSMA expression is differentially regulated across metastatic lesions and in the context of the AR, which may inform selection for PSMA-targeted therapies and development of complementary biomarkers.

Abstract 3997: Preclinical characterization of ARX517, a next-generation anti-PSMA antibody drug conjugate for the treatment of metastatic castration-resistant prostate cancer

Abstract Prostate cancer is the most common cancer, and the second leading cause of cancer death, among men in the United States. Metastatic castration-resistant prostate cancer (mCRPC) is an advanced stage of disease in which patients ultimately fail androgen-deprivation therapies and exhibit a poor survival rate. Recently, prostate-specific membrane antigen (PSMA) has been validated as a prostate cancer tumor antigen with its over-expression in prostate tumors and low level of expression in select normal tissues. Using an expanded genetic code to create Engineered Precision Biologics (EPBs), Ambrx has developed ARX517, an anti-PSMA targeted next-generation antibody drug conjugate (ADC), for treatment of mCRPC patients. ARX517 is composed of a humanized anti-PSMA antibody site-specifically conjugated to drug linker AS269 (a potent tubulin inhibitor), yielding a drug-to-antibody ratio of 2. After binding to PSMA expressed on the surface of tumor cells, ARX517 is internalized and delivers a cytotoxic payload which inhibits tubulin polymerization and induces cellular apoptosis. In vitro testing of ARX517 in prostate cancer cell lines with variable PSMA expression demonstrated highly specific and potent sub-nanomolar activity in cells with high PSMA expression. To minimize premature payload release, ARX517 employs a non-cleavable PEG linker and stable oxime conjugation chemistry to enhance stability in circulation. ARX517 exhibited a long terminal half-life and high serum exposure in mice. The serum stability of ARX517 should effectively deliver more payload to target tumor cells, and in multiple CDX and PDX prostate cancer models, ARX517 showed dose-dependent anti-tumor activity in both enzalutamide-sensitive and enzalutamide-resistant models. Repeat dose toxicokinetic studies in non-human primates demonstrated ARX517 was tolerated at exposures well above therapeutic exposures in mouse pharmacology studies, indicating a wide therapeutic index. In summary, ARX517 elicited highly specific, potent cell killing in cell lines with high PSMA expression, inhibited tumor growth in enzalutamide-sensitive and enzalutamide-resistant CDX and PDX models, demonstrated a tolerable safety profile in cynomolgus monkeys, and has a clear therapeutic index based on preclinical serum exposure data. The strong preclinical data and recent clinical validation of PSMA as a mCRPC target provide rationale for evaluation of ARX517 as a potential prostate cancer treatment. ARX517 is currently in a Phase 1 dose escalation trial (ARX517-2011 [NCT04662580]) in the United States. Citation Format: Lillian Skidmore, David Mills, Ji Young Kim, Prathap Shastri, Nick A. Knudsen, Jeff Steen, Jay Nelson, Ying Buechler, Feng Tian, Shawn Zhang. Preclinical characterization of ARX517, a next-generation anti-PSMA antibody drug conjugate for the treatment of metastatic castration-resistant prostate cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3997.

PD04-04 MOLECULAR CORRELATES WITH PSMA EXPRESSION IN PROSTATE CANCER

You have accessJournal of UrologyCME1 Apr 2023PD04-04 MOLECULAR CORRELATES WITH PSMA EXPRESSION IN PROSTATE CANCER Adam Weiner, Eric Li, JJ Zhang, Elai Davicioni, Edward Schaeffer, Ashley Ross, Luca Valle, Paul Boutros, Jeremie Calais, Amar Kishan, and Robert Reiter Adam WeinerAdam Weiner More articles by this author , Eric LiEric Li More articles by this author , JJ ZhangJJ Zhang More articles by this author , Elai DavicioniElai Davicioni More articles by this author , Edward SchaefferEdward Schaeffer More articles by this author , Ashley RossAshley Ross More articles by this author , Luca ValleLuca Valle More articles by this author , Paul BoutrosPaul Boutros More articles by this author , Jeremie CalaisJeremie Calais More articles by this author , Amar KishanAmar Kishan More articles by this author , and Robert ReiterRobert Reiter More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003228.04AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Not all prostate cancer (PCa) is detected by prostate-specific membrane antigen (PSMA)-based imaging or responsive to PSMA-based radiopharmaceuticals. We sought to define the molecular processes associated with PSMA expression. METHODS: Using multiple datasets (n=5 Homo sapiens; n=2 mouse xenograft models; n=1 cell line), we correlated PSMA gene expression (FOLH1) with biological processes and treatments. RESULTS: In an exploratory analysis of a prospective cohort of 7,000 tumors from radical prostatectomy, tumors with high PSMA RNA expression (one standard deviation above mean) tended to demonstrate more androgen receptor activity, high genomic risk scores (Decipher), more markers of homologous recombination deficiency, less immune content, lower predicted response to radiotherapy (“PORTOS”), and enrichment for P13K/AKT/mTOR pathways (Figure 1). In a validation cohort, adenocarcinoma tumors (n=49) expressed more PSMA than benign tissue (n=12; Wilcoxon p=0.020) and castration resistant tumors (n=27; p=0.015). An additional cohort showed adenocarcinoma (n=110) expressed more PSMA than neuroendocrine tumors (n=20; p=4.4e-6). In a mouse xenograft model (n=1) of high-grade adenocarcinoma, PSMA expression declined as the model underwent conversion to castration resistance and subsequent neuroendocrine transformation following castration. From both mouse and human data, treatment with androgen deprivation was associated with an initial increase in PSMA expression. From TCGA (n=491), tumors with high PSMA expression also tended to have a higher mutational burden and fewer tumor infiltrating lymphocytes in a subset with immunohistochemistry data (n=330). To assess the association between PSMA and P13K/AKT/mTOR, we used data from a cell line exposed to the MAPK inhibitor trametinib which upregulates P13K/AKT/mTOR pathways. VCaP cells treated with both enzalutamide and trametinib expressed two-fold more PSMA compared to those treated with the individual medications or neither. CONCLUSIONS: PCa with high PSMA expression is characterized by relevant differences in biological processes. If corroborated with PSMA-PET avidity, these results could optimize precision PCa care by informing adjunctive molecular testing or treatment paradigms for low or high PSMA expressing tumors. Source of Funding: None © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e143 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Adam Weiner More articles by this author Eric Li More articles by this author JJ Zhang More articles by this author Elai Davicioni More articles by this author Edward Schaeffer More articles by this author Ashley Ross More articles by this author Luca Valle More articles by this author Paul Boutros More articles by this author Jeremie Calais More articles by this author Amar Kishan More articles by this author Robert Reiter More articles by this author Expand All Advertisement PDF downloadLoading ...

Synthesis and preclinical evaluation of novel 99mTc-labeled PSMA ligands for radioguided surgery of prostate cancer

BackgroundRadioguided surgery (RGS) has recently emerged as a valuable new tool in the management of recurrent prostate cancer (PCa). After preoperative injection of a 99mTc-labeled prostate-specific membrane antigen (PSMA) inhibitor, radioguided intraoperative identification and resection of lesions is facilitated by means of suitable γ-probes. First clinical experiences show the feasibility of RGS and suggest superiority over conventional lymph node dissection in recurrent PCa. However, commonly used [99mTc]Tc-PSMA-I&S exhibits slow whole-body clearance, thus hampering optimal tumor-to-background ratios (TBR) during surgery. We therefore aimed to develop novel 99mTc-labeled, PSMA-targeted radioligands with optimized pharmacokinetic profile to increase TBR at the time of surgery.MethodsThree 99mTc-labeled N4-PSMA ligands were preclinically evaluated and compared to [99mTc]Tc-PSMA-I&S. PSMA affinity (IC50) and internalization were determined on LNCaP cells. Lipophilicity was assessed by means of the distribution coefficient logD7.4 and an ultrafiltration method was used to determine binding to human plasma proteins. Biodistribution studies and static µSPECT/CT-imaging were performed at 6 h p.i. on LNCaP tumor-bearing CB17-SCID mice.ResultsThe novel N4-PSMA tracers were readily labeled with [99mTc]TcO4− with RCP > 95%. Comparable and high PSMA affinity was observed for all [99mTc]Tc-N4-PSMA-ligands. The ligands showed variable binding to human plasma and medium to low lipophilicity (logD7.4 − 2.6 to − 3.4), both consistently decreased compared to [99mTc]Tc-PSMA-I&S. Biodistribution studies revealed comparable tumor uptake among all [99mTc]Tc-N4-PSMA-ligands and [99mTc]Tc-PSMA-I&S, while clearance from most organs was superior for the novel tracers. Accordingly, increased TBR were achieved. [99mTc]Tc-N4-PSMA-12 showed higher TBR than [99mTc]Tc-PSMA-I&S for blood and all evaluated tissue. In addition, a procedure suitable for routine clinical production of [99mTc]Tc-N4-PSMA-12 was established. Labeling with 553 ± 187 MBq was achieved with RCP of 98.5 ± 0.6% (n = 10).ConclusionHigh tumor accumulation and favorable clearance from blood and non-target tissue make [99mTc]Tc-N4-PSMA-12 an attractive tracer for RGS, possibly superior to currently established [99mTc]Tc-PSMA-I&S. Its GMP-production according to a method presented here and first clinical investigations with this novel radioligand is highly recommended.

Theranostics in prostate cancer

SummaryThis review summarizes current evidence of “theranostics” for patients with prostate cancer. Prostate-specific membrane antigen (PSMA) is a glycoprotein which can be labeled with positron-emitting tomographic (PET) tracers like fluorine-18, gallium-68, or copper-64 and can be labeled with beta emitters like lutetium-177 to treat patients with metastatic castration-resistant prostate cancer (mCRPC). PSMA PET/CT has been shown to be superior to computer tomography (CT) and bone scintigraphy in accuracy, sensitivity, and specificity in the evaluation of metastatic tumor sites and may change treatment management. However, outcome studies showing an improvement in progression-free survival (PFS) and/or overall survival (OS) after management change is missing. PSMA PET/CT is highly recommended in prostate cancer patients with biochemical recurrence (PSA &gt; 0.2 ng/ml). Patients presenting with high PSMA expression in PSMA PET/CT may be favorably treated with 177lutetium-617. In the TheraP study, a multicenter phase 2 trial, patients with mCRPC were randomly assigned to receive either 177lutetium-617 or cabazitaxel. The results indicate fewer treatment-related adverse events in patients treated with 177lutetium-617, an improvement in PSA response, but no improvement in OS after 36 months follow-up. In the VISION trial, a phase 3 international study, patients with mCRPC were randomly assigned to receive either 177lutetium-617 and standard of care (SOC) or SOC alone. At 12 months, radiographic PFS or PSA-PFS was 18% in patients treated with 177lutetium-617 and 3% in patients treated with SOC alone. The real status of 177lutetium-617 in the sequel of treatment regimens remains unclear and additional studies are therefore warranted.

Using PSMA imaging for prognostication in localized and advanced prostate cancer.

The use of prostate-specific membrane antigen (PSMA)-directed applications in modern prostate cancer management has evolved rapidly over the past few years, helping to establish new treatment pathways and provide further insights into prostate cancer biology. However, the prognostic implications of PSMA-PET have not been studied systematically, owing to rapid clinical implementation without long follow-up periods to determine intermediate-term and long-term oncological outcomes. Currently available data suggest that traditional prognostic factors and survival outcomes are associated with high PSMA expression (both according to immunohistochemistry and PET uptake) in men with localized and biochemically recurrent disease. Treatment with curative intent (primary and/or salvage) often fails when PSMA-positive metastases are present; however, the sensitivity of PSMA-PET in detecting all metastases is poor. Low PSMA-PET uptake in recurrent disease is a favourable prognostic factor; however, it can be associated with poor prognosis in conjunction with high 18F-fluorodeoxyglucose uptake in metastatic castration-resistant prostate cancer. Clinical trials embedding PSMA-PET for guiding management with reliable oncological outcomes are needed to support ongoing clinical use.