Prostate-specific Membrane Antigen Research Articles

Synthesis and Preclinical Evaluation of Dual-Specific Probe Targeting Glypican-3 and Prostate-Specific Membrane Antigen for Hepatocellular Carcinoma PET Imaging.

Positron emission tomography (PET) is a promising modality for early diagnosis, accurate detection, and staging of hepatocellular carcinoma (HCC). Hereby, a dual-specific probe targeting Glypican-3 (GPC3) and prostate-specific membrane antigen (PSMA) was evaluated for HCC PET imaging. The probe was prepared by conjugating TJ12P2, a GPC3-targeting peptide previously reported by our group, to a highly potent PSMA inhibitor via a polyethylene glycol linker and further tethered to the 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) chelator. The resultant probe, NOTA-TJ12P2-PSMA, abbreviated as T2P, was labeled with gallium-68 and fluorine-18, respectively, and evaluated in murine HCC models of various levels of GPC3 and PSMA expression. Targeting specificity was confirmed by blocking studies. The synthesized [68Ga]Ga-T2P and [18F]AlF-T2P were stable in saline and fetal bovine serum for over 2 h, and bound to their respective targets with high affinity and specificity in cell assays. PET imaging at 60 min postinjection (p.i.) showed that [68Ga]Ga-T2P exhibited higher uptake (1.75 ± 0.16%ID/g) in Huh7 models with high expression of GPC3 and PSMA than gallium-68 labeled TJ12P2 (1.25 ± 0.07%ID/g, p < 0.01) or gallium-68 labeled PSMA-617 (1.07 ± 0.06%ID/g, p < 0.001). The uptake of [68Ga]Ga-T2P in Huh7 tumors was higher than that in PC-3 tumors with low expression of GPC3 or PSMA (0.55 ± 0.24%ID/g, p < 0.01). The uptake of [18F]AlF-T2P or [68Ga]Ga-T2P in the Huh7 tumor was substantially blocked by TJ12P2, TJ12P2 + PSMA, or T2P, but only partially blocked by PSMA. And the PSMA and TJ12P2 monomer blocking effect was less than that of TJ12P2 + PSMA and T2P. [18F]AlF-T2P had higher tumor-to-muscle ratios than [68Ga]Ga-T2P at 90 min postinjection (4.31 ± 0.10 vs 3.80 ± 0.17, p < 0.05) in Huh7 tumor models. To conclude, radiolabeled T2P exhibited a higher uptake and longer retention in Huh7 tumors than its monomeric counterparts. PET imaging via gallium-68 and fluorine-18 labeled T2P showed a similar imaging quality with comparable signal-to-background ratios. Our results demonstrate that T2P is a promising tool for future clinical diagnosis of HCC.

Radionuclide treatments of cancer: molecular mechanisms, biological responses, histopathological changes, and role of PET imaging.

Radiation treatments [radiotherapy and radionuclide treatments (RNTs)] are one of the main and effective treatment modalities of cancer. Globally, the number of cancer patients treated with radionuclides are much less as compared to number of radiotherapy cases but with the development of new radiotracers, most notably 177Lu and 225Ac-labeled prostate-specific membrane antigen ligands, and 223Ra-dichloride for prostate cancer and 177Lu-somatostatin analogs for neuroendocrine tumors, there is a significant rise in RNTs in the last decade. As therapeutic applications of nuclear medicine is on the rise, the aim of this review is to summarize biological responses to radiation treatments and molecular mechanisms of radiation-induced cell death (e.g. ionization, DNA damages such as double-strand breaks, DNA repair mechanisms, types of cell deaths such as apoptosis, necrosis, and immunogenic cell death), histopathological changes with radiation treatments, and role of PET imaging in RNTs as part of radionuclide theranostics for selecting and planning patients for RNTs, dosimetry, predicting and assessing response to RNTs, predicting toxicities, and other possible PET findings which may be seen after RNTs such as activation of immune system.

The Evaluation of Radiolabeled Prostate-Specific Membrane Antigen Positron Emission Tomography/Computed Tomography for Initial Staging in Intermediate-Risk Prostate Cancer Patients: A Retrospective Multicenter Analysis

Objectives. The aim of the present study was to assess the performance of radiolabeled-PSMA PET/CT in a cohort of intermediate-risk prostate cancer (PCa) patients for initial staging. Methods. This is a retrospective, multicenter analysis of patients diagnosed with intermediate-risk PCa who were staged using radiolabeled PSMA PET/CT to evaluate the extent of the disease before initiating appropriate treatment. The study included patients from the Nuclear Medicine Units of the Humanitas group between 2021 and 2024. The change in management due to the PSMA PET/CT examination was assessed. Results. A total of 181 patients were enrolled across all three centers. Histopathological assessment from biopsy revealed that 51.4% of patients had favorable PCa, while 48.6% had unfavorable disease. PET/CT was positive for the primary lesions in all patients, but it revealed a positivity rate in 23 (12.7%) patients for nodes and distant organs, with a positivity rate of 0.21 in the unfavorable group and 0.05 in the favorable group (p &lt; 0.005). Based on follow-up data, diagnostic accuracy was higher than 90% in both the favorable and unfavorable groups for lymph node and distant metastases. The inclusion of PSMA PET/CT in the diagnostic algorithm for patients with intermediate-risk PCa impacted patient management in 24 (13.3%) cases, based on the multidisciplinary team decision. Conclusions. PSMA PET/CT can affect the management of patients with intermediate-risk PCa in up to 13% of cases, mainly for unfavorable diseases. New imaging techniques as a first-line imaging procedure can help to plan the correct therapeutic approach in the intermediate-risk PCa group.

CXCR2 expression is associated with prostate-specific membrane antigen expression in hepatocellular carcinoma: reappraisal of tumor microenvironment and angiogenesis.

Angiogenesis is a critical component of neoplastic progression, and inflammatory cells within the tumor microenvironment contribute to neoangiogenesis. Prostate-specific membrane antigen (PSMA)is expressedin the neovasculature of various solid tumors, including hepatocellular carcinoma (HCC). Also, CXCR2 + inflammatory cells, including CD15 + neutrophils, play crucial roles in HCC progression.We evaluated the associations between PSMA expression and CXCR2 + inflammatory cells in HCC by immunohistochemistry (IHC). CXCR2 expression and its correlation with PSMA, the PSMA/CD34 ratio, immune markers (CD3, CD15, CD68, and CD163), clinical parameters, and oncologic outcomes were evaluated in 76HCC and background benign liver tissue. PSMA and the PSMA/CD34 ratioshowed a positive correlationwith intratumoralCXCR2,but not with intratumoral CD15. Intratumoral CXCR2 + cell count was positively associated with intratumoral CD3, CD15, CD68, and CD163 expression levels. In the benign compartment, CXCR2 was significantly associated with CD15. Metabolic dysfunction-associated steatotic liver disease (MASLD) risk factors and cirrhosis had an opposite effect on CXCR2 + cell count in benign liver tissue. Higher CD15 + cell count in the benign liver was associated with decreased overall survival (OS) and recurrence-free survival (RFS). In HCC, intratumoral CXCR2 + cell count is associated with PSMA expression. Intratumoral and benign compartments had different CXCR2 + inflammatory cell makeup. The immune microenvironment of HCC appears to differ depending on underlying risk factors. Further investigations are warranted to elucidate PSMA biology and assess the potential utility of CXCR2 IHC in PSMA-targeted theranostics.

A Pilot Study of PSMA PET/CT and MRI Fusion for Prostate Cancer: Software to Replace PET/MRI Hardware

Introduction: Prostate-specific membrane antigen positron emission tomography/computed tomography (PSMA PET/CT), in combination with magnetic resonance imaging (MRI), may enhance the diagnosis and staging of prostate cancer. Image fusion of separately acquired PET/CT and MRI images serve to facilitate clinical integration and treatment planning. This study aimed to investigate different PSMA PET/CT and MRI image fusion workflows for prostate cancer visualisation. Methods: Eighteen patients with prostate cancer who underwent PSMA PET/CT and MRI prior to radical prostatectomy were retrospectively selected. Alignment of the prostate was performed between PET/CT and MRI via three techniques: semi-automatic rigid, automatic rigid, and automatic non-rigid. Image fusion accuracy was evaluated through boundary and volume agreement, quantified by the Dice Similarity Coefficient (DSC), 95% Hausdorff Distance (HD), and Mean Surface Distance (MSD), with comparison against reconstructed histopathology slices. Results: Image fusion using all techniques resulted in clear lesion visualisation from PSMA PET/CT overlay and anatomical detail afforded by the MRI base and was consistent with histopathology tumour location. Image fusion accuracy was within the recommended range based on a DSC of 0.8–0.9. The automatic non-rigid registration method had the highest volume agreement (DSC: 0.96 ± &lt;0.01) and boundary agreement (HD: 1.17 ± 0.35 mm) when compared to automatic rigid (DSC 0.88 ± 0.02, HD 3.18 ± 0.29 mm) and semi-automatic rigid (DSC 0.80 ± 0.06, HD 5.25 ± 1.68 mm). Conclusions: Image fusion of clinically obtained PET/CT and MRI is feasible and clinically acceptable for use in prostate cancer diagnosis and surgical management. While the best accuracy was observed with the automatic non-rigid technique, which requires further validation, image fusion with clinically accessible methods (semi-automatic rigid) may currently aid patient education, pre-operative planning, and intra-operative guidance.

Synthesis and Evaluation of 99mTc-Labeled l-Aspartic Acid as a EuK Polymer Linker for Targeting PSMA to a Novel SPECT Tumor Tracer.

The development of novel tracers targeting prostate-specific membrane antigen (PSMA) has great potential for improving the diagnosis and treatment of prostate cancer (PCa). This study aimed to improve the absolute tumor uptake and tumor-to-background ratios (TBRs) of this novel PSMA tracer by increasing the number of pharmacophores, Glu-urea-Lys (EuK), that specifically bind to PSMA. We successfully synthesized four radioligands and prepared a total of 12 stable radiotracers by coordinating 99mTc with various coligands. [99mTc]Tc-EUKD-EDDA showed the best pharmacokinetic properties both in vitro and in vivo. It effectively increased the absolute uptake in tumors and resulted in good tumor retention. Rapid clearance in nontarget organs resulted in high TBRs. High-contrast SPECT/CT images were obtained within 2-6 h after injection, suggesting that [99mTc]Tc-EUKD-EDDA has great application potential in time-lapse imaging of PCa, which is important for improving the diagnostic accuracy of PCa in clinical practice.

PSMA Accumulation in Lower Extremity Lymphedema and Hydrocele.

The development of radiolabeled small-molecule prostate-specific membrane antigen (PSMA) inhibitors has advanced molecular imaging in prostate cancer. The use of 177Lu-PSMA is especially beneficial because its therapeutic β-emission combined with γ-radiation enables precise treatment and comprehensive imaging in patients with prostate cancer. We present a case of a prostate cancer patient who developed lower extremity lymphedema and hydrocele secondary to prior radiotherapy. Posttherapy whole-body imaging following 177Lu-PSMA treatment revealed dermal backflow with a notable accumulation of soft tissue in the lower extremities and hydrocele.

PSMA Radiotheranostics in Prostate Cancer: Principles, Practice, and Future Prospects.

Prostate cancer is a leading cause of cancer-related mortality in men, with metastatic castration-resistant prostate cancer presenting a substantial treatment challenge. The authors focuse on prostate-specific membrane antigen (PSMA) radiotheranostics, particularly lutetium 177 (177Lu)-PSMA radioligand therapy, as an emerging treatment modality for metastatic castration-resistant prostate cancer. The U.S. Food and Drug Administration approval of 177Lu-PSMA-617 marked a substantial advancement in the treatment paradigm of metastatic castration-resistant prostate cancer, based on the VISION trial that showed improved overall survival and quality of life compared with those for standard care. PSMA expression, assessed via PSMA PET, is crucial for patient selection and assessment of treatment eligibility. The authors discuss current practices, including therapy administration, dosing, and side effects, with a particular focus on eligibility criteria and the added value of posttherapy imaging. Response assessment criteria using PSMA PET are discussed, although these require further validation. The discussion of future directions highlights ongoing trials investigating PSMA targeting agents, the extension of radioligand therapy to earlier stages of prostate cancer, and combination therapies. This review underscores the role of PSMA radioligand therapy in the evolving landscape of prostate cancer treatment and its promise for improving patient outcomes. ©RSNA, 2024 Supplemental material is available for this article.

68Ga-Prostate-Specific Membrane Antigen PET/CT in Endometrial Cancer: A Preliminary Report.

Endometrial cancer is the most common gynecological cancer. Prostate-specific membrane antigen (PSMA) is expressed in prostate cancer cells but can be found in other cancers, such as endometrial cancer, during angiogenesis.The aim of this prospective pilot study was to evaluate the feasibility of using 68Ga-PSMA-11 PET/CT in endometrial cancer patients before surgical treatment. Seven women with a mean age of 58 ± 7.9 years were included in the study. All patients underwent standard imaging studies involving transvaginal ultrasound, ceCT scans of the chest and abdomen, and MRI as qualified for surgery. Additionally, PET/CT was performed on a Siemens Biograph scanner 60 minutes after the injection of 2 MBq/kg 68Ga-PSMA-11. Six of 7 patients had positive 68Ga-PSMA-11 PET/CT images, and histopathology confirmed endometrial cancer. One patient also exhibited uptake in the left ovary, and final histopathology revealed a hemorrhagic cyst. Lymph node involvement was further confirmed after ceCT fusion with 68Ga-PSMA-11. The consensus of histopathological staging of endometrial cancer and ceCT was 4/7, that of MR was 6/7, and that of 68Ga-PSMA-11 PET/CT was 5/7. All methods were consistent in terms of staging in 3/7 patients. The initial experience showed the possibility of using 68Ga-PSMA-11 in endometrial cancer patients. However, prospective large studies are needed to explore the real diagnostic role of radiolabelled PSMA in this field.This study was approved by the Ethical Committee of the Medical University of Warsaw (KB/2/A/2018).

Defining the Position of [177Lu]Lu-PSMA Radioligand Therapy in the Treatment Landscape of Metastatic Castration-Resistant Prostate Cancer: A Meta-analysis of Clinical Trials.

In recent years, theranostics has become a promising approach for treating metastatic castration-resistant prostate cancer (mCRPC), with trials investigating targeted radioligand therapy, particularly using prostate-specific membrane antigen labeled with lutetium-177 ([177Lu]Lu-PSMA). The proper position of [177Lu]Lu-PSMA in the therapeutic algorithm of mCRPC is yet to be identified. We conducted a systematic review and meta-analysis of phase II/III randomized controlled trials to assess the efficacy of [177Lu]Lu-PSMA in treating mCRPC. Study endpoints included radiographic progression-free survival (rPFS), prostate-specific antigen-PFS, objective response rate, and overall survival. Data were extracted according to the PRISMA statement. Summary hazard ratios (HRs) were calculated using random- or fixed-effects models. Statistical analyses were performed with RevMan software (v.5.2.3). [177Lu]Lu-PSMA reduced the risk of rPFS (HR 0.55; 95% confidence interval [CI] 0.43-0.71; p < 0.00001) and prostate-specific antigen-PFS (HR 0.53; 95% CI 0.41-0.67; p < 0.00001), and improved the objective response rate compared with control therapies (response rate 3.55; 95% CI 1.91-6.60; p < 0.0001), whereas no significant cumulative effect on overall survival was documented (HR 0.92; 95% CI 0.65-1.31; p = 0.63). Notably, in a dedicated subanalysis, comparable effects on rPFS were observed when [177Lu]Lu-PSMA was compared with active therapy. [177Lu]Lu-PSMA has a favorable impact on the radiographic and biochemical control of mCRPC and represents a potential treatment in a scenario where other valuable options are available. Further efforts are required to identify clinical and molecular markers necessary for proper patient stratification.

The Added Value of Prostate-specific Membrane Antigen Positron Emission Tomography/Computed Tomography to Magnetic Resonance Imaging for Local Staging of Prostate Cancer in Patients Undergoing Radical Prostatectomy

Background and objectiveThe role of prostate-specific membrane antigen (PSMA)-based positron emission tomography (PET)/computed tomography (CT) in addition to magnetic resonance imaging (MRI) for local staging of prostate cancer (PC) has been poorly addressed so far. Our aim was to assess the diagnostic accuracy of PSMA PET/CT and MRI, alone and combined, for detection of extraprostatic extension (EPE) and seminal vesicle invasion (SVI) in PC. MethodsWe conducted a multicenter retrospective study evaluating patients undergoing PSMA PET/CT and MRI before radical prostatectomy. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and area under the receiver operating characteristic curve (AUC) for detection of EPE and SVI were calculated for MRI and PSMA PET/CT alone and combined. Key findings and limitationsWe included 550 patients, of whom 2%, had low-risk, 43% had intermediate-risk, and 55% had high-risk PC. Overall, 52% of patients had EPE and 21% had SVI at histopathology. Patient-based comparison of MRI versus PSMA PET/CT for detection of EPE revealed sensitivity of 60% versus 41% (p < 0.001), specificity of 77% versus 83% (p = 0.075), PPV of 75% versus 73% (p = 0.6), NPV of 64% versus 56% (p < 0.001), and AUC of 69% versus 62% (p = 0.01). Combining the modalities increased the sensitivity (73%; p < 0.001) and NPV (69%; p < 0.001) and decreased the specificity (67%; p < 0.001) and PPV (71%; p = 0.01) over MRI alone. Patient-based comparison of MRI versus PSMA PET/CT for detection of SVI revealed sensitivity of 36% versus 44% (p = 0.2), specificity of 96% versus 96% (p > 0.99), PPV of 71% versus 75% (p = 0.6), NPV of 85% versus 87% (p = 0.2), and AUC of 66% versus 70% (p = 0.2). Combining the modalities increased the sensitivity (60%; p < 0.001), NPV (90%; p < 0.001), and AUC (76%; p < 0.001) and decreased the specificity (92%; p < 0.001) over MRI alone. Limitations include the retrospective nature of the study, selection of higher-risk cases for PSMA PET/CT, and lack of central review. Conclusions and clinical implicationsPSMA PET/CT has lower sensitivity for EPE detection in comparison to MRI. However, addition of PSMA PET information to MRI improved the sensitivity for EPE and SVI detection. Thus, the two modalities should be combined to guide treatment selection. Patient summaryCombining MRI (magnetic resonance imaging) scans with another type of imaging called PSMA PET/CT (prostate-specific membrane antigen positron emission tomography/computed tomography) for patients with prostate cancer leads to better identification of cancer growth outside the prostate in comparison to MRI alone. This could potentially improve the choice of prostate cancer treatment.

Intratumoral Distribution of [177Lu]Lu-PSMA-617 Over Time and in Relation to Diagnostic Tracers in Animal Models of Prostate Cancer.

Introduction: Prostate-specific membrane antigen (PSMA) is a target for diagnostic positron emission tomography (PET)-tracers and radiopharmaceutical therapy (RPT), for example, [177Lu]Lu-PSMA-617, in prostate cancer. This autoradiography study investigates [177Lu]Lu-PSMA-617 intratumoral distribution over time, compared with PSMA expression, proliferation (Ki67), and [68Ga]Ga-PSMA-11, [18F]F-PSMA-1007, [18F]-fluorodeoxyglucose, and [18F]-fluorocholine distribution. Mice with LNCaP, 22Rv1, or PC-3 PIP xenografts got [177Lu]Lu-PSMA-617 i.v. Sacrificed 1 h p.i. if coinjected with diagnostic tracers, otherwise at 20 min, 1-2, 12, 24, 48, 72 h, or 2-3 weeks p.i. Cryosectioned tumors imaged by autoradiography, adjacent sections Ki67 or PSMA stained. Results: Heterogeneous distribution of [177Lu]Lu-PSMA-617 was seen 20 min p.i., with visible overlap between tumor cells, Ki67, PSMA, and radioactivity at 1-2 h p.i. Strongest Ki67-correlation at 48 h, which became negative at 72 h and beyond with some Ki67+/PSMA+ low radioactivity areas. Uptake in necrotic tissue was only observed at 2-3 weeks p.i. PSMA-targeted tracers distributed identically to [177Lu]Lu-PSMA-617 whereas other tracers only had some overlap. Conclusion: Regrowth of the tumor post-[177Lu]Lu-PSMA-617 administration creates Ki67+/PSMA+ areas that have no radioactivity uptake and need additional therapy fractions. The identical intratumoral distribution of [177Lu]Lu-PSMA-617 and PSMA-targeted PET-tracers indicate that these will reveal the areas inside the tumor targeted by RPT at least at 1 h p.i.

Outcome and Renal Safety of PSMA-Targeted Radioligand Therapy in mCRPC Patients With Preexisting Impaired Renal Function.

This study aims to evaluate the outcome and renal safety of prostate-specific membrane antigen (PSMA)-radioligand therapy (RLT) in patients with metastatic castration-resistant prostate carcinoma (mCRPC) and preexisting renal impairment. Ninety-four patients with preexisting renal impairment were included in this retrospective analysis. Inclusion criterion was a glomerular filtration rate (GFR) of ≤60 mL/min (equivalent to Common Terminology Criteria of Adverse Events [CTCAE] ≥2). Patients underwent either [177Lu]Lu-PSMA-617 RLT exclusively (n = 63) or additionally in augmented manner with [225Ac]Ac-PSMA-617 (n = 31). The median number of administered cycles was 4 (range, 1-16 cycles) with a mean cumulative activity of 29.9 ± 16.3 GBq (range, 6.9-87.2 GBq) [177Lu]Lu-PSMA-617. Main blood parameters of interest were creatinine, cystatin C, and the respective GFR values. Changes in GFR were categorized according to CTCAE v5.0. In the entire cohort, mean best PSA response was -56.73% ± 45.71%, with 63 of 94 patients (67%) experiencing partial remission. The median progression-free survival and overall survival were 6.7 and 14.1 months, respectively. Under PSMA-RLT, 5 of 94 patients (5.3%) improved to CTCAE grade 0, and 23 of 94 (24.5%) improved to CTCAE grade 1. Three of 94 patients (3.2%) improved from CTCAE grade 3 to grade 2, and only 5 of 94 (5.3%) decreased. The majority (58/94 [61.7%]) of patients stayed stable in terms of CTCAE grading. PSMA-RLT is an effective and safe treatment in mCRPC patients with preexisting impaired renal function (CTCAE ≥2). In daily clinical practice, patients should not be categorically excluded from enrolment to PSMA-RLT due to renal impairment.

Diffuse Peritoneal Carcinomatosis of Prostate Cancer Unveiled by [89Zr]Zr-PSMA-617 PET/CT

Abstract We report an interesting case of a 64-year-old man with a history of radical prostatectomy for prostate cancer. The patient presented with steady increasing prostate-specific antigen levels, but with negative findings on previous multiple conventional prostate-specific membrane antigen (PSMA) PET/CT (with [68Ga]Ga-PSMA-11) and [18F]FDG PET/CT. A recently introduced PSMA tracer using long-lived 89Zr (half-life 3.3 days), [89Zr]Zr-PSMA-617, was administered in attempt to localize potential local recurrence or metastasis. [89Zr]Zr-PSMA-617 PET/CT clearly revealed diffuse peritoneal carcinomatosis and local recurrence of the prostate cancer, which were unidentified on previous conventional PET/CT scans. This case highly demonstrates the potential of PET imaging with the novel PSMA tracer [89Zr]Zr-PSMA-617.

68Ga]Ga-PSMA-617 PET/MRI for imaging patients suspected of hepatocellular carcinoma.

Radiolabeled probes targeting prostate-specific membrane antigen (PSMA) have been used in prostate cancer. Moreover, PSMA is also overexpressed on neovessels in hepatocellular carcinoma (HCC). This study aimed to preliminarily evaluate the diagnostic effectiveness of [68Ga]Ga-PSMA-617 PET/MRI for HCC. Patients suspected of HCC were prospectively enrolled in this single-center study (NCT05006326, 2021-08-16) to perform [68Ga]Ga-PSMA-617 PET/MRI, along with contrast enhanced CT (ceCT) or ceMRI. The main suspicious intrahepatic lesions were resected and pathologically verified. Visual evaluation of [68Ga]Ga-PSMA-617 PET/MRI images was performed on all lesions. Maximum standard uptake value (SUVmax), mean standard uptake value (SUVmean), tumor-to-liver ratio (TLR), tumor-to-blood ratio (TBR), and tumor-to-parotid ratio (TPR) were measured or calculated. The diagnostic efficiency of different modalities was summarized. PSMA expression was evaluated by immunohistochemistry and the correlation of PSMA expression and [68Ga]Ga-PSMA-617 uptake in HCC primary tumors was quantitatively analyzed. A total of 12 patients (ten men and two women; mean age 58.75 ± 12.08 years) were included. Ten patients were diagnosed with HCC, 2 with intrahepatic cholangiocarcinoma (ICC), and 4 with hemangioma. The SUVmax, TLR, TBR, and TPR of HCC primary tumors were higher than those of ICC and hemangioma. The diagnostic accuracy of [68Ga]Ga-PSMA-617 PET/MRI for primary HCC was 82.4%. When combined with ceCT or ceMRI, the accuracy increased to 88.2%. A moderate correlation was observed between SUVmax and mean PSMA expression in HCC primary tumors (R = 0.788). Utilizing a hybrid PET/MRI system to combine [68Ga]Ga-PSMA-617 PET/MRI with ceMRI is a promising one-stop solution for the accurate diagnosis of HCC. NCT05006326. Registered August 16, 2021, https://clinicaltrials.gov/study/NCT05006326 .

Prostate-Specific Membrane Antigen (PSMA) PET/CT in the Detection and Diagnosis of Hepatocellular Carcinoma (HCC): A Systematic Review and Meta-Analysis.

Prostate-specific membrane antigen (PSMA) positron emission tomography (PET) is widely used in prostate cancer. Recent studies indicate hepatocellular carcinoma (HCC) demonstrates PSMA PET uptake. The diagnostic accuracy of PSMA PET for HCC is not known. We conducted a systematic review and meta-analysis of studies assessing 68Ga-PSMA-11 in HCC. Nine studies were included, with 196 patients and a total of 491 HCC lesions. Per-patient analysis yielded a pooled sensitivity of 89.8% (95% CI 78.5-95.5). Specificity was poorly reported, with insufficient data. When per-lesion level analysis was performed on seven studies, the pooled sensitivity was 94.5% (95% CI 82.9-98.4), and specificity was again poorly reported with insufficient data. Among the three studies with adequate data for full per-lesion meta-analysis, 115 lesions in 41 patients demonstrated sensitivity of 97.1% (95% CI 87.8-99.4), while specificity was 42.2% (95% CI 0.3-99.4). Two studies provided sufficient data for meta-analysis on a per-patient level (n = 50 patients), demonstrating a sensitivity of 92.5% (95% CI 64.0-98.9) and specificity of 72.4% (95% CI 1.3-99.8). PSMA PET demonstrates a high sensitivity for HCC and shows promise as an imaging modality for diagnosis and staging of HCC. However, the existing literature does not provide enough data to confidently evaluate its specificity and, therefore, accuracy. Further prospective studies are necessary, with a focus on the accurate reporting of benign lesions and inclusion of patients with an intermediate probability of HCC.

Thapsigargin and its prodrug derivatives: exploring novel approaches for targeted cancer therapy through calcium signaling disruption.

Thapsigargin, a sesquiterpene lactone derived from Thapsia garganica L., has demonstrated mixed potential as an anticancer agent due to its potent ability to disrupt calcium signaling and induce apoptosis. This review evaluates the chemopreventive and chemotherapeutic potential of thapsigargin, focusing on its molecular mechanisms and toxicity. An extensive literature review of studies published since 2015 was conducted using databases such as PubMed/MedLine and Science Direct. Findings indicate that thapsigargin's primary mechanism is the inhibition of sarco/endoplasmic reticulum calcium ATPase, leading to endoplasmic reticulum stress and cell death in various cancer types. Despite these effects, thapsigargin's non-specific cytotoxicity results in significant side effects, including organ damage and histamine-related reactions. Recent advances in targeted delivery, especially with the prodrug mipsagargin, initially suggested promise in minimizing these toxicities by selectively activating in cancer cells expressing prostate-specific membrane antigen (PSMA). However, the completion of clinical trials with no ongoing studies suggests that the viability of mipsagargin and other prodrugs remains uncertain, especially in light of the toxicities observed. While thapsigargin and its derivatives present a potential pathway in cancer treatment, their future role in oncology requires careful re-evaluation.

Repurposing of PSMA-targeted diagnostic and therapeutic agents for the detection and treatment of giant cell tumors of bone.

Giant cell tumor of bone (GCTB) is a rare bone tumor often necessitating surgical intervention, radiation therapy, or treatment with bisphosphonates or denosumab. 99mTc-MDP bone scintigraphy for GCTB has limited specificity, and the relatively high uptake of 18F-FDG in GCTB makes it challenging to differentiate it from other benign bone tumors. More specific detection and treatment modalities for GCTB are needed to enhance patient monitoring and outcomes. Prostate Specific Membrane Antigen (PSMA) is present in the neovasculature of various tumors, yet unexplored in GCTB. PSMA-targeted imaging and radiotherapeutic agents Locametz and Pluvicto are a powerful theranostic pair for detecting and treating PSMA-positive metastatic tumors, including those in bone, and thus have considerable potential to be repurposed for GCTB. This study aimed to determine if the vasculature of GCTB was PSMA-positive and whether targeting it with PSMA-specific agents was feasible. Using bone core samples from 28 GCTB patients and 9 negative controls, we present the first robust detection of PSMA on the tumor vasculature of GCTB. To demonstrate the potential repurposed use of PSMA-targeted agents in detecting and treating GCTB, we used a PSMA-specific fluorescent probe (FAM-C6-1298) as a model for these radiopharmaceutical agents. Incubation of fresh GCTB tissue samples with FAM-C6-1298 showed increased fluorescence intensity compared to controls, indicating successful targeting of PSMA in GCTB tissue. In conclusion, our data established that PSMA is not only present in the tumor vasculature of GCTB patient tissue but can be effectively targeted with repurposed PSMA-specific radiopharmaceuticals for diagnosis and therapy.

A PSMA-targeted Tri-specific Killer Engager enhances NK cell cytotoxicity against prostate cancer.

Natural killer (NK) cell tumor infiltration is associated with good prognosis in patients with metastatic castration-resistant prostate cancer (mCRPC). NK cells recognize and kill targets by a process called natural cytotoxicity. We hypothesized that promoting an antigen-specific synapse with co-activation may enhance NK cell function in mCRPC. We describe a Tri-specific Killer Engager (TriKE) construct that engages with the activating receptor CD16 on NK cells, prostate-specific membrane antigen (PSMA) on mCRPC cells, and has an interleukin (IL)-15 moiety that is essential for NK cell survival, proliferation, and priming. We show that the PSMA TriKE specifically binds to PSMA-expressing cells and significantly enhances expansion, degranulation and cytokine production of NK cells derived from healthy donors or prostate cancer patients. Bystander killing of PSMA-negative was also achieved with PSMA TriKE treatment when co-cultured with PSMA-positive cells, suggesting potential PSMA TriKE benefit in controlling tumor antigen escape. When tested under physiologic conditions recapitulating the mCRPC tumor microenvironment (TME), NK cells treated with PSMA TriKE and prolonged exposure to hypoxia or MDSCs maintained their potent function while IL-15 treated NK cells showed greatly impaired cytotoxicity. Finally, in vivo testing of PSMA TriKE showed improved tumor control and survival of mice as compared to IL-15 and untreated control groups. In conclusion, PSMA TriKE demonstrates potential as a new therapy for advanced prostate cancer by providing additional signals to NK cells to maximize their anti-tumor potential in prostate cancer, especially in the setting of a hostile TME.

A novel androgen-independent radiotracer with dual targeting of NTSR1 and PSMA for PET/CT imaging of prostate cancer

A substantial proportion of patients with prostate cancer (PCa) develop treatment resistance or mortality after androgen deprivation therapy (ADT). Current methods for identifying and locating recurrent lesions using prostate-specific membrane antigen (PSMA)-based positron emission tomography (PET) imaging, which relies on androgen levels, often result in diagnostic delays. Therefore, the development of an androgen-independent radiotracer is critical for the early identification of recurrent lesions. The neurotensin receptor 1 (NTSR1) is highly expressed in androgen-independent PCa lesions. Here, we synthesized a bispecific ligand targeting PSMA and NTSR1 by solid-phase peptide synthesis and formulated a68Ga-labeled bispecific radiotracer, ([68Ga]Ga-NT-PSMA). This radiotracer exhibited a high radiochemical yield (71.27 % ± 1.58 %) and demonstrated an affinity for NTSR1 (39.32 ± 2.98 nM) and PSMA (63.47 ± 5.14 nM) in vitro. Small animal PET imaging showed comparable uptake of [68Ga]Ga-NT-PSMA and the monomeric radiotracer [68Ga]Ga-DOTA-NT20.3 in mice bearing androgen-independent PC3 (3.64 ± 0.49 %ID/g vs. 5.60 ± 1.42 %ID/g, nonsignificant [ns]) and DU145 tumors (2.49 ± 0.20 %ID/g vs. 2.34 ± 0.18 %ID/g, ns) at 90 min post-injection. In androgen-dependent 22Rv1 xenografts, [68Ga]Ga-NT-PSMA uptake was lower (1.94 ± 0.29 %ID/g) than [68Ga]Ga-PSMA-11 (3.94 ± 0.26 %ID/g, P < 0.001). Nevertheless, [68Ga]Ga-NT-PSMA effectively imaged all three xenograft types with high contrast, an achievement not possible with monomeric radiotracers alone. These results indicate that imaging with [68Ga]Ga-NT-PSMA is independent of the androgen dependence of the model, highlighting its potential as a promising nuclear medicine diagnostic tool for the early identification and localization of castration-resistant PCa lesions.