Prostate-specific membrane antigen-targeted surgery in prostate cancer: Accurate identification, real-time diagnosis, and precise resection.

Radical prostatectomy (RP) combined with pelvic lymph node dissection (PLND) is the first step in multimodal treatment of prostate cancer (PCa) without distant metastases. For a long time, the surgical resection range has been highly dependent on the surgeon's visualization and experience with preoperative imaging. With the rapid development of prostate-specific membrane antigen positron emission tomography and single-photon emission computed tomography (PSMA-PET and PSMA-SPECT), PSMA-targeted surgery has been introduced for a more accurate pathological diagnosis and complete resection of positive surgical margins (PSMs) and micro-lymph node metastases (LNMs). We reviewed PSMA-targeted surgeries, including PSMA-PET-guided prostatic biopsy (PSMA-TB), PSMA-targeted radio-guided surgery (PSMA-RGS), PSMA-targeted fluorescence-guided surgery (PSMA-FGS), and multi-modality/multi-targeted PSMA-targeted surgery. We also discuss the strengths and challenges of PSMA-targeted surgery, and propose that PSMA-targeted surgery could be a great addition to existing surgery protocols, thereby improving the accuracy and convenience of surgery for primary and recurrent PCa in the near future.

Deep learning-based whole-body PSMA PET/CT attenuation correction utilizing Pix-2-Pix GAN.

PURPOSE: Sequential PET/CT studies oncology patients can undergo during their treatment follow-up course is limited by radiation dosage. We propose an artificial intelligence (AI) tool to produce attenuation-corrected PET (AC-PET) images from non-attenuation-corrected PET (NAC-PET) images to reduce need for low-dose CT scans. METHODS: A deep learning algorithm based on 2D Pix-2-Pix generative adversarial network (GAN) architecture was developed from paired AC-PET and NAC-PET images. 18F-DCFPyL PSMA PET-CT studies from 302 prostate cancer patients, split into training, validation, and testing cohorts (n = 183, 60, 59, respectively). Models were trained with two normalization strategies: Standard Uptake Value (SUV)-based and SUV-Nyul-based. Scan-level performance was evaluated by normalized mean square error (NMSE), mean absolute error (MAE), structural similarity index (SSIM), and peak signal-to-noise ratio (PSNR). Lesion-level analysis was performed in regions-of-interest prospectively from nuclear medicine physicians. SUV metrics were evaluated using intraclass correlation coefficient (ICC), repeatability coefficient (RC), and linear mixed-effects modeling. RESULTS: Median NMSE, MAE, SSIM, and PSNR were 13.26%, 3.59%, 0.891, and 26.82, respectively, in the independent test cohort. ICC for SUVmax and SUVmean were 0.88 and 0.89, which indicated a high correlation between original and AI-generated quantitative imaging markers. Lesion location, density (Hounsfield units), and lesion uptake were all shown to impact relative error in generated SUV metrics (all p < 0.05). CONCLUSION: The Pix-2-Pix GAN model for generating AC-PET demonstrates SUV metrics that highly correlate with original images. AI-generated PET images show clinical potential for reducing the need for CT scans for attenuation correction while preserving quantitative markers and image quality.

Design, synthesis and evaluation of novel prostate-specific membrane antigen-targeted aryl [18F]fluorosulfate PET tracers.

The expression of prostate-specific membrane antigen (PSMA) in prostate cancer is 100-1000 times higher than that in normal tissues, and it has shown great advantages in the diagnosis and treatment of prostate cancer. The combination of PSMA and PET imaging technology based on the principle of metabolic imaging can achieve high sensitivity and high specificity for diagnosis. Due to its suitable half-life (109 min) and good positron abundance (97%), as well as its cyclotron accelerated generation, 18F has the potential to be commercialize, which has attracted much attention. In this article, we synthesized a series of fluorosulfate PET tracers targeting PSMA. All four analogues have shown high affinity to PSMA (IC50 = 1.85-5.15 nM). After the radioisotope exchange labeling, [18F]L9 and [18F]L10 have PSMA specific cellular uptake (0.65 ± 0.04% AD and 1.19 ± 0.03% AD) and effectively accumulated in 22Rv1 xenograft mice model. This study demonstrates that PSMA-1007-based PSMA-targeted aryl [18F]fluorosulfate novel tracers have the potential for PET imaging in tumor tissues.

Dual FDG/PSMA PET imaging to predict lesion-based progression of mCRPC during PSMA-RLT.

Candidates for prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT) of metastatic castration-resistant prostate cancer (mCRPC) frequently have "mismatch" lesions with pronounced 18-fluorodeoxyglucose ([18F]FDG) but attenuated PSMA ligand uptake on positron emission tomography (PET). However, no quantitative criteria yet exist to identify mismatch lesions and predict their response to RLT. To define such criteria, we retrospectively analyzed 267 randomly-selected glucometabolic mCRPC metastases from 22 patients. On baseline PET, we determined [18F]FDG and [68Ga]Ga-PSMA-11 maximum standardized uptake value (SUVmax), and calculated the [18F]FDG SUVmax/[68Ga]Ga-PSMA-11 SUVmax quotient (FPQ). From follow-up [18F]FDG PET after two lutetium-177-PSMA-617 RLT cycles, we evaluated the treatment response and categorized the lesions into three subgroups (partial remission, stable disease, progression) based on change in [18F]FDG SUVmax. Lastly, we compared the baseline PET variables in progressing versus non-progressing lesions. Variables differing significantly, and a score incorporating them, were assessed via receiver operator characteristic (ROC) curve analysis, regarding ability to predict lesional progression, with area under the curve (AUC) as metric. Cut-offs with optimal sensitivity and specificity were determined using the maximum value of Youden's index. Fifty-one of 267 lesions (19.1%) progressed, 102/267 (38.2%) manifested stable disease, and 114/267 (42.7%) partially responded after two RLT cycles. At baseline, median [68Ga]Ga-PSMA-11 SUVmax was significantly lower (p < 0.001), median FPQ significantly higher (p < 0.001), and median [18F]FDG SUVmax similar in progressing versus non-progressing lesions. [68Ga]Ga-PSMA-11 SUVmax and FPQ showed predictive power regarding progression (AUCs: 0.89, 0.90). An introduced clinical score combining both further improved predictive performance (AUC: 0.94). Optimal cut-offs to foretell progression were: [68Ga]Ga-PSMA-11 SUVmax < 11.09 (88.2% sensitivity, 81.9% specificity), FPQ ≥ 0.92 (90.2% sensitivity, 78.7% specificity), clinical score ≥ 6/9 points (88.2% sensitivity, 87.5% specificity). At baseline, a low [68 Ga]Ga-PSMA-11 SUVmax and a high FPQ predict early lesional progression under RLT; [18F]FDG SUVmax does not. A score combining [68 Ga]Ga-PSMA-11 SUVmax and FPQ predicts early lesional progression even more effectively and might therefore be useful to quantitatively identify mismatch lesions.

PSMA-Targeted Radiopharmaceuticals for Prostate Cancer Diagnosis and Therapy.

ABSTRACT: Prostate cancer (PCa) is the most common noncutaneous malignancy in men. Until recent years, accurate imaging of men with newly diagnosed PCa, or recurrent or low-volume metastatic disease, was limited. Further, therapeutic options for men with advanced, metastatic, castration-resistant disease were increasingly limited as a result of increasing numbers of systemic therapies being combined in the upfront metastatic setting. The advent of urea-based, small-molecule inhibitors of prostate-specific membrane antigen (PSMA) has partially addressed those shortcomings in diagnosis and therapy of PCa. On the diagnostic side, there are multiple pivotal phase III trials with several different agents having demonstrated utility in the initial staging setting, with generally modest sensitivity but very high specificity for determining otherwise-occult pelvic nodal involvement. That latter statistic drives the utility of the scan by allowing imaging interpreters to read with very high sensitivity while maintaining a robust specificity. Other pivotal phase III trials have demonstrated high detection efficiency in patients with biochemical failure, with high positive predictive value at the lesion level, opening up possible new avenues of therapy such as metastasis-directed therapy. Beyond the diagnostic aspects of PSMA-targeted radiotracers, the same urea-based chemical scaffolds can be altered to deliver therapeutic isotopes to PCa cells that express PSMA. To date, one such agent, when combined with best standard-of-care therapy, has demonstrated an ability to improve overall survival, progression-free survival, and freedom from skeletal events relative to best standard-of-care therapy alone in men with metastatic, castration-resistant PCa who are post chemotherapy. Within the current milieu, there are a number of important future directions including the use of artificial intelligence to better leverage diagnostic findings, further medicinal chemistry refinements to the urea-based structure that may allow improved tumor targeting and decreased toxicities, and the incorporation of new radionuclides that may better balance efficacy with toxicities than those nuclides that are available.

Exploring the role of combined external beam radiotherapy and targeted radioligand therapy with [177Lu]Lu-PSMA-617 for prostate cancer - from bench to bedside.

Management of prostate cancer (PC) might be improved by combining external beam radiotherapy (EBRT) and prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT) with lutetium-177 (177Lu)-labeled PSMA inhibitors. We hypothesized a higher efficacy of the combination due to augmentation of the radiation dose to the tumor and interactions of EBRT with PSMA expression potentially increasing radiopharmaceutical uptake. Therefore, this study analyzed the influence of radiation on PSMA expression levels in vitro. The results were translated to evaluate the efficacy of the combination of photon EBRT and [177Lu]Lu-PSMA-617 in a murine PC xenograft model. Finally, a clinical case report on a combined elective field EBRT with RLT dose escalation illustrates a proof-of-concept. Methods: PSMA gene and protein expression were assessed in human PSMA-overexpressing LNCaP cells after irradiation using reverse transcription quantitative polymerase chain reaction (RT-qPCR), flow cytometry and On-Cell Western assays. In the in vivo therapy study, LNCaP tumor-bearing BALB/c nu/nu mice were irradiated once with 2 Gy X-ray EBRT and injected with 40 MBq [177Lu]Lu-PSMA-617 after 4 h or received single or no treatment (n = 10 each). Tumor-absorbed doses by [177Lu]Lu-PSMA-617 were calculated according to the Medical Internal Radiation Dosimetry (MIRD) formalism after deriving time-activity curves using a gamma probe. An exemplified patient case is demonstrated where fractionated EBRT (54 Gy to prostate; 45 Gy to pelvic lymphatics) and three cycles of [177Lu]Lu-PSMA-617 (3.4-6.0 GBq per cycle) were sequentially combined under concurrent androgen deprivation for treating locally advanced PC. Results: At 4 h following irradiation with 2-8 Gy, LNCaP cells displayed a PSMA protein upregulation by around 18% relative to non-irradiated cells, and a stronger upregulation on mRNA level (up to 2.6-fold). This effect was reversed by 24 h when PSMA protein levels were downregulated by up to 22%. Mice treated with the combination therapy showed significantly improved outcomes regarding tumor control and median survival (p < 0.0001) as compared to single or no treatment. Relative to monotherapy with PSMA-RLT or EBRT, the tumor doubling time was prolonged 1.7- or 2.7-fold and the median survival was extended by 24% or 60% with the combination, respectively. Additionally, tumors treated with EBRT exhibited a 14% higher uptake of the radiopharmaceutical as evident from the calculated tumor-absorbed dose, albeit with high variability in the data. Concerning the patient case, the tri-modality treatment was well tolerated and the patient responded with a long-lasting complete biochemical remission for five years following end of PSMA-RLT. The patient then developed a biochemical relapse with oligo-recurrent disease on follow-up imaging. Conclusion: The present preclinical and clinical data demonstrate that the combination of EBRT with dose escalation by PSMA-RLT improves tumor control and potentially prolongs survival. This may pave the way for further clinical investigations of this approach to explore the curative potential of the combination therapy.

Plasmodium yoelii surface-related antigen (PySRA) modulates the host pro-inflammatory responses via binding to CD68 on macrophage membrane.

Malaria, one of the major infectious diseases in the world, is caused by the Plasmodium parasite. Plasmodium antigens could modulate the inflammatory response by binding to macrophage membrane receptors. As an export protein on the infected erythrocyte membrane, Plasmodium surface-related antigen (SRA) participates in the erythrocyte invasion and regulates the immune response of the host. This study found that the F2 segment of P. yoelii SRA activated downstream MAPK and NF-κB signaling pathways by binding to CD68 on the surface of the macrophage membrane and regulating the inflammatory response. The anti-PySRA-F2 antibody can protect mice against P. yoelii, and the pro-inflammatory responses such as IL-1ß, TNF-α, and IL-6 after infection with P. yoelii are attenuated. These findings will be helpful for understanding the involvement of the pathogenic mechanism of malaria with the exported protein SRA.

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

PURPOSE: 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. EXPERIMENTAL DESIGN: 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. RESULTS: 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. CONCLUSIONS: 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.

Prostate-Specific Membrane Antigen-Avid Neurofibroma Mimicking Cutaneous Metastasis in Metastatic Castration-Resistant Prostate Cancer on 18 F-PSMA-1007 PET/CT.

ABSTRACT: The occurrence of cutaneous metastases in prostate cancer is exceedingly rare. Many benign lesions and nonprostatic cancers can express the prostate-specific membrane antigen (PSMA). They can potentially mimic metastasis of prostate cancer and lead to misinterpretation of PSMA PET/CT findings. Additionally, it has significant management and prognostic implications. We present a rare case of an 88-year-old man with metastatic castration-resistant prostate cancer who showed a PSMA-expressing subcutaneous nodule in the scalp on 18 F-PSMA-1007 PET/CT, raising the suspicion of cutaneous metastasis. However, its biopsy revealed a neurofibroma, altering the disease prognosis and management.

Heterogeneous PSMA ligand uptake inside parotid glands.

The purpose of this investigation is to quantify the spatial heterogeneity of prostate-specific membrane antigen (PSMA) positron emission tomography (PET) uptake within parotid glands. We aim to quantify patterns in well-defined regions to facilitate further investigations. Furthermore, we investigate whether uptake is correlated with computed tomography (CT) texture features. METHODS: Parotid glands from [18F]DCFPyL PSMA PET/CT images of 30 prostate cancer patients were analyzed. Uptake patterns were assessed with various segmentation schemes. Spearman's rank correlation coefficient was calculated between PSMA PET uptake and feature values of a Grey Level Run Length Matrix using a long and short run length emphasis (GLRLML and GLRLMS) in subregions of the parotid gland. RESULTS: PSMA PET uptake was significantly higher (p < 0.001) in lateral/posterior regions of the glands than anterior/medial regions. Maximum uptake was found in the lateral half of parotid glands in 50 out of 60 glands. The difference in SUVmean between parotid halves is greatest when parotids are divided by a plane separating the anterior/medial and posterior/lateral halves symmetrically (out of 120 bisections tested). PSMA PET uptake was significantly correlated with CT GLRLML (p < 0.001), and anti-correlated with CT GLRLMS (p < 0.001). CONCLUSION: Uptake of PSMA PET is heterogeneous within parotid glands, with uptake biased towards lateral/posterior regions. Uptake within parotid glands was strongly correlated with CT texture feature maps.

A PSMA-targeted doxorubicin small-molecule drug conjugate.

We developed a model small-molecule drug conjugate (SMDC) that employed doxorubicin as a representative chemotherapeutic targeted to the cell membrane biomarker PSMA (prostate-specific membrane antigen) expressed on prostate cancer cells. The strategy capitalized on the clatherin-mediated internalization of PSMA to facilitate the selective uptake and release of doxorubicin in the target cells. The SMDC was prepared and assessed for binding kinetics, plasma stability, cell toxicity, and specificity towards PSMA expressing prostate cancer cell lines. We observed high affinity of the SMDC for PSMA (IC50 5 nM) with irreversible binding, as well as specific effectiveness against PSMA(+) cells. These findings validated the strategy for a small molecule-based approach in targeted cancer therapy.

A multicentric, single arm, open-label, phase I/II study evaluating PSMA targeted radionuclide therapy in adult patients with metastatic clear cell renal cancer (PRadR).

BACKGROUND: Despite advancements in managing metastatic clear cell renal carcinoma (mccRCC) through antiangiogenic tyrosine kinase inhibitors and immunotherapy, there remains a demand for novel treatments for patients experiencing progression despite the use of these medications. There is currently no established standard treatment for patients receiving third therapy line. Prostate Specific Membrane Antigen (PSMA) whose high expression has been demonstrated in metastatic aggressive prostate adenocarcinoma is also highly expressed in neovessels of various solid tumors including renal cell carcinoma (RCC): 86% of clear cell RCC, 61% of chromophobe RCC, and 28% of papillary RCC. Therefore, PSMA may be a target expressed in metastatic ccRCC for radionuclide therapy using PSMA ligands radiolabeled with Lutetium-177 (PRLT). 177Lu-PSMA delivers ß-particle radiation to PSMA-expressing cells and the surrounding microenvironment with demonstrated efficacy in metastatic prostate cancer. METHODS: This is a multicenter phase I/II study designed to assess the tolerability and effectiveness of 177Lu-PSMA-1 in individuals with PSMA-positive metastatic clear cell renal cell carcinoma (ccRCC), identified through 68Ga-PSMA PET, conducted in France (PRadR). 48 patients will be treated with 4 cycles of 7.4 GBq of 177Lu-PSMA-1 every 6 weeks. The primary objective is to evaluate the safety of 177Lu-PSMA-1 (phase I) and the efficacy of 177Lu-PSMA-1 in mccRCC patients (phase II). Primary endpoints are incidence of Severe Toxicities (ST) occurring during the first cycle (i.e. 6 first weeks) and disease Control Rate after 24 weeks of treatment (DCR24w) as per RECIST V1.1. Secondary objective is to further document the clinical activity of 177Lu-PSMA-1 in mccRCC patients (duration of response (DoR), best overall response rate (BORR), progression fee survival (PFS) and overall survival (OS). DISCUSSION: Our prospective study may lead to new potential indications for the use of 177Lu-PSMA-1 in mccRCC patients and should confirm the efficacy and safety of this radionuclide therapy with limited adverse events. The use of 177Lu-PSMA-1may lead to increase disease control, objective response rate and the quality of life in mccRCC patients. TRIAL REGISTRATION: ClinicalTrials.gov: NCT06059014.

Development and Preclinical Evaluation of [211At]PSAt-3-Ga: An Inhibitor for Targeted α-Therapy of Prostate Cancer.

The application of prostate-specific membrane antigen (PSMA)-targeted α-therapy is a promising alternative to ß--particle-based treatments. 211At is among the potential α-emitters that are favorable for this concept. Herein, 211At-based PSMA radiopharmaceuticals were designed, developed, and evaluated. Methods: To identify a 211At-labeled lead, a surrogate strategy was applied. Because astatine does not exist as a stable nuclide, it is commonly replaced with iodine to mimic the pharmacokinetic behavior of the corresponding 211At-labeled compounds. To facilitate the process of structural design, iodine-based candidates were radiolabeled with the PET radionuclide 68Ga to study their preliminary in vitro and in vivo properties before the desired 211At-labeled lead compound was formed. The most promising candidate from this evaluation was chosen to be 211At-labeled and tested in biodistribution studies. Results: All 68Ga-labeled surrogates displayed affinities in the nanomolar range and specific internalization in PSMA-positive LNCaP cells. PET imaging of these compounds identified [68Ga]PSGa-3 as the lead compound. Subsequently, [211At]PSAt-3-Ga was synthesized in a radiochemical yield of 35% and showed tumor uptake of 19 ± 8 percentage injected dose per gram of tissue (%ID/g) at 1 h after injection and 7.6 ± 2.9 %ID/g after 24 h. Uptake in off-target tissues such as the thyroid (2.0 ± 1.1 %ID/g), spleen (3.0 ± 0.6 %ID/g), or stomach (2.0 ± 0.4 %ID/g) was low, indicating low in vivo deastatination of [211At]PSAt-3-Ga. Conclusion: The reported findings support the use of iodine-based and 68Ga-labeled variants as a convenient strategy for developing astatinated compounds and confirm [211At]PSAt-3 as a promising radiopharmaceutical for targeted α-therapy.

Potent CTLs can be induced against tumor cells in an environment of lower levels of systemic MFG-E8.

The direction and magnitude of immune responses are critically affected when dead cells are disposed of. Milk fat globule-epidermal growth factor-factor 8 (MFG-E8) promotes the engulfment of apoptotic normal and cancerous cells without inducing inflammation. We have previously reported that a certain proportion of the cancer cells express abundant MFG-E8, and that such expression is associated with the shorter survival of patients with esophageal cancer who had received chemotherapy before surgery. However, the influence of tumor-derived and systemically existing MFG-E8 on antitumor immune responses has not yet been fully investigated. Herein, we showed that CTL-dependent antitumor immune responses were observed in mice with no or decreased levels of systemic MFG-E8, and that such responses were enhanced further with the administration of anti-PD-1 antibody. In mice with decreased levels of systemic MFG-E8, the dominance of regulatory T cells in tumor-infiltrating lymphocytes was inverted to CD8+ T cell dominance. MFG-E8 expression by tumor cells appears to affect antitumor immune responses only when the level of systemic MFG-E8 is lower than the physiological status. We have also demonstrated in the clinical setting that lower levels of plasma MFG-E8, but not MFG-E8 expression in tumor cells, before the treatment was associated with objective responses to anti-PD-1 therapy in patients with non-small cell lung cancer. These results suggest that systemic MFG-E8 plays a critical role during the immunological initiation process of antigen-presenting cells to increase tumor-specific CTLs. Regulation of the systemic level of MFG-E8 might induce efficient antitumor immune responses and enhance the potency of anti-PD-1 therapy.

Breast cancer malignancy is governed by regulation of the macroH2A2/TM4SF1 axis, the AKT/NF-κB pathway, and elevated MMP13 expression.

The histone variant, macroH2A (mH2A) influences gene expression through epigenetic regulation. Tumor suppressive function of mH2A isoforms has been reported in various cancer types, but few studies have investigated the functional role of mH2A2 in breast cancer pathophysiology. This study aimed to determine the significance of mH2A2 in breast cancer development and progression by exploring its downstream regulatory mechanisms. Knockdown of mH2A2 facilitated the migration and invasion of breast cancer cells, whereas its overexpression exhibited the opposite effect. In vivo experiments revealed that augmenting mH2A2 expression reduced tumor growth and lung metastasis. Microarray analysis showed that TM4SF1 emerged as a likely target linked to mH2A2 owing to its significant suppression in breast cancer cell lines where mH2A2 was overexpressed among the genes that exhibited over twofold upregulation upon mH2A2 knockdown. Suppressing TM4SF1 reduced the migration, invasion, tumor growth, and metastasis of breast cancer cells in vitro and in vivo. TM4SF1 depletion reversed the increased aggressiveness triggered by mH2A2 knockdown, suggesting a close interplay between mH2A2 and TM4SF1. Our findings also highlight the role of the mH2A2/TM4SF1 axis in activating the AKT/NF-κB pathway. Consequently, activated NF-κB signaling leads to increased expression and secretion of MMP13, a potent promoter of metastasis. In summary, we propose that the orchestrated regulation of the mH2A2/TM4SF1 axis in conjunction with the AKT/NF-κB pathway and the subsequent elevation in MMP13 expression constitute pivotal factors governing the malignancy of breast cancer.

PTP1B mediates the inhibitory effect of MFGE8 on insulin signaling through the ß5 integrin.

Integrins are cell adhesion receptors that dimerize to mediate cell-cell interactions and regulate processes, including proliferation, inflammation, and tissue repair. The role of integrins in regulating insulin signaling is incompletely understood. We have previously shown that binding of the integrin ligand milk fat globule epidermal growth factor like 8 (MFGE8) to the αvß5 integrin promotes termination of insulin receptor signaling in mice. Upon ligation of MFGE8, integrin ß5 complexes with the insulin receptor beta (IRß) in skeletal muscle, resulting in dephosphorylation of IRß and reduction of insulin-stimulated glucose uptake. Here, we investigate the mechanism by which the interaction between ß5 and IRß impacts IRß phosphorylation status. We show in in vitro and in vivo in skeletal muscle in mice that antibody-mediated blockade of the ß5 integrin inhibits and recombinant MFGE8 promotes PTP1B binding to and dephosphorylation of IRß resulting in increased or reduced insulin-stimulated glucose uptake, respectively. The ß5-PTP1B complex is recruited by MFGE8 to IRß leading to termination of canonical insulin signaling. ß5 blockade enhances insulin-stimulated glucose uptake in wildtype but not Ptp1b KO mice indicating that PTP1B functions downstream of MFGE8 in modulating insulin receptor signaling. Furthermore, in a human cohort, we report serum MFGE8 levels correlate with indices of insulin resistance. These data provide mechanistic insights into the role of MFGE8 and ß5 in regulating insulin signaling.

Radiochemistry and In Vivo Imaging of [45Ti]Ti-THP-PSMA.

Titanium-45 (45Ti) is a radionuclide with excellent physical characteristics for use in positron emission tomography (PET) imaging, including a moderate half-life (3.08 h), decay by positron emission (85%), and a low mean positron energy of 0.439 MeV. However, challenges associated with titanium chemistry have led to the underdevelopment of this radionuclide for incorporation into radiopharmaceuticals. Expanding on our recent studies, which showed promising results for the complexation of 45Ti with the tris hydroxypyridinone (THPMe) chelator, the current work aimed to optimize the chemistry and imaging attributes of [45Ti]Ti-THP-PSMA as a new PET radiopharmaceutical. Methods. Radiolabeling of THP-PSMA was optimized with [45Ti]Ti-citrate at varying pHs and masses of the precursor. The stability of the radiolabeled complex was assessed in mouse serum for up to 6 h. The affinity of [45Ti]Ti-THP-PSMA for prostate-specific membrane antigen (PSMA) was assessed using LNCaP (PSMA +) and PC3 (PSMA -) cell lines. In vivo imaging and biodistribution analysis were performed in tumor-bearing xenograft mouse models to confirm the specificity of the tumor uptake. Results. > 95% of radiolabeling was achieved with a high specific activity of 5.6 MBq/nmol under mild conditions. In vitro cell binding studies showed significant binding of the radiolabeled complex with the PSMA-expressing LNCaP cell line (11.9 ± 1.5%/mg protein-bound activity) compared to that with the nonexpressing PC3 cells (1.9 ± 0.4%/mg protein-bound activity). In vivo imaging and biodistribution studies confirmed specific uptake in LNCaP tumors (1.6 ± 0.27% ID/g) compared to that in PC3 tumors (0.39 ± 0.2% ID/g). Conclusion. This study showed a simple one-step radiolabeling method for 45Ti with THP-PSMA under mild conditions (pH 8 and 37 °C). In vitro cell studies showed promise, but in vivo tumor xenograft studies indicated low tumor uptake. Overall, this study shows the need for more chelators for 45Ti for the development of a PET radiopharmaceutical for cancer imaging.

First-in-human study of PSMA-targeting agent, [18F]AlF-P16-093: dosimetry and initial evaluation in prostate cancer patients.

PURPOSE: This is a first-in-human study to evaluate the radiation dosimetry of a new prostate-specific membrane antigen (PSMA)-targeted radiopharmaceutical, [18F]AlF-P16-093, and also initial investigation of its ability to detect PSMA-positive tumors using PET scans in a cohort of prostate cancer (PCa) patients. METHODS: The [18F]AlF-P16-093 was automatically synthesized with a GE TRACERlab. A total of 23 patients with histopathologically proven PCa were prospectively enrolled. Dosimetry and biodistribution study investigations were carried out on a subset of six (6) PCa patients, involving multiple time-point scanning. The mean absorbed doses were estimated with PMOD and OLINDA software. RESULTS: [18F]AlF-P16-093 was successfully synthesized, and radiochemical purity was > 95%, and average labeling yield was 36.5 ± 8.3% (decay correction, n = 12). The highest tracer uptake was observed in the kidneys, spleen, and liver, contributing to an effective dose of 16.8 ± 1.3 µSv/MBq, which was ~ 30% lower than that of [68Ga]Ga-P16-093. All subjects tolerated the PET examination well, and no reportable side-effects were observed. The PSMA-positive tumors displayed rapid uptake, and they were all detectable within 10 min, and no additional lesions were observed in the following multi-time points scanning. Each patient had at least one detectable tumor lesion, and a total of 356 tumor lesions were observed, including intraprostatic, lymph node metastases, bone metastases, and other soft tissue metastases. CONCLUSIONS: We report herein a streamlined method for high yield synthesis of [18F]AlF-P16-093. Preliminary study in PCa patients has demonstrated its safety and acceptable radiation dosimetry. The initial diagnostic study indicated that [18F]AlF-P16-093 PET/CT is efficacious and potentially useful for a widespread application in the diagnosis of PCa patients.