Background:Antihypertensive drug targets are associated with various cancers, but their relationship with clear cell renal cell carcinoma (CCRCC) risk remains unclear. Methods:Summary-data-based Mendelian randomization (SMR) and colocalization analyses were performed. Four antihypertensive drug targets (ACE, ADRB1, ADRB2, and SLC12A3) and CCRCC were included. Patients with CCRCC were identified from two large GWAS databases, including 752,817 and 315,137 individuals (Finnish cohorts), for the discovery and external validation analyses, respectively. Meta-analysis was conducted to integrate the results from both cohorts. Western blotting and prognostic analyses of tumor survival revealed the relationship between ADRB1 and CCRCC. Results:ADRB1 was associated with CCRCC risk in both the discovery and validation cohorts (odds ratio (OR): 1.097, per standard deviation unit (SD) change in antihypertensive drug target perturbation equivalent to 1 SD unit of decreased blood pressure; 95% confidence interval (95% CI): 1.063-1.132; P-value = 0.016) vs. OR: 1.284; 95% CI: 1.014-1.627; P-value = 0.013). ADRB2 was associated with CCRCC risk in discovery cohort (OR: 1.224; 95% CI: 1.045-1.433; P-value = 0.019). Integrated outcomes demonstrated that both ADRB1 (OR: 1.100; 95% CI: 1.066-1.135; P-value<0.0001) and ADRB2 (OR: 1.313; 95% CI: 1.137-1.517; P-value = 0.0002) were associated with CCRCC risk. Colocalization analyses indicated that ADRB1 (PP4 = 0.996) and ADRB2 (PP4 = 0.895) shared the same region of genetic variation with CCRCC. Furthermore, ADRB1 was highly expressed in CCRCC tumor tissues and was associated with poor tumor survival and prognosis. Conclusion:ADRB1 was associated with the risk of CCRCC, providing additional perspectives into potential treatment strategies for CCRCC.

Osteosarcoma (OS) is the most common primary malignant bone tumor in children and adolescents, characterized by aggressive behavior and poor prognosis. Despite advances in multimodal therapies, outcomes for patients with metastatic or recurrent OS remain poor. Non-SMC Condensin II Complex Subunit D3 (NCAPD3) is a core component of the condensin II complex involved in chromosome condensation and segregation; however, its role in OS progression and the tumor immune microenvironment remains unclear. Publicly available transcriptomic datasets were analyzed to evaluate NCAPD3 expression and prognostic relevance in OS. Using single-cell RNA sequencing (scRNA-seq; n = 6), we characterized tumor cell heterogeneity and NCAPD3-expressing subsets within the osteosarcoma tumor microenvironment. In vitro, NCAPD3 knockdown was performed in RAW264.7 macrophages, primary murine macrophages, and THP-1–derived macrophages to assess changes in macrophage polarization markers at the transcriptional and protein levels. Functional assays, including conditioned-media experiments, evaluated tumor–macrophage crosstalk. The effects of NCAPD3 on osteosarcoma cell proliferation, migration, and tumor growth were assessed in vitro and in vivo. Pathway enrichment analyses were conducted in NCAPD3⁺ macrophages and tumor cells, and in silico drug sensitivity prediction was performed as an exploratory analysis. NCAPD3 was significantly overexpressed in OS tissues and associated with poorer overall survival. scRNA-seq analysis identified distinct tumor cell subsets and a population of NCAPD3⁺ macrophages characterized by reduced inflammatory activity. NCAPD3 knockdown in macrophages consistently upregulated pro-inflammatory markers and downregulated anti-inflammatory markers, indicating a shift toward a pro-inflammatory phenotype. Conditioned-media experiments demonstrated that NCAPD3-dependent tumor–macrophage crosstalk regulates osteosarcoma cell proliferation and migration. Pathway analyses revealed downregulation of IL2/STAT5 and IL6/JAK/STAT3 signaling in NCAPD3⁺ macrophages, while NCAPD3⁺ tumor cells exhibited reduced apoptotic signaling and enhanced DNA repair and PI3K/AKT/mTOR pathway activity. Functional assays confirmed that NCAPD3 promotes osteosarcoma cell growth and tumor progression in vitro and in vivo. NCAPD3 promotes osteosarcoma progression through coordinated effects on tumor cell proliferation and suppression of macrophage-mediated inflammatory responses. These findings identify NCAPD3 as a context-dependent regulator of tumor–immune interactions in OS and support its potential as a prognostic biomarker and therapeutic target.

TPS5148 Background: Oligometastatic hormone-sensitive prostate cancer (omHSPC), defined by ≤5 metastases, represents a distinct disease state with a more favorable prognosis, offering a critical window for treatment intensification aimed at improving long-term outcomes. Cytoreductive radical prostatectomy (cRP) has emerged as a feasible local treatment option for select patients, with phase II data suggesting a survival benefit over systemic therapy alone. The foundation of systemic therapy for metastatic HSPC (mHSPC) is an androgen receptor pathway inhibitor (ARPI) combined with androgen deprivation therapy (ADT). Rezvilutamide, a second-generation ARPI, demonstrated superior efficacy over bicalutamide when combined with ADT in patients with mHSPC. Furthermore, the addition of docetaxel to an ARPI and ADT (triplet therapy) significantly improved survival in mHSPC, including in patients with low metastatic burden. We hypothesize that intensifying neoadjuvant systemic therapy with triplet therapy prior to cRP may maximize tumor cytoreduction and pathologic response in omHSPC. Methods: This is a prospective, open-label, parallel-cohort, multicenter phase II study. Patients with newly diagnosed, biopsy-proven omHSPC (≤5 bone or lymph node metastases on conventional imaging, no visceral metastases) who are candidates for and desire cRP are eligible. All patients undergo baseline prostate-specific membrane antigen positron emission tomography/computed tomography (PSMA-PET/CT) prior to ADT initiation. Patients select their neoadjuvant regimen: Cohort A receives ADT plus oral rezvilutamide (240 mg daily) for 24 weeks; Cohort B receives ADT, rezvilutamide (same dose), plus docetaxel (75 mg/m² IV q3w for 6 cycles) for 24 weeks. Upon completion of the 24-week neoadjuvant therapy, metastases are reconfirmed by conventional imaging, and a second PSMA-PET/CT assessment is performed. All patients subsequently undergo cRP with extended pelvic lymph node dissection within 6 weeks. After surgery, patients may opt to continue with ADT or rezvilutamide at their discretion until disease progression. Based on assumed pCR rates of <10% (Cohort A) and 25% (Cohort B) (α=0.05, power=80%), 40 evaluable patients are required per cohort. Accounting for 20% dropout, 100 total patients (50 per cohort) will be enrolled. Key inclusion criteria: ECOG PS 0-1, adequate organ function. Key exclusion criteria: prior systemic therapy for PCa (except ≤4 weeks of ADT), prior second-generation ARPI use, and prostate pathology results indicating neuroendocrine carcinoma. As of January 15, 2026, enrollment is ongoing with 6 patients accrued to date. No data analysis has been performed. Clinical trial information: ChiCTR2400093262.

Objective Recent studies have shown that 68Ga-prostate-specific membrane antigen (68Ga-PSMA) positron emission tomography/computed tomography (PET/CT) can open a non-invasive diagnostic pathway in prostate cancer (PCa). However, the relatively small number of enrolled patients in these studies limits statistical validation and causes bias to some extent. In addition, the performance of 68Ga-PSMA PET/CT radiomics analysis in detecting PCa has not been widely evaluated. Hence, the present multicenter study endeavored to develop and validate radiomics models based on 68Ga-PSMA PET/CT for the detection of primary PCa in a relatively larger cohort. Methods This study enrolled consecutive patients with suspected PCa who underwent systematic biopsy (SB) and PSMA PET/CT-targeted biopsy (TB) after 68Ga-PSMA PET/CT in three medical centers. The whole prostate gland was adopted as the volume of interest (VOI). Eight machine learning (ML) algorithms were utilized to develop models with selected radiomics features separately, after which the best-performing radiomics model was integrated with maximum standardized uptake value (SUVmax) to create the combined model. The receiver operating characteristic (ROC) curves and area under the curve (AUC) value, accuracy, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated for each model. Results Overall, 609 patients were recruited, including 195 patients with benign prostate diseases (BPD), 30 patients with clinically insignificant prostate cancer (ciPCa, Gleason score [GS] = 3 + 3), and 384 patients with clinically significant prostate cancer (csPCa, GS ≥ 3 + 4). For csPCa prediction, the radiomics model developed by the eXtreme Gradient Boosting (XGBoost) algorithm demonstrated the best performance. After integrating with SUVmax, the combined model achieved the highest AUC of 0.921 in internal validation cohort. External validation cohort 1 and 2 also showed promising results with AUC of 0.906 and 0.898, respectively. For PCa prediction, the XGBoost algorithm combined with SUVmax also peformed well in three validation cohorts with the AUC ranging from 0.860 to 0.918. Conclusions This is the largest multicenter study to date, providing a noninvasive and quantitative method based on 68Ga-PSMA PET/CT radiomics analysis modeled with ML for predicting PCa. This method has the potential to gauge the risk of PCa before biopsy.

e17090 Background: The ARASENS trial established that androgen deprivation therapy (ADT) combined with Darolutamide and Docetaxel improves survival in mHSPC. Given the lower chemotherapy tolerance reported in Asian populations and the paucity of Chinese real-world data, The Yi-Huan Genitourinary Cancer Group conducted a multicenter analysis (YHCG-006) to validate the efficacy and safety of this triplet regimen in a Chinese cohort in Zhejiang Province. Methods: We retrospectively analyzed 100 consecutive mHSPC patients (pts) treated with ADT, Darolutamide, and Docetaxel across 18 centers in Zhejiang Province, China (Aug 2022–Jan 2026). Evaluations included baseline characteristics, Docetaxel utilization, PSA dynamics, and treatment-related adverse events (AEs). Results: 100 mHSPC pts were included. The median age was 70 years (range, 43–87). All pts had metastatic disease at baseline, distributed as non-regional lymph nodes (M1a) 12%, bone (M1b) 70% with a median of 8 lesions, and visceral metastasis (M1c) 18%. High-grade histology was common (Gleason score ≥8 in 83%), and performance status was favorable in most (ECOG PS 0–1 in 86%; ECOG PS 2 in 12%). A high-risk classification was present in 80%, and high-volume disease was prevalent (69%). The median baseline PSA was 121.76 ng/ml (IQR, 33.60–375.07). With a median follow-up of 9.2 months (range, 0.8–37.3), ≥6 cycles of Docetaxel were administered in 62% of pts. Dose modifications included Docetaxel reduction in 18 pts (typically to 60 mg/m²) and Darolutamide reduction in 1 patient (to 600 mg/day due to rash). Supportive care included bone-protective agents in 41% and granulocyte colony-stimulating factor (G-CSF) in 32% (prophylactic in 5 pts). At 3 and 6 months, PSA 90 rates were 95.5% (84/88) and 97.8% (90/92), respectively. The proportions achieving PSA < 0.2 ng/ml were 44.3% (39/88) at 3 months and 59.1% (55/93) at 6 months. During follow-up, 67% of pts achieved a nadir PSA < 0.2 ng/ml, and 44% reached an ultra-low nadir PSA < 0.02 ng/ml. The median time to PSA < 0.2 ng/ml was 4.7 months. 9 pts experienced disease progression; median radiographic progression-free survival (rPFS) and overall survival (OS) were not reached at the time of analysis. 38 of 100 pts experienced ≥grade 3 AEs. Neutropenia was the most frequent grade 3 or 4 AE (30 cases), with febrile neutropenia in 13.3% (4/30) of these neutropenia cases. Conclusions: In this real-world Chinese cohort characterized by predominantly high-volume and high-risk disease, Darolutamide-based triplet therapy yielded rapid and deep PSA responses with acceptable toxicity. These findings support the feasibility and clinical utility of this regimen in Chinese mHSPC pts, while underscoring the importance of vigilant monitoring for chemotherapy-related AEs, particularly neutropenia.

Multiparametric MRI (mpMRI) and ^68 Ga-PSMA PET/CT are widely used for prostate cancer (PCa) diagnosis but remain limited by false positives and modest specificity, particularly in distinguishing benign prostate diseases (BPDs) and clinically significant PCa (csPCa). Existing studies often rely on small, single-center cohorts with limited generalizability. This study aimed to develop and externally validate a multimodal radiomics model integrating PET/CT and mpMRI for automated PCa diagnosis, and to evaluate the impact of prostate VOI delineation strategies. A total of 488 patients with suspected PCa who underwent both ^68 Ga-PSMA PET/CT and mpMRI (T2 and DWI) followed by biopsy were retrospectively enrolled from two centers (366 for model development and ten-fold internal validation; 41 for external validation cohort 1; 81 for external validation cohort 2). Radiomics features were extracted from both modalities, and six classical machine learning classifiers (LR, SVM, Random Forest, Extra Trees, XGBoost, LightGBM) were trained for three tasks: (1) csPCa diagnosis, (2) overall PCa detection, and (3) comparison between expert-drawn and deep learning generated prostate VOIs. Model performance was assessed using AUC, sensitivity, specificity, accuracy, PPV, and NPV. Among 407 patients, 137 had BPD, 25 had clinically insignificant PCa, and 250 had csPCa. The multimodal PET/mpMRI radiomics model achieved the best performance with LightGBM (AUC = 0.91 internally; 0.825 externally). Automatically segmented VOIs achieved comparable diagnostic accuracy to expert annotations, with AUC differences within 3–8

Prostate cancer (PCa) progression to treatment-related neuroendocrine PCa (t-NEPC) often involves an early neuroendocrine differentiation (NED) phase lacking identified biomarkers. We utilized GeoMx Digital Spatial Profiling and single-cell RNA sequencing on human PCa tissues ranging from hormone-naïve (HNPC) to t-NEPC, with extensive multi-omics validation. Our results established early NED as a distinct, prognostically adverse subtype. We identified and validated 6 NED markers (FMN2, APLP1, SCG2, SCG3, CHGB, and RIMBP2), demonstrating specificity for NE cells and consistent upregulation throughout NEPC progression. Notably, the Hedgehog (Hh) pathway was specifically activated in early NED, manifested by high SHH ligand in neuroendocrine cells, GLI1 upregulation, and intercellular communication mediated via the SHH-Hh axis. Conversely, in late-stage t-NEPC, Hh pathway activity was significantly downregulated, while MYC-driven proliferation pathways predominated. A risk score derived from the 6-gene NED markers effectively stratified patients, correlating with pronounced NE features and shorter progression-free survival in 86 endocrine-treated patients and externally in The Cancer Genome Atlas (TCGA). In conclusion, this study delineates the dynamic molecular landscape of early NED, establishing a clinically promising biomarker panel and highlighting the Hh pathway as a stage-specific therapeutic target.

Objective This trial investigates the efficacy of neoadjuvant therapy using rezvilutamide combined with androgen deprivation therapy (ADT), with or without docetaxel, in treating oligometastatic hormone-sensitive prostate cancer (omHSPC).Methods and analysis This prospective, open-label, multicentre trial aims to enrol 100 patients newly diagnosed with omHSPC (defined as ≤5 bone or lymph node metastases confirmed by conventional imaging, without visceral metastasis) who must express a desire to undergo surgery. All patients undergo a prostate-specific membrane antigen positron emission tomography/CT (PSMA-PET/CT) scan at enrolment or within 4 weeks before enrolment to assess and confirm the number of metastases at baseline. Scans should be performed before initiating ADT to avoid compromising test sensitivity. Then patients will be allocated into groups in parallel according to their own preferences: one group will receive an LHRH agonist or antagonist for 24 weeks to maintain continuous ADT or have undergone bilateral orchiectomy. Treatment with rezvilutamide will be maintained daily. The other group will be scheduled to complete up to six cycles of docetaxel within 24 weeks, with maintenance of continuous ADT and rezvilutamide for 24 weeks. Both groups will receive a conventional imaging evaluation at the 12th week. After neoadjuvant therapy, patients will undergo conventional imaging and a second PSMA-PET/CT assessment, followed by cytoreductive radical prostatectomy within the subsequent 6 weeks. After surgery, patients may choose to continue with ADT or rezvilutamide at their own discretion, until disease progression. The primary endpoint is pathological complete response, defined as the absence of residual viable tumour cells in the tumour bed on pathological evaluation of the postoperative specimen. Secondary endpoints include 1 year biochemical progression-free survival, overall survival, radiographic progression-free survival, time to prostate-specific antigen progression, quality of life scores (total and subscale) assessed using the Functional Assessment of Cancer Therapy-Prostate questionnaire, time to symptomatic progression, time to deterioration in Eastern Cooperative Oncology Group performance status, the interval from enrolment to an increase in score from baseline, the proportion of patients with a ≥30% reduction in prostate volume on imaging before cytoreductive surgery compared with pre-neoadjuvant therapy, minimal residual disease and major pathological response. The study plans to enrol a total of 100 patients. Patient recruitment for this study is scheduled to begin in May 2025.Ethics and dissemination This has been approved by the Ethics Committee in Clinical Research of the First Affiliated Hospital of Wenzhou Medical University (number KY2024-231). Results will be published in peer-reviewed publications.Discussion This study is expected to provide prospective evidence on the feasibility and potential clinical value of rezvilutamide combined with ADT, with or without docetaxel, as neoadjuvant treatment for newly diagnosed omHSPC.Trial registration number Chinese Clinical Trial Registry (ChiCTR2400093262).

BACKGROUND:Among Chinese men with prostate-specific antigen (PSA) 4-20 ng/mL scheduled for biopsy, <20% harbor clinically significant prostate cancer (csPCa, International Society of Urological Pathology [ISUP] ≥2); most procedures target non-clinically significant prostate cancer (non-csPCa; ISUP <2) or benign prostatic hyperplasia (BPH). We tested whether prostate-specific membrane antigen (PSMA) positron-emission tomography/computed tomography (PET/CT) combined with multiparametric imaging and laboratory assays can accurately identify non-csPCa/BPH and safely reduce unnecessary biopsies. MATERIALS AND METHODS:We retrospectively enrolled patients from two centers. In the discovery cohort, participants underwent PSA testing, mpMRI, and 68Ga-PSMA-PET/CT, and were assessed for Prostate Imaging Reporting and Data System (PI-RADS) and PRIMARY scores. Receiver operating characteristic (ROC) curves, decision curve analysis, and diagnostic tests compared the efficacy of each indicator for non-csPCa/BPH and established the optimal strategy. The validation cohort independently verified this strategy. RESULTS:Discovery cohort (n = 243): PRIMARY score area under the curve (AUC) 0.92 (95% confidence interval [CI]: 0.88-0.95); cutoff ≤3 provided 83.5% sensitivity and 90.9% specificity, outperforming PI-RADS (P = 0.002), PSA density (PSAD), free/total PSA (f/tPSA), and total PSA (tPSA) (all P < 0.0001). Combined models: PRIMARY score + PI-RADS AUC 0.95 (0.92-0.97); PRIMARY + PSAD or + f/tPSA both 0.94. A strategy of PRIMARY score ≤3 plus PSAD ≤0.2 achieved 100% specificity and positive predictive value (PPV) for csPCa, sparing 54.1% of unnecessary biopsies with zero csPCa missed - superior to European Association of Urology (EAU)-recommended PI-RADS ≤2 + PSAD ≤0.2 (sensitivity 19.6%). External cohort (n = 149) validated 100% specificity/PPV, avoiding 69.6% of biopsies while maintaining 0% csPCa miss rate. CONCLUSIONS:In men with suspected prostate cancer (PSA 4-20 ng/mL or abnormal digital rectal examination), the combined criterion of PRIMARY score ≤3 and PSAD ≤0.2 ng/mL/cm3 enabled pre-biopsy triage that safely avoided immediate diagnostic biopsy in more than 50% of patients ultimately found to harbor non-csPCa and BPH in our cohorts, while ensuring that no csPCa was missed. These findings require confirmation in larger prospective, multicenter studies before routine clinical implementation.

Bladder cancer possesses the highest incidence rates globally. Integrative bioinformatics analyses are necessary to develop predictive biomarkers and potential therapeutic targets. Absorption, distribution, metabolism, and excretion (ADME), the disposition of pharmaceutical compounds in organisms, exert a crucial effect on tumorigenesis. Herein, the Least Absolute Shrinkage and Selection Operator (LASSO) algorithm identified a 6-ADME gene signature comprising CYP1A1, CYP3A5, SLC15A2, SLCO1B3, TPMT, and UGT1A1. Lower risk scores were significantly linked to higher disease-specific survival (DSS)/overall survival (OS) in patients with bladder cancer. The receiver operating characteristic (ROC) curve demonstrated that the risk score-based model exhibited a limited to moderate predictive performance in discriminating bladder cancer patients’ outcomes. Univariate and multivariate Cox risk regression analyses identified risk factors for bladder cancer patients’ prognosis: risk scores and grade. The nomogram model revealed that its prognostic outcome is reliable. In other words, the risk model could stratify patients with bladder cancer by different clinical characteristics. Moreover, among these 6 ADME key genes, SLCO1B3 was strongly associated with disease-free survival in bladder cancer patients according to GSE32894; however, its specific roles in bladder cancer have not yet been fully elucidated. In vitro, SLCO1B3 knockdown markedly inhibited cell proliferation, migration, and invasion in bladder cancer by regulating the Wnt/β-catenin signaling axis, which may correlate with its regulation of epithelial-mesenchymal transition (EMT)-related proteins. A risk model based on 6 key ADME genes has been established using the LASSO algorithm and shows good prognostic potential for patients with bladder cancer. The risk score can also significantly distinguish bladder cancer samples across different clinical statuses, suggesting that the risk model may have diagnostic value for bladder cancer patients.

"CLO25-076: CD13 as a Potential Membrane Marker in PSMA-Negative Prostate Cancer and First-in-Human Study of [18F]AlF-CD13-L1 PET/CT Imaging" published on 28 Mar 2025 by National Comprehensive Cancer Network.

Background:Persistent prostate-specific antigen (PSA) after radical prostatectomy (RP) is associated with increased metastasis and mortality. However, the value of the radiomics for predicting persistent PSA is unclear. Our study aimed to evaluate the diagnostic performance of 18F-PSMA-1007 positron emission tomography (PET) and multiparametric magnetic resonance imaging (mpMRI) radiomics for the prediction of persistent PSA after RP. Methods:Retrospective analysis was performed on 141 patients with prostate cancer (PCa) who had undergone 18F-prostate-specific membrane antigen (PSMA)-1007 PET and mpMRI scans before RP. Patients were placed into two groups according to PSA levels examined within 4-8 weeks after surgery: a nonpersistent PSA group and a persistent PSA group. PET-derived and mpMRI-derived radiomics features were used to develop radiomics models. Age and initial PSA were incorporated into the clinical model. Individual models and their various combinations were developed and their performance evaluated. Results:All radiomics models consistently outperformed the clinical model [C model: area under curve (AUC) =0.744]. The best-performing radiomics model was the PET- and mpMRI-derived model (PM model) created by combining the radiomics features of PET and mpMRI, which yielded an AUC of 0.849 in the validation cohort, and was superior to the other radiomics models, including the PET-derived model (P model: AUC =0.794) and the mpMRI-derived model (M model: AUC =0.815). The combined model, integrating the clinical variables and the best-performing radiomics model, demonstrated the highest performance (AUC =0.903) and significantly outperformed the C model (P<0.05). Decision curve analysis indicated that the combined model provided greater net benefits than did the C model and PM model. Conclusions:The combined radiomics-clinical model was the best-performing model and outperformed both clinical and radiomics models in predicting persistent PSA, indicating that clinical variables can complement PSMA-PET and mpMRI radiomics for early risk stratification following RP.

PURPOSE:Approximately 10% of prostate cancer (PCa) are prostate-specific membrane antigen (PSMA)-negative, leading to blind spots in PSMA-based diagnosis. This study aimed to identify a potential target for PSMA-negative PCa and preliminarily evaluate the feasibility of using radionuclide probe targeting the identified target for PCa diagnosis. METHODS:Quantitative protein analysis was performed on eight PSMA-negative PCa and eleven controls to identify a potential molecular target, followed by validation with an expanded cohort using immunohistochemistry. Sixteen participants underwent [18F]AlF-CD13-L1 PET/CT scanning, with the PCa pathological tissues used as references to interpret the imaging results. RESULTS:Quantitative protein analysis revealed CD13 as the most significantly upregulated membrane protein in PSMA-negative PCa. Expanded validation results indicated that CD13 positivity rates were 92.9% (13/14), 82.7% (105/127), 91.7% (11/12), and 70% (14/20) in PSMA-negative PCa, PSMA-positive PCa, ductal adenocarcinoma of the prostate (DAC), and intraductal carcinoma of the prostate (IDC-P), respectively. In PCa participants, the median [18F]AlF-CD13-L1 PET/CT maximum standardized uptake value (SUVmax) of tumors and tumor-to-muscle ratio were 4.3 (1.5-5.8) and 4.6 (1.7-6.1), respectively. The SUVmax value of the PCa lesions and the tumor-to-muscle ratio showed a positive correlation with the immunohistochemical score of CD13 of the PCa lesions (rspearman = 0.6249, p = 0.025; rspearman = 0.6714, p = 0.015, respectively), with CD13-positive tumors showing significant radiotracer accumulation. CONCLUSION:CD13 was a potential target for PSMA-negative PCa and also showed high positivity rates in PSMA-positive PCa, DAC, and IDC-P. [18F]AlF-CD13-L1 selectively accumulated in CD13-positive PCa, enabling visualization. (Trial registration: ChiCTR2300077817. Registered November 21, 2023).

Besides its potential as a PET/CT tracer, the Gastrin-Releasing Peptide Receptor (GRPR) has been shown to predict the prognosis of Prostate Cancer (PCa). Herein, we aimed to evaluate the additive ability of 68Ga-RM26 PET/CT as a tracer to predict the prognosis of patients with metastatic Castration-Resistant Prostate Cancer (mCRPC) following Androgen Receptor Signal Inhibitors (ARSIs) therapy. This retrospective single-center study involved patients who underwent both 68Ga-PSMA-617 PET/CT and 68Ga-RM26 PET/CT scans. Based on the GRPR status of their lesions (positive/negative), the patients were stratified into two cohorts, and their actual prognosis was assessed by comparing their maximum Prostate-Specific Antigen (PSA) response rates and Progression-Free Survival (PFS) durations following ARSI therapy. This study involved 44 patients. Among them, 41 and 23 showed PSMA uptake and GRPR uptake, respectively, with 3 exhibiting GRPR uptake alone. The GRPR + group had an median PSA response rate of 37.78

Chemoresistance represents a major challenge for osteosarcoma treatment. Despite the improved knowledge of cancer biology, the core determinants of cisplatin (DDP) resistance in osteosarcoma remain unclear and deserve further exploration. Here, RFWD3 is identified as a key regulator of DDP sensitivity in osteosarcoma using a genome-wide CRISPR screen. It is demonstrated that RFWD3 is overexpressed in post-chemotherapy osteosarcoma tissues compared to pre-chemotherapy tissues. Knocking out RFWD3 increased the sensitivity of osteosarcoma cells to DDP treatment. Mechanistically, RFWD3 bound to and ubiquitinated PHGDH at the Lys137 residue, promoting its degradation and conserving cellular oxidized nicotinamide adenine dinucleotide (NAD+). The resulting surplus of NAD+ enhanced the TCA cycle, leading to increased production of aspartic acid and glutamic acid for de novo nucleotide biosynthesis. In addition, virtual screening techniques are employed to identify Lomitapide as a specific inhibitor of the RFWD3-PHGDH interaction, capable of disrupting the binding between RFWD3 and PHGDH. It is found that Lomitapide exhibits a significant synergistic anti-osteosarcoma effect when combined with DDP. In conclusion, a specific role of RFWD3 in regulating nucleotide metabolism is revealed and comprised of targetable candidates for overcoming chemoresistance in osteosarcoma.

Osteosarcoma tissues demonstrated elevated expression of proteins (FDX1 and DLAT) integral to cuproptosis in our preliminary study, indicating the potential effectiveness of anti-tumor strategies predicated on this process. Nevertheless, the overexpression of copper export proteins and the challenge of copper ion penetration may contribute to insufficient local copper ion concentration for inducing cuproptosis. Herein, we engineered a biomimetic copper-elesclomol-polyphenol network for the efficient delivery of copper ions and the copper ionophore elesclomol. Simultaneously, we integrated catalase (CAT) to alleviate tumor hypoxia, thereby inducing a greater reliance of tumor cells on aerobic respiration and enhancing cuproptosis sensitivity. In vitro analyses revealed that the nanocomplex exhibited potent cytotoxicity and displayed hallmark characteristics of cuproptosis. In vivo trials further validated targeted tumor accumulation, resulting in the suppression of tumor growth and lung metastasis. An augmentation in the proportion of activated immune cells in both tumor and draining lymph nodes was observed. The improvement of immunosuppressive microenvironment facilitated a synergistic antitumor effect with cuproptosis. The therapeutic efficacy was further evidenced in two osteosarcoma models, highlighting the potential as a safe and effective strategy against osteosarcoma and lung metastasis. Statement of significance Osteosarcoma tissues exhibit a marked increase in the expression of proteins FDX1 and DLAT, which are crucial for cuproptosis. Moreover, cells that depend on mitochondrial respiration are more susceptible to cuproptosis. Here we developed a biomimetic copper-based nanocomplex to trigger cuproptosis against osteosarcoma and lung metastases. The nanocomplex demonstrated excellent biocompatibility and tumor targeting. Catalase incorporating facilitated oxygen generation within tumor microenvironment and alleviated hypoxia, thereby inducing a greater reliance of tumor cells on aerobic respiration and enhancing cuproptosis sensitivity. Simultaneously, the released Cu-elesclomol complexes induced proteotoxic stress responses and efficiently elicited cuproptosis, leading to increased release of proinflammatory factors and triggering anti-tumor immune activation. Our strategy holds promise for osteosarcoma treatment by inducing cuproptosis and achieving potent tumor suppression.