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Black men die more often of prostate cancer yet, interestingly, may derive greater survival benefits from immune-based treatment with sipuleucel-T. Since no signatures of immune-responsiveness exist for prostate cancer, we explored race-based immune-profiles to identify vulnerabilities. Here we show in multiple independent cohorts comprised of over 1,300 patient samples annotated with either self-identified race or genetic ancestry, prostate tumors from Black men or men of African ancestry have increases in plasma cell infiltrate and augmented markers of NK cell activity and IgG expression. These findings are associated with improved recurrence-free survival following surgery and nominate plasma cells as drivers of prostate cancer immune-responsiveness. A recent report suggested Black men with prostate cancer were more responsive to immunotherapy. Here, the authors analysed prostate cancer gene expression profiles and show tumours from Black men and men with African ancestry have an increased proportion of plasma cells compared to those of White men and this correlates with improved outcome following treatment. [ABSTRACT FROM AUTHOR]

Notch signalling is implicated in the pathogenesis of a variety of cancers, but its role in prostate cancer is poorly understood. However, selected Notch pathway members are overrepresented in high-grade prostate cancers. We comprehensively profiled Notch pathway components in prostate cells and found prostate cancer-specific up-regulation of NOTCH3 and HES6. Their expression was particularly high in androgen responsive lines. Up- and down-regulating Notch in these cells modulated expression of canonical Notch targets, HES1 and HEY1, which could also be induced by androgen. Surprisingly, androgen treatment also suppressed Notch receptor expression, suggesting that androgens can activate Notch target genes in a receptor-independent manner. Using a Notch-sensitive Recombination signal binding protein for immunoglobulin kappa J region (RBPJ) reporter assay, we found that basal levels of Notch signalling were significantly lower in prostate cancer cells compared to benign cells. Accordingly pharmacological Notch pathway blockade did not inhibit cancer cell growth or viability. In contrast to canonical Notch targets, HES6, a HES family member known to antagonize Notch signalling, was not regulated by Notch signalling, but relied instead on androgen levels, both in cultured cells and in human cancer tissues. When engineered into prostate cancer cells, reduced levels of HES6 resulted in reduced cancer cell invasion and clonogenic growth. By molecular profiling, we identified potential roles for HES6 in regulating hedgehog signalling, apoptosis and cell migration. Our results did not reveal any cell-autonomous roles for canonical Notch signalling in prostate cancer. However, the results do implicate HES6 as a promoter of prostate cancer progression. [ABSTRACT FROM AUTHOR]

OBJECTIVES • To evaluate the cytotoxicity of dimeric naphthoquinones (BiQs) in prostate cancer cells. • To assess the interaction of dimeric naphthoquinones with common therapies including radiation and docetaxel. MATERIALS AND METHODS • The cytotoxicity of 12 different dimeric naphthoquinones was assessed in androgen-independent (PC-3, DU-145) and androgen-responsive (LNCaP, 22RV1) prostate cancer cell lines and in prostate epithelial cells (PrECs). • BiQ2 and BiQ11 were selected for determination of dose response, effects on colony formation and initial exploration into mechanism of action. • Synergistic effects with radiation and docetaxel were explored using colonyforming and MTT assays. RESULTS • At concentrations of 15μM, BiQ2, BiQ3, BiQ11, BiQ12, and BiQ15 demonstrated cytotoxicity in all prostate cancer cell lines. • Treatment with BiQs limited the ability of prostate cancer cells to form colonies in clonogenic assays. • Exposure of prostate cancer to BiQs increased cellular reactive oxygen species (ROS), decreased ATP production, and promoted apoptosis. • BiQ cytotoxicity was independent of NADP(H):quinone oxidoreductase 1 ( NQO1 ) activity in PrECs, PC-3 and 22RV1, but not DU-145 cells. • Exposure of prostate cancer cells to radiation before treatment with BiQs increased their activity allowing for inhibitory effects well below the IC50 s of these compounds in PrECs. • Co-administration of BiQs with docetaxel had minimal additive effects. CONCLUSIONS • Dimeric naphthoquinones represent a new class of compounds with prostate cancer cytotoxicity and synergistic effects with radiation. The cytotoxic effect of these agents is probably contributed to by the accumulation of ROS and mitochondrial dysfunction. • Further studies are warranted to better characterize this class of potential chemotherapeutics. [ABSTRACT FROM AUTHOR]

• Validation of the multimodal AI (MMAI) biomarker in oligometastatic CSPC. • MMAI score is prognostic for OS and time to castration-resistance. • MMAI score appears to stratify for response to metastasis directed therapy. There is a need for clinically actionable prognostic and predictive tools to guide the management of oligometastatic castration-sensitive prostate cancer (omCSPC). This is a multicenter retrospective study to assess the prognostic and predictive performance of a multimodal artificial intelligence biomarker (MMAI; the ArteraAI Prostate Test) in men with omCSPC (n = 222). The cohort also included 51 patients from the STOMP and ORIOLE phase 2 clinical trials which randomized patients to observation versus metastasis-directed therapy (MDT). MMAI scores were computed from digitized histopathology slides and clinical variables. Overall survival (OS) and time to castration-resistant prostate cancer (TTCRPC) were assessed for the entire cohort from time of diagnosis. Metastasis free survival (MFS) was assessed for the trial cohort from time of randomization. In the overall cohort, patients with a high MMAI score had significantly worse OS (HR = 6.46, 95 % CI = 1.44–28.9; p = 0.01) and shorter TTCRPC (HR = 2.07, 95 % CI = 1.15–3.72; p = 0.015). In a multivariable Cox model, MMAI score remained the only variable significantly associated with OS (HR = 6.51, 95 % CI = 1.32–32.2; p = 0.02). In the subset of patients randomized in the STOMP and ORIOLE trials, high MMAI score corresponded to improved MFS with MDT (p = 0.039) compared to patients with a low score, with p interaction = 0.04. The ArteraAI MMAI biomarker is prognostic for OS and TTCRPC among patients with omCSPC and may predict for response to MDT. Further work is needed to validate the MMAI biomarker in a broader mCSPC cohort. [ABSTRACT FROM AUTHOR]

• We are the first to investigate using radiomic imaging biomarkers from both pre-and post-treatment PSMA-PET/CT together with clinical information for predicting outcomes in omCSPC patients undergoing MDT. • Multi-zone feature extraction – We extracted features from two distinct zones: zone 1 corresponds to the GTV, and zone 2 encompasses a 5 mm expansion ring area surrounding the GTV. • Multi-institutional validation − our study benefits from patient data collected from two institutions (Johns Hopkins Hospital and Baskent University), which validated the robustness and generalizability of our findings. • Predicting 2-year MFS with AUC 0.81 is feasible from PET radiomic information derived from the GTV and its surrounding area in both pre- and post-PSMA-PET scans for omCSPS patients. This study investigated imaging biomarkers derived from PSMA-PET acquired pre- and post-metastasis-directed therapy (MDT) to predict 2-year metastasis-free survival (MFS), which provides valuable early response assessment to improve patient outcomes. An international cohort of 117 oligometastatic castration-sensitive prostate cancer (omCSPC) patients, comprising 34 from John Hopkins Hospital (JHH) and 83 from Baskent University (BU), were treated with stereotactic ablative radiation therapy (SABR) MDT with both pre- and post-MDT PSMA-PET/CT scans acquired. PET radiomic features were analyzed from a CT-PET fusion defined gross tumor volume ((GTV) or zone 1), and a 5 mm expansion ring area outside the GTV (zone 2). A total of 1748 PET radiomic features were extracted from these zones. The six most significant features selected using the Chi2 method, along with five clinical parameters (age, Gleason score, number of total lesions, untreated lesions, and pre-MDT prostate-specific antigen (PSA)) were extracted as inputs to the models. Various machine learning models, including Random Forest, Decision Tree, Support Vector Machine, and Naïve Bayesian, were employed for 2-year MFS prediction and tested using leave-one-out and cross-institution validation. Six radiomic features, including Total Energy, Entropy, and Standard Deviation from pre-PSMA-PET zone 1, Total Energy and Contrast from post-PSMA-PET zone 1, and Entropy from pre-PSMA-PET zone 2, along with five clinical parameters were selected for predicting 2-year MFS. In a leave-one-out test with all the patients, random forest achieved an accuracy of 80 % and an AUC of 0.82 in predicting 2-year MFS. In cross-institution validation, the model correctly predicted 2-year MFS events with an accuracy of 75 % and an AUC of 0.77 for patients from JHH, and an accuracy of 78 % and an AUC of 0.80 for BU patients, respectively. Our study demonstrated the promise of using pre- and post-MDT PSMA-PET-based imaging biomarkers for MFS prediction for omCSPC patients. [ABSTRACT FROM AUTHOR]

Background Radical prostatectomy (RP) is a primary treatment option for men with intermediate- and high-risk prostate cancer. Although many are effectively cured with local therapy alone, these men are by definition at higher risk of adverse pathologic features and clinical disease recurrence. It has been shown that the Decipher test predicts metastatic progression in cohorts that received adjuvant and salvage therapy following RP. Objective To evaluate the Decipher genomic classifier in a natural history cohort of men at risk who received no additional treatment until the time of metastatic progression. Design, setting, and participants Retrospective case-cohort design for 356 men who underwent RP between 1992 and 2010 at intermediate or high risk and received no additional treatment until the time of metastasis. Participants met the following criteria: (1) Cancer of the Prostate Risk Assessment postsurgical (CAPRA-S) score ≥3; (2) pathologic Gleason score ≥7; and (3) post-RP prostate-specific antigen nadir <0.2 ng/ml. Outcome measurements and statistical analysis The primary endpoint was defined as regional or distant metastases. Time-dependent receiver operating characteristic (ROC) curves, extension of decision curve analysis to survival data, and univariable and multivariable Cox proportional-hazards models were used to measure the discrimination, net benefit, and prognostic potential of genomic and pathologic risk factors. Cumulative incidence curves were constructed using Fine-Gray competing-risks analysis with appropriate weighting of the controls to account for the case-cohort study design. Results and limitations Ninety six patients had unavailable tumor blocks or failed microarray quality control. Decipher scores were then obtained for 260 patients, of whom 99 experienced metastasis. Decipher correlated with increased cumulative incidence of biochemical recurrence, metastasis, and prostate cancer–specific mortality ( p < 0.01). The cumulative incidence of metastasis was 12% and 47% for patients with low and high Decipher scores, respectively, at 10 yr after RP. Decipher was independently prognostic of metastasis in multivariable analysis (hazard ratio 1.26 per 10% increase; p < 0.01). Decipher had a c -index of 0.76 and increased the c -index of Eggener and CAPRA-S risk models from 0.76 and 0.77 to 0.86 and 0.87, respectively, at 10 yr after RP. Although the cohort was large, the single-center retrospective design is an important limitation. Conclusions In a patient population that received no adjuvant or salvage therapy after prostatectomy until metastatic progression, higher Decipher scores correlated with clinical events, and inclusion of Decipher scores improved the prognostic performance of validated clinicopathologic risk models. These results confirm the utility already reported for Decipher. Patient summary The Decipher test improves identification of patients most at risk of metastatic progression and death from prostate cancer after radical prostatectomy. [ABSTRACT FROM AUTHOR]