Treatment Of Prostate Cancer Patients Research Articles

Effects of Concurrent Administration of Spironolactone in Veterans with Metastatic Prostate Cancer Receiving Abiraterone: A Real-World Retrospective Study.

Prostate cancer is the most common cancer in men in the United States with low survival rates once metastasized. Abiraterone is approved for use in castrate-sensitive and castrate-resistant prostate cancer and is used extensively in the Veterans Affairs (VA) healthcare system. Spironolactone, a diuretic used to treat heart failure, edema, ascites, and hypertension, may increase androgen levels and reduce effectiveness of abiraterone when used concurrently to treat prostate cancer patients. While previous case studies support this, no large epidemiology studies have been conducted. The current study utilizes the large, VA prostate cancer data core and evaluates the effect of concomitant spironolactone on efficacy of abiraterone treatment in metastatic prostate cancer patients. The study selected 18,943 veterans with metastatic prostate cancer on abiraterone treatment. Of these, 581 patients (3.1%) were also on concomitant spironolactone. The concomitant treatment group, abiraterone + spironolactone, significantly differed from the abiraterone-only group in body mass index, prevalence rates of heart failure and liver disease, and being previously treated with docetaxel. A 1:1 propensity score matching method was used to balance sample sizes and baseline traits between the two treatment groups, abiraterone versus abiraterone + spironolactone. Kaplan-Meier curves and Cox proportional hazard model were used to compare 5-year overall survival and all-cause mortality outcomes, respectively, between the two groups. After propensity score matched, the abiraterone + spironolactone group was treated with abiraterone significantly longer than the abiraterone-only group (mean ± standard deviation days 549.0 ± 552.3 vs. 435.5 ± 474.1; p = 0.0002) and had a higher 5-year overall survival rate (44% vs. 37%; p = 0.0116). Veterans with metastatic prostate cancer treated with abiraterone + spironolactone also had a lower 5-year all-cause mortality compared to those only on abiraterone (hazard ratio 0.80, 95% confidence intervals 0.61-0.96; p = 0.012). This large VA observational study suggests that concomitant use of spironolactone does not compromise cancer control or survival of metastatic prostate cancer patients treated with abiraterone.

Disulfidptosis-related subtype and prognostic signature in prostate cancer

BackgroundDisulfidptosis refers to cell death caused by the accumulation and bonding of disulfide in the cytoskeleton protein of SLC7A11-high level cells under glucose deprivation. However, the role of disulfidptosis-related genes (DRGs) in prostate cancer (PCa) classification and regulation of the tumor microenvironment remains unclear.MethodsFirstly, we analyzed the expression and mutation landscape of DRGs in PCa. We observed the expression levels of SLC7A11 in PCa cells through in vitro experiments and assessed the inhibitory effect of the glucose transporter inhibitor BAY-876 on SLC7A11-high cells using CCK-8 assay. Subsequently, we performed unsupervised clustering of the PCa population and analyzed the differentially expressed genes (DEGs) between clusters. Using machine learning techniques to select a minimal gene set and developed disulfidoptosis-related risk signatures for PCa. We analyzed the tumor immune microenvironment and the sensitivity to immunotherapy in different risk groups. Finally, we validated the accuracy of the prognostic signatures genes using single-cell sequencing, qPCR, and western blot.ResultsAlthough SLC7A11 can increase the migration ability of tumor cells, BAY-876 effectively suppressed the viability of prostate cancer cells, particularly those with high SLC7A11 expression. Based on the DRGs, PCa patients were categorized into two clusters (A and B). The risk label, consisting of a minimal gene set derived from DEGs, included four genes. The expression levels of these genes in PCa were initially validated through in vitro experiments, and the accuracy of the risk label was confirmed in an external dataset. Cluster-B exhibited higher expression levels of DRG, representing lower risk, better prognosis, higher immune cell infiltration, and greater sensitivity to immune checkpoint blockade, whereas Cluster A showed the opposite results. These findings suggest that DRGs may serve as targets for PCa classification and treatment. Additionally, we constructed a nomogram that incorporates DRGs and clinical pathological features, providing clinicians with a quantitative method to assess the prognosis of PCa patients.ConclusionThis study analyzed the potential connection between disulfidptosis and PCa, and established a prognostic model related to disulfidptosis, which holds promise as a valuable tool for the management and treatment of PCa patients.

Therapeutic Potential of Decoys for Prostate Cancers: A Review of Recent Updates.

Prostate cancer is ranked second among the most common male cancers. Androgen deprivation therapy (ADT) has long been the first-line treatment and the basis for all other therapies, reducing circulating androgens to castration levels and preventing disease development. Nevertheless, ADT monotherapy may not always limit disease development, and even at low testosterone levels, hormone-sensitive prostate cancer will become castration-resistant. Recent research demonstrates that prostate cancer can have a range of potentially actionable genetic abnormalities; no medications that target these variations have yet been shown to elicit therapeutic advantages. Despite their established efficacy in the management of other cancers, advanced genetic or immunological approaches are not regularly used to treat prostate cancer patients. As a result, there is an unmet demand for medicines that offer a better chance of survival than the existing castration- resistance prostate cancer (CRPC) therapy regimens. The use of oligodeoxynucleotides (ODN) and peptides in decoy technology have been developed as novel therapeutic approaches. Decoy ODNs bind to a particular transcription factor with high affinity and may suppress gene transcription. Peptide decoys bind to specific ligands with high specificity and inhibit signaling pathways. Recent evidence supports the notion that these techniques are promising and attractive in the fight against cancer. In the present review, we discuss the use of decoy technology as a novel therapeutic approach against prostate cancer.

Stereotactic body radiation therapy for prostate cancer: a dosimetric comparison of IMRT and VMAT using flattening filter and flattening filter-free beams.

This retrospective study was performed to evaluate plan quality and treatment delivery parameters of stereotactic body radiation therapy (SBRT) for prostate cancer. The study utilized different isocentric modulated techniques: intensity modulated radiotherapy (IMRT) and volumetric modulated arc therapy (VMAT) using 6 MV flattening filter (FF) and 10 MV flattening filter-free beams (FFF). Fifteen retrospective prostate cancer patients were selected for this study. Sixty plans were created with an SBRT-prescribed dose of 36.25Gy delivered in five fractions. Planning target volume (PTV) coverage, plan quality indices, doses delivered to organs at risk (OARs), and treatment delivery parameters were compared for all plans. It turned out that VMAT plans, particularly those using the FFF beam, provided superior target conformality and a steeper dose gradient as compared to IMRT plans. Additionally, VMAT plans showed better OARs sparing compared to IMRT plans. However, IMRT plans delivered a lower maximum dose to the target than VMAT plans. Importantly, the VMAT plans resulted in reduced treatment delivery parameters, including beam on time (BOT), monitor unit (MU), and modulation factor (MF), compared to IMRT plans. Furthermore, a statistically significant difference was observed in BOT and mean body dose between FF and FFF beams, with FFF beams showing superior performance. Considering all results, VMAT using 10 MV (FFF) is suggested for treating prostate cancer patients with SBRT. This offers the fastest delivery in addition to maintaining the highest plan quality.

Combined holmium laser enucleation of the prostate with high-intensity focused ultrasound in treating patients with localized prostate cancer in a prostate with volume > 60 g: Oncological and functional outcomes from single-institution study

ObjectiveTo assess the efficacy and safety of combined High-Intensity Focused Ultrasound (HIFU) and Holmium Laser Enucleation of the Prostate (HoLEP) in treating patients with both localized prostate cancer (PCa) and prostate > 60 g. MethodsAll patients who underwent HIFU for treatment of localized PCa were prospectively enrolled in our study. We reviewed records of patients undergoing procedures from January 2016 to January 2023. For patients with prostate sizes > 60 g, HoLEP was offered before HIFU to prevent worsened urinary symptoms post-treatment. Oncological outcomes—prostatic-specific (PSA) kinetics, recurrence rates, treatment failure - and functional results—Sexual Health Inventory for Men (SHIM), International Prostate Symptoms Score (IPSS), and urinary complications were compared between patients undergoing combined HoLEP and HIFU with those underwent HIFU-monotherapy. ResultsAmong 100 patients, 74 underwent HIFU-monotherapy and 26 underwent the combined HoLEP and HIFU. The majority had intermediate-risk PCa (67%). Pathologic assessment of HoLEP specimens showed no tumor evidence in 57% of cases. In comparison to the HIFU-only group, the combined group exhibited significantly lower PSA metrics across various intervals, however, no differences were found regarding overall and infield recurrences and treatment failure rates. While the combined treatment initially resulted in higher incontinence rates and shorter catheterization durations (P < 0.001), no significant difference in IPSS was observed during subsequent follow-ups. ConclusionHoLEP and HIFU can be safely combined for the treatment of PCa in patients with >60 g prostate volume without compromising early oncological outcomes thereby expanding the therapeutic scope of HIFU in treating patients with localized PCa and large adenomas.

Statin use and mortality risk in Asian patients with prostate cancer receiving androgen deprivation therapy: A population-based cohort study.

This study aimed to examine the associations between the use of statins concurrent with androgen deprivation therapy (ADT) and the risks of mortality in Asian patients diagnosed with prostate cancer (PCa). Adult patients (≥18 years old) diagnosed with PCa who were receiving any form of ADT and were being treated at public hospitals in Hong Kong from December 1999 to March 2021 were retrospectively identified, with follow-up conducted until September 2021. Patients who had received medical castration for <180 days without subsequent bilateral orchidectomy, those who had used statins concurrently with ADT for <180 days, and those with missing baseline total cholesterol levels were excluded. Statin users were defined as individuals who had used statins for ≥180 days concurrent with ADT, while non-users were those who had not used any statins. PCa-related mortality was the primary outcome, while all-cause mortality served as the secondary outcome. Inverse probability treatment weighting was employed to balance the covariates. A total of 4920 patients were included, consisting of 2578 statin users and 2342 non-users (mean age 76.1 ± 8.2 years). Over a mean follow-up period of 4.2 ± 3.3 years, it was observed that statin users had significantly lower risks of both PCa-related mortality (weighted hazard ratio [wHR] 0.56 [95% confidence interval (CI) 0.48, 0.65], p < 0.001) and all-cause mortality (wHR 0.57 [95% CI 0.51, 0.63], p < 0.001), regardless of the type of ADT used. Notably, these associations were more pronounced among patients with less advanced PCa, as indicated by the absence of androgen receptor antagonist or chemotherapy usage (p value for interaction <0.001 for both outcomes). The use of statins concurrent with ADT was associated with reduced mortality risks among Asian patients with PCa. These findings suggest the need for additional research to explore the potential role of statins in the treatment of PCa patients.

Abstract B119: First-in-class orally active pharmacological inhibitors of TRPV6 for the treatment of advanced prostate cancer

Abstract The highly calcium selective ion channel TRPV6, has pronouced overexpression in many prostate cancers, is a promotor of prostate cancer growth and has been proposed as a prognostic marker in prostate cancer. A novel series of first-in-class TRPV6 inhibitors has been developed by the Queensland Emory Drug Discovery Initiative (QEDDI), a drug discovery and development group aiming to collaborativey translate academic biomedical research into new medicines. The preclinical lead drug candidate QED-203, is orally active and potently inhibits (low nM) calcium influx mediated by TRPV6 as assessed by both Ca2+ probe and electrophysiology assays, and TRPV6-driven NFAT activation as assessed by a luciferase reporter assay. Using RNAseq and qPCR analysis TRPV6 pharmacological inhibition and/or siRNA-mediated silencing was shown to remodel the expression of genes related to both NFAT and WNT signalling, as well as ER stress and the cell cycle. In prostate cancer cell lines that had increased levels of TRPV6, TRPV6 inhibition promoted cell cycle arrest, decreased proliferation and promoted apoptosis. Proliferation of enzalutamide resistant prostate cancer cell lines was also inhibited by QED-203. QED-203 exhibited greater potency over enzalutamide, darolutamide and apalutamide [androgen receptor targeting agents (ARTA)] in prostate cancer cell lines with clinically relevant AR mutations or those with the ARV7 splice variant. QED-203 appeared well suited to once-a-day oral dosing with a high bioavailability and an advantageous pharmacokinetic profile. In preclinical models, QED-203 was well tolerated in rodents and had similar in vivo efficacy to enzalutamide in a castrated LNCaP mouse model of prostate cancer as assessed by tumour growth and PSA levels. Increases in urine calcium levels and gene expression changes consistent with TRPV6 inhibition in isolated xenograft tumours, confirmed QED-203 TRPV6 target engagement in vivo. These studies suggest that the orally active TRPV6 inhibitor QED-203 represents a first-in-class mechanism to treat prostate cancer patients whose tumours have become resistant to current ARTA therapies. Pharmacological inhibitors of TRPV6, could be particularly valuable during the advanced stages of prostate cancer, where there is a clear unmet clinical need. Citation Format: Gregory Monteith, Kimberley Beaumont, Rebecca Pouwer, Rebecca Farrow, Matthew McLachlan, Mei Yeh, Therese Johnson, Raphael Rahmani, Claire Levrier, Hasanthi Wijesekera, Malika Kumarasiri, Grant Stuchbury, Terrie-Anne Cock, Andrew Harvey, Brian Dymock. First-in-class orally active pharmacological inhibitors of TRPV6 for the treatment of advanced prostate cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B119.

Gastrointestinal Toxicity Following Proton and Photon Radiation for Prostate Cancer in Patients with Inflammatory Bowel Disease.

Inflammatory bowel disease (IBD) has been considered a relative contraindication for radiation for prostate cancer (PC) due to concern for gastrointestinal (GI) toxicity. Modern radiation planning techniques such as intensity modulated radiation therapy (IMRT) have resulted in a significant decrease in GI toxicity in the general PC population. Several published case series have suggested overall excellent outcomes using IMRT in PC patients with IBD. Proton therapy (PT) with improved dosimetric sparing of bowel and rectum may offer additional benefit, but to our knowledge, there is no published data assessing outcomes after PT in PC patients with IBD. We report our institutional experience treating PC patients with IBD with both PT and IMRT. We identified patients with an IBD diagnosis treated for PC at our institution from 2012-2022 with either IMRT or PT. Baseline clinical characteristics were captured, along with radiation parameters, including dose, fractionation, inclusion of pelvic nodes, and use of a rectal spacer. IBD specifics captured included type of IBD, use of IBD medication, and pre radiation colonoscopy findings when available. Early and late GI toxicities were captured via retrospective chart review and graded per the Common Terminology Criteria for Adverse Events (CTCAE) version 5. Eighteen patients with IBD were treated with RT for PC at our institution, including 10 with ulcerative colitis, 7 with Crohn's disease, and 1 with IBD NOS. Nine of these patients were treated with PT and 9 with IMRT. Most were treated with conventional fractionation (n = 14) and the rest with moderate hypofractionation. Fourteen received primary RT to an intact prostate, and the rest received salvage RT. In four patients, the pelvic nodes were also treated. Rectal spacers were used for 8 patients. Nine of the patients were on IBD medications, and of the 15 patients with records of pre-RT colonoscopy, only 1 demonstrated inflammatory findings, which were noted in the ileum. Median follow-up was 3.5 years (1-6) Acute grade (Gr)1 GI toxicity was seen in 6(33%) patients with diarrhea and proctitis. No patients developed acute Gr 2 GI toxicity, and 1 patient developed acute Gr 3 diarrhea and proctitis. This patient had asymptomatic Crohn's disease prior to IMRT, not on medication, and was treated to the prostate and pelvic nodes. Late Gr 1 GI toxicity was seen in 4 (22%) patients. Median time to late GI toxicity was 9.5 months. No patients developed late Gr 2 or higher GI toxicity. Modern radiation techniques including IMRT and PT are well tolerated in PC patients with well-controlled IBD. Larger studies with longer follow up would be helpful to further characterize these patients' outcomes. In the meantime, IMRT and PT should be considered as treatment options in patients with well-controlled IBD.

Adherence to Hormonal Therapies in Prostate Cancer.

Hormonal therapy is the standard of care in prostate cancer treatment. The approval of the first oral androgen deprivation therapy, relugolix, to treat prostate cancer patients provides an opportunity to review adherence to oral and injectable/implantable hormonal therapies to aid patients and physicians in making informed decisions. A PubMed search for available literature on adherence to hormonal therapy in prostate cancer was conducted, including published data on relugolix. Adherence to oral antiandrogen therapy was above 90% by medication possession ratio in several studies worldwide and from 75% to 91% by proportion of days covered. For injectable/implantable androgen deprivation therapy, adherence to treatment ranged from 71% to 95%. In general, 60% and 29% of injections were reported to be delayed by more than 1 week and 2 weeks, respectively, with some patients experiencing testosterone increases (tests above 50 ng/dL). Although real-world data on adherence to relugolix are currently unavailable, pharmacokinetic/pharmacodynamics models demonstrated that, if necessary, treatment interruption up to 7 days would still maintain testosterone suppression levels. In general, adherence to hormonal therapy is high in prostate cancer. Studies revealed that adherence to injectable androgen deprivation therapy dosing schedules is important to maintain castrate levels. Pharmacokinetic/pharmacodynamics models showed that relugolix treatment interruption up to 7 days had minimal impact on testosterone suppression levels.

Development and validation of a clinic machine-learning nomogram for the prediction of risk stratifications of prostate cancer based on functional subsets of peripheral lymphocyte

BackgroundNon-invasive risk stratification contributes to the precise treatment of prostate cancer (PCa). In previous studies, lymphocyte subsets were used to differentiate between low-/intermediate-risk and high-risk PCa, with limited clinical value and poor interpretability. Based on functional subsets of peripheral lymphocyte with the largest sample size to date, this study aims to construct an easy-to-use and robust nomogram to guide the tripartite risk stratifications for PCa.MethodsWe retrospectively collected data from 2039 PCa and benign prostate disease (BPD) patients with 42 clinical characteristics on functional subsets of peripheral lymphocyte. After quality control and feature selection, clinical data with the optimal feature subset were utilized for the 10-fold cross-validation of five Machine Learning (ML) models for the task of predicting low-, intermediate- and high-risk stratification of PCa. Then, a novel clinic-ML nomogram was constructed using probabilistic predictions of the trained ML models via the combination of a multivariable Ordinal Logistic Regression analysis and the proposed feature mapping algorithm.Results197 PCa patients, including 56 BPD, were enrolled in the study. An optimal subset with nine clinical features was selected. Compared with the best ML model and the clinic nomogram, the clinic-ML nomogram achieved the superior performance with a sensitivity of 0.713 (95% CI 0.573–0.853), specificity of 0.869 (95% CI 0.764–0.974), F1 of 0.699 (95% CI 0.557–0.841), and AUC of 0.864 (95% CI 0.794–0.935). The calibration curve and Decision Curve Analysis (DCA) indicated the predictive capacity and net benefits of the clinic-ML nomogram were improved.ConclusionCombining the interpretability and simplicity of a nomogram with the efficacy and robustness of ML models, the proposed clinic-ML nomogram can serve as an insight tool for preoperative assessment of PCa risk stratifications, and could provide essential information for the individual diagnosis and treatment in PCa patients.

Abstract PR010: First-in-class TRPV6 inhibitors for the treatment of prostate cancer

Abstract TRPV6, a calcium channel, is an oncochannel that is overexpressed in epithelial cancers including prostate cancer. We have developed a novel series of first-in-class small molecule TRPV6 inhibitors for the treatment of advanced prostate cancer. Our preclinical candidate QED-203 has been shown to inhibit calcium influx at low nM potency in TRPV6 cellular assays (FLIPR, electrophysiology), and has low nM potency in a TRPV6-driven NFAT assay (NFAT luciferase reporter). Inhibition of TRPV6 with our TRPV6 inhibitors or by siRNA knockdown causes changes in genes related to NFAT and WNT signalling, ER stress and the cell cycle (RNAseq and qPCR analysis), and causes cell cycle arrest, decreased proliferation and apoptosis in prostate cancer cells (demonstrated via imaging and FACS analysis). Importantly, QED-203 demonstrates potency in enzalutamide resistant cell lines (in vitro proliferation inhibition) and has superior potency over enzalutamide and darolutamide [androgen receptor targeting agents (ARTA)] in prostate cancer cell lines with clinically relevant AR mutations or the ARV7 splice variant. The ARV7 variant in particular is represented in a significant portion of patients no longer responding to ARTA SoC interventions. QED-203 has high bioavailability with a pharmacokinetic profile amenable to once-a-day oral dosing. QED-203 is well tolerated in rodents and has similar in vivo efficacy (tumour growth and PSA inhibition) to enzalutamide in a castrated LNCaP mouse model of prostate cancer. We have also shown QED-203 target engagement in rodents by demonstrating a change in calcium levels in the urine, and have observed changes in genes consistent with a TRPV6-specific mode of action in xenograft tumours (demonstrated via qPCR). QED-203 targets a novel, non-hormonal mechanism in prostate cancer, and could be used to treat prostate cancer patients who have developed resistance to AR therapies, where there is a large unmet need. Citation Format: Kimberley Beaumont, Rebecca Pouwer, Raphael Rahmani, Matthew McLachlan, Claire Levrier, Rebecca Farrow, Mei Yeh, Therese Johnson, Malika Kumarasiri, Hasanthi Wijesekera, Grant Stuchbury, Terrie-Anne Cock, Andrew Harvey, Gregory Monteith, Brian Dymock. First-in-class TRPV6 inhibitors for the treatment of prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr PR010.

Abstract B073: Inhibiting prostate cancer by targeting the metabolic mevalonate pathway

Abstract Background: A major challenge in the clinical management of prostate cancer (PCa) is inhibiting progression to lethal castrate-resistant PC (CRPC). Deregulated activity of mevalonate (MVA), cholesterol biosynthetic pathway is a recognized hallmark of PCa cells. Statins are potent inhibitors of this metabolic pathway that have been used for decades in the control of hypercholesterolemia. Statins have recently been shown to have anti-PCa activity, however statin treatment triggers a feedback response that restores the MVA pathway, which reduces statin efficacy and contributes to resistance. This restorative feedback loop is controlled by the transcriptional activity of sterol regulatory-element binding protein (SREBP), which primarily induces fatty acid biosynthesis and MVA pathway genes. We have recently identified the anti-platelet agent dipyridamole (DP) as an inhibitor of the statin-induced SREBP-mediated feedback response. However, DP is not SREBP-specific and given its anti-platelet activity, may not be suitable for every cancer patient. Thus, our goal was to identify additional drugs that potentiate the pro-apoptotic activity of statins, which can be used to treat PCa patients. Methods: Two independent, yet complimentary strategies were used. The first focused on performing an in silico analysis to identify drugs that had similar properties to DP at the level of drug structure, molecular perturbations and cell line sensitivity. The second strategy involved a high-content imaging analysis of 1508 FDA approved drugs, which was performed in LNCaP (relatively statin insensitive and feedback competent) and PC3 cells (statin sensitive and feedback incompetent). Cells were treated with a sub-lethal dose of fluvastatin, the drugs or the fluvastatin-drug combination, then treated with apoptotic stains (TMRE, Annexin, Draq 5). Captured images were analyzed using a machine learning approach. Results: Validation of hits from the in silico MVA-DNF approach and high-content screening has identified several drugs that fulfill our criteria of potentiating statin-induced cell death in a feedback-dependent or feedback-independent manner. Interestingly, many show higher Z-scores compared to DP indicating their superior statin potentiation activity to drive PCa cell death. Moreover, a sub-set of these drug significantly inhibit statin-triggered expression of MVA pathway genes HMGCS1 and INSIG1 (p &amp;lt; 0.001) more potently than DP. Conclusions: We have detailed two successful strategies to identify drugs that inhibit SREBP activation in response to statin treatment. These statin-drug combinations represent an effective ‘one-two punch’ to inhibit CRPC progression. These novel inhibitors of SREBP activation potentiate statin at clinically relevant concentrations more potently than DP and have no effect on the platelet activity. Excitingly, many of these agents are FDA-approved and can be immediately used in combination with statins for the treatment of PCa. Overall, our research will lead to novel therapies to improve patient outcome. Citation Format: Diandra Zipinotti dos Santos, Mohamad Elbaz, Emily Branchard, Wiebke Schormann, David W. Andrews, Linda Z. Penn. Inhibiting prostate cancer by targeting the metabolic mevalonate pathway [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr B073.

Novel Histopathological Biomarkers in Prostate Cancer: Implications and Perspectives.

Prostate cancer (PCa) is the second most frequently diagnosed cancer in men. Despite the significant progress in cancer diagnosis and treatment over the last few years, the approach to disease detection and therapy still does not include histopathological biomarkers. The dissemination of PCa is strictly related to the creation of a premetastatic niche, which can be detected by altered levels of specific biomarkers. To date, the risk factors for biochemical recurrence include lymph node status, prostate-specific antigen (PSA), PSA density (PSAD), body mass index (BMI), pathological Gleason score, seminal vesicle invasion, extraprostatic extension, and intraductal carcinoma. In the future, biomarkers might represent another prognostic factor, as discussed in many studies. In this review, we focus on histopathological biomarkers (particularly CD169 macrophages, neuropilin-1, cofilin-1, interleukin-17, signal transducer and activator of transcription protein 3 (STAT3), LIM domain kinase 1 (LIMK1), CD15, AMACR, prostate-specific membrane antigen (PSMA), Appl1, Sortilin, Syndecan-1, and p63) and their potential application in decision making regarding the prognosis and treatment of PCa patients. We refer to studies that found a correlation between the levels of biomarkers and tumor characteristics as well as clinical outcomes. We also hypothesize about the potential use of histopathological markers as a target for novel immunotherapeutic drugs or targeted radionuclide therapy, which may be used as adjuvant therapy in the future.

Predictive Factors for Gleason Score Upgrading in Patients with Prostate Cancer after Radical Prostatectomy: A Systematic Review and Meta-Analysis

Introduction: Previous studies have revealed that Gleason score upgrading (GSU) was closely related to an increased biochemical recurrence rate and adverse oncologic outcomes in patients with prostate cancer (PC). Therefore, we performed a meta-analysis to determine the predictive factors for GSU following radical prostatectomy (RP). Methods: We performed an extensive literature search using PubMed, Embase, and Cochrane in September 2022. In order to calculate the pooled odds ratio (OR), standardized mean difference (SMD), and 95% confidence intervals, a fixed effect or a DerSimonian and Laird random effect was applied. Results: Twenty-six studies included 18,745 PC patients that were available for further analysis. Our results revealed that GSU was significantly correlated with age (summary SMD = 0.13; p = 0.004), prostate volume (PV) (summary SMD = −0.19;p < 0.001), preoperative PSA (p-PSA) (summary SMD = 0.18; p < 0.001), PSA density (PSAD) (summary SMD = 0.40; p < 0.001), number of positive cores (summary SMD = 0.28; p = 0.001), percentage of positive cores (summary SMD = 0.36; p < 0.001), Prostate Imaging Reporting and Data System (PI-RADS) scores (>3/≤3) (summary OR = 2.27; p = 0.001), clinical T stage (>T2/≤T2) (summary OR = 1.73; p < 0.001), positive surgical margins (PSM) (summary OR = 2.12; p < 0.001), extraprostatic extension (EPE) (summary OR = 2.73; p < 0.001), pathological T stage (>T2/≤T2) (summary OR = 3.45; p < 0.001), perineural invasion (PNI) (summary OR = 2.40; p = 0.008), and neutrophil to lymphocyte ratio (NLR) (summary SMD = 0.50; p < 0.001). However, we found that GSU was not significantly correlated with body mass index (BMI) (summary SMD = −0.02; p = 0.602). Moreover, our sensitivity and subgroup analyses showed that the findings were reliable. Conclusions: Age, PV, p-PSA, PSAD, number of positive cores, percentage of positive cores, PI-RADS score, clinical T stage, PSM, EPE, pathological T stage, PNI, and NLR are independent factors predicting GSU following RP. The findings may be helpful in risk stratification and personalized treatment in PC patients.

Retreatment Plan Success through Patient Health Awareness, Health Behavior, and Access to Doctor after a Focal Therapy Procedure for Prostate Cancer

Objective: The research aimed to investigate the retreatment plan success through patient health awareness, health behavior, and access to a doctor when patients have in-field or outfield recurrence after a focal therapy procedure for prostate cancer. This research is initiated because many men are victims of prostate cancer. Methods: The research collected data from patient's focal therapy clinics for their treatment of prostate cancer. The data for this research was collected with a longitudinal design because a complete procedure of patient treatment was required in this study. Results: The findings disclosed that prostate cancer patients' retreatment can be a success when they have health awareness and access to a doctor for focal therapy. The model developed in this research is a significant contribution to the literature on patient satisfaction and prostate cancer treatment. The research has contributed remarkable implications to the theory by presenting a newly developed relationship with empirical evidence based on patients' responses. Conclusion: The study has presented a roadmap for the practical treatment of prostate cancer patients and treatment success for the patient's treatment in the future. Some future recommendations are also reported for future investigation and work on prostate cancer and retreatment success.

The Gut-Prostate Axis: A New Perspective of Prostate Cancer Biology through the Gut Microbiome.

Obesity and a high-fat diet are risk factors associated with prostate cancer, and lifestyle, especially diet, impacts the gut microbiome. The gut microbiome plays important roles in the development of several diseases, such as Alzheimer's disease, rheumatoid arthritis, and colon cancer. The analysis of feces from patients with prostate cancer by 16S rRNA sequencing has uncovered various associations between altered gut microbiomes and prostate cancer. Gut dysbiosis caused by the leakage of gut bacterial metabolites, such as short-chain fatty acids and lipopolysaccharide results in prostate cancer growth. Gut microbiota also play a role in the metabolism of androgen which could affect castration-resistant prostate cancer. Moreover, men with high-risk prostate cancer share a specific gut microbiome and treatments such as androgen-deprivation therapy alter the gut microbiome in a manner that favors prostate cancer growth. Thus, implementing interventions aiming to modify lifestyle or altering the gut microbiome with prebiotics or probiotics may curtail the development of prostate cancer. From this perspective, the "Gut-Prostate Axis" plays a fundamental bidirectional role in prostate cancer biology and should be considered when screening and treating prostate cancer patients.

Consecutive Prostate-Specific Membrane Antigen (PSMA) and Antigen Receptor (AR) PET Imaging Shows Positive Correlation with AR and PSMA Protein Expression in Primary Hormone-Naïve Prostate Cancer.

The present study was carried out to investigate whether PET imaging can be used as a potential substitute for immunohistochemical analysis of tumor samples in prostate cancer (PC) patients. Correlation between imaging signals of 2 PET tracers and the corresponding target structures was assessed. The first tracer was [68Ga]Ga-PSMA (prostate-specific membrane antigen)-HBED-CC (N,N'-bis [2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N'-diacetic acid) [68Ga]Ga-PSMAHBED-CC ([68Ga]PSMA), which is already implemented in clinical routines. The second tracer was 16β-[18F]fluoro-5α-dihydrotestosterone (16β-[18F]FDHT), which binds to the androgen receptor (AR). The AR is particularly interesting in PC, because AR expression status and its shift during therapy might directly influence patient care. Methods: This prospective, explorative clinical study included 10 newly diagnosed PC patients. Each patient underwent [68Ga]PSMA PET/MRI and [18F]FDHT PET/MRI scans before prostatectomy. Cancer SUVs were determined and related to background SUVs. After prostatectomy, tumor tissue was sampled, and AR and prostate-specific membrane antigen (PSMA) expression was determined. AR and PSMA expression was evaluated quantitatively with the open-source bioimage analysis software QuPath and with a 4-tier rating system. Correlation between imaging signals and marker expression was statistically assessed. Results: For [18F]FDHT, the SUVmax/SUVbackground ratio showed a significant, strong correlation (r = 0.72; P = 0.019) with the AR optical density of the correlating tissue sample. The correlation between PSMA optical density and the [68Ga]PSMA SUVmax/SUVbackground ratio was not significant (P = 0.061), yet a positive correlation trend could be observed (r = 0.61). SUVmax/SUVbackground ratios were higher for [68Ga]PSMA (mean ± SD, 34.9 ± 24.8) than for [18F]FDHT (4.8 ± 1.2). In line with these findings, the tumor detection rates were 90% for the [68Ga]PSMA PET scan but only 40% for the [18F]FDHT PET scan. The 4-tier rating of PSMA staining intensity yielded very homogeneous results, with values of 3+ for most subjects (90%). AR staining was rated as 1+ in 2 patients (20%), 2+ in 4 patients (40%), and 3+ in 4 patients (40%). Conclusion: [18F]FDHT PET may be useful for monitoring AR expression and alterations in AR expression during treatment of PC patients. This approach may facilitate early detection of treatment resistance and allows for adaptation of therapy to prevent cancer progression. [18F]FDHT PET is inferior to [68Ga]PSMA PET for primary PC diagnosis, but the correlation between [68Ga]PSMA SUVs and PSMA expression is weaker than that between [18F]FDHT and the AR.

Adaptive magnetic resonance image guided radiation for intact localized prostate cancer how to optimally test a rapidly emerging technology.

IntroductionProstate cancer is a common malignancy for which radiation therapy (RT) provides an excellent management option with high rates of control and low toxicity. Historically RT has been given with CT based image guidance. Recently, magnetic resonance (MR) imaging capabilities have been successfully integrated with RT delivery platforms, presenting an appealing, yet complex, expensive, and time-consuming method of adapting and guiding RT. The precise benefits of MR guidance for localized prostate cancer are unclear. We sought to summarize optimal strategies to test the benefits of MR guidance specifically in localized prostate cancer.MethodsA group of radiation oncologists, physicists, and statisticians were identified to collectively address this topic. Participants had a history of treating prostate cancer patients with the two commercially available MRI-guided RT devices. Participants also had a clinical focus on randomized trials in localized prostate cancer. The goal was to review both ongoing trials and present a conceptual focus on MRI-guided RT specifically in the definitive treatment of prostate cancer, along with developing and proposing novel trials for future consideration. Trial hypotheses, endpoints, and areas for improvement in localized prostate cancer that specifically leverage MR guided technology are presented.ResultsMultiple prospective trials were found that explored the potential of adaptive MRI-guided radiotherapy in the definitive treatment of prostate cancer. Different primary areas of improvement that MR guidance may offer in prostate cancer were summarized. Eight clinical trial design strategies are presented that summarize options for clinical trials testing the potential benefits of MRI-guided RT.ConclusionsThe number and scope of trials evaluating MRI-guided RT for localized prostate cancer is limited. Yet multiple promising opportunities to test this technology and potentially improve outcomes for men with prostate cancer undergoing definitive RT exist. Attention, in the form of multi-institutional randomized trials, is needed.

Clinical Applications of PSMA PET Examination in Patients with Prostate Cancer.

Simple SummaryThe prostate specific membrane antigens, abbreviated as PSMAs, are type II membrane proteins that are highly ex-pressed on the surface of malignant prostate tissue in prostate cancer (PCa), particularly in aggressive, andro-gen-deprived, metastatic, and hormone-refractory PCa. Today, radionuclides that bind to these PSMA peptides are widely available for diagnostic and therapeutic purposes to specifically image and target prostate tumor cells at molec-ular level. In this descriptive review, we aimed to emphasize the usefulness of PSMA positron emission tomography (PET) examination in the management of patients with various stages of PCa. In addition, we outlined the main pitfalls and limitations of this scan to avoid misinterpretation of the results and to improve the decision making process in rela-tion to the patient’s further treatment. We concluded that PSMA PET examination in primary PCa patients has an es-sential role in the high-risk group. It is the new imaging standard in patients with in biochemical recurrence PCa and plays an important role in treatment decision. Furthermore, PSMA PET scan is a gold standard for the evaluation of PSMA targeted therapies in patients having progress of the disease. Future prospective studies, particularly on the im-pact of PSMA PET on therapy stratification, may further strengthen the role of PSMA in the treatment of PCa patients. With the progressive aging of the population in industrially developed countries, as well as advances in diagnostic and biopsy techniques and improvements in patient awareness, the incidence of prostate cancer (PCa) is continuously increasing worldwide. Therefore, PCa is currently considered as the second leading cause of tumor-related death. Early detection of the tumor and its metastasis is essential, as the rate of disease recurrence is high and occurs in 27% to 53% of all patients who underwent curative therapy with radical prostatectomy or local radiotherapy. In this regard, the prostate specific membrane antigens, abbreviated as PSMAs, are type II membrane proteins that are highly expressed on the surface of malignant prostate tissue in PCa, particularly in aggressive, androgen-deprived, metastatic, and hormone-refractory PCa, and they are inversely associated with the androgen level. Up to 95% of adenocarcinomas of the prostate express PSMA receptors on their surface. Today, radionuclides that bind to these PSMA peptides are widely accepted for diagnostic and therapeutic purposes to specifically image and target prostate tumor cells at the molecular level, a process referred to as targeted theranostics. Numerous studies have demonstrated that the integration of these peptides into diagnostic and therapeutic procedures plays a critical role in the primary staging and treatment decisions of especially high-risk PCa, expands therapeutic options for patients with advanced stage of prostate tumor, and prolongs patients’ survival rate. In this review article, we intend to briefly spotlight the latest clinical utilization of the PSMA-targeted radioligand PET imaging modality in patients with different stages of PCa. Furthermore, limitations and pitfalls of this diagnostic technique are presented.

The Androgen Receptor and Its Crosstalk With the Src Kinase During Castrate-Resistant Prostate Cancer Progression.

While the androgen receptor (AR) signalling is the mainstay therapeutic target for metastatic prostate cancers, these tumours will inevitably develop therapy resistance to AR pathway inhibitors suggesting that prostate tumour cells possess the capability to develop mechanisms to bypass their dependency on androgens and/or AR to survive and progress. In many studies, protein kinases such as Src are reported to promote prostate tumour progression. Specifically, the pro-oncogene tyrosine Src kinase regulates prostate cancer cell proliferation, adhesion, invasion, and metastasis. Not only can Src be activated under androgen depletion, low androgen, and supraphysiological androgen conditions, but also through crosstalk with other oncogenic pathways. Reciprocal activations between Src and AR proteins had also been reported. These findings rationalize Src inhibitors to be used to treat castrate-resistant prostate tumours. Although several Src inhibitors had advanced to clinical trials, the failure to observe patient benefits from these studies suggests that further evaluation of the roles of Src in prostate tumours is required. Here, we summarize the interplay between Src and AR signalling during castrate-resistant prostate cancer progression to provide insights on possible approaches to treat prostate cancer patients.