Background: Most therapy options for castration-resistant prostate cancer (CRPCa) target the androgen axis. Human kallikrein-related peptidase (KLK) 2, a serine protease, is a downstream target gene of the androgen receptor (AR) involved in cancer progression, but also known to have an AR-independent function. Tissue KLKs, especially KLK2, are promising targets for therapy in advanced PCa because of their high PCa specificity and their correlation to the rising cancer grade and stage. By inhibition with the recombinant protease inhibitor MDPK67b targeting KLK2 and other trypsin-like KLKs including KLK4 and KLK14, we investigated the antitumor response and the influence on AR downstream target genes with MDPK67b in PCa cell lines in vitro.
Methods: Human PCa cells were cultured in a charcoal-stripped media and treated with MDPK67b (0.75 mg/mL). Cell viability was measured by CellTiter-Glo luminescent assay, cell death by flow cytometry. Gene analysis of AR, PSA, and PSMA was performed by qPCR. Correlating protein levels were evaluated by immunoblotting and confirmed by immunocytochemical staining.
Results: Treatment with 0.75 mg/mL MDPK67b led to a reduction of cell proliferation of 40% by day 5 in androgen-sensitive LNCaP cells. Immunostaining confirmed the decrease in cell proliferation by antibody labeling of Ki-67. Treatment induced apoptosis, which was visible by flow cytometry of annexin V in LNCaP cells. Further, MDPK67b induced a reduction in AR and PSA gene and protein expression but upregulated PSMA, a target for PCa imaging and therapy.
Conclusion: Treatment with MDPK67b demonstrates a significant antitumor effect by relevant reduction in cell proliferation and upregulation of apoptosis in LNCaP cells. Blockage of secreted KLKs can downregulate the AR and thereby influence its downstream target genes like PSA and PSMA. Upregulation of PSMA can lead to a theranostic, that is, therapeutic and diagnostic, advantage in clinics in a CR setting. Therefore, inhibition of KLKs represents a promising and AR-independent approach to treat advanced and CRPCa.
Trial registration: ClinicalTrials.gov ID: NCT04644770.
The first cellular cancer immunotherapy, sipuleucel-T, was approved for metastatic castration-resistant prostate cancer (mCRPC) patients 15 years ago. Since then, the therapeutic landscape of advanced prostate cancer has significantly evolved. Sipuleucel-T is a personalized, autologous immunotherapy that activates the patient's immune system to target prostatic acid phosphatase (PAP)-expressing tumor cells and has demonstrated survival benefit in patients with nonopioid requiring mCRPC. Subsequent clinical trials and abundant real-world data have provided further evidence of this novel immunotherapy's clinical benefit for patients with mCRPC, as well as demonstrating the numerous immune and biologic responses that sipuleucel-T induces. These data have also identified patient-specific factors associated with longer survival, including race, baseline disease burden, and treatment-induced immune responses. Despite the addition of multiple life-prolonging therapeutic modalities now available to treat patients with mCRPC, the mechanism of action of sipuleucel-T remains unique for patients with advanced prostate cancer. Therefore, maximizing the appropriate clinical utilization of sipuleucel-T in patients with mCRPC within current treatment paradigms is essential.
Background: Prostate cancer is the second leading cause of cancer death among men, with a disproportionate burden on Black men. Racial disparities in care delivery for early-stage disease are well documented but less is known about racial gaps in advanced prostate cancer care, a stage where effective therapies can prolong life for years. We sought to evaluate potential treatment disparities among Black and White men with metastatic prostate cancer.
Methods: We performed a retrospective cohort study of patients with metastatic prostate cancer receiving treatment at a large public tertiary care health system between 2015 and 2020 using electronic health record data. We estimated the prevalence ratio (PR) of being prescribed each of the recommended treatment options for metastatic prostate cancer as per National Comprehensive Care Network guidelines, including androgen receptor pathway inhibitors (ARPIs) and other antiandrogens, chemotherapy, and bone protection, comparing Black men to White men.
Results: We identified 1166 patients with metastatic prostate cancer treated with androgen deprivation therapy (ADT); 370 (32%) were Black. Prescribing of systemic treatments did not differ by race, notably including ARPI (PR: 0.98 95% CI: 0.98-1.1, p=0.8). About 30% of both Black and White patients interacted with our patient navigation team, a group of oncology nurses focused on ensuring patients receive recommended care.
Conclusions: In a large public tertiary care health system, we did not observe racial disparities in the prescribing of guideline-recommended therapies for metastatic prostate cancer. High rates of insurance, a robust patient navigation program, and a well-developed pharmacy assistance program may have helped mitigate racial disparities in care. Future studies should prospectively evaluate the delivery of prostate cancer therapies across health systems and the influence of navigation and pharmacy assistance programs.
Objectives: To assess the validity of magnetic resonance imaging-determined tumor contact area (MRI-TCA) as a predictive factor for pathological extraprostatic extension (EPE) in cT2N0M0 prostate cancer patients.
Methods: We retrospectively analyzed 72 cT2N0M0 prostate cancer patients who underwent multiparametric MRI (mpMRI) followed by robot-assisted laparoscopic prostatectomy (RARP) between February 2014 and April 2021. Patients whose MRI-based index lesion did not match the pathological specimens were excluded. MRI-TCA was approximated using an elliptical shape and calculated by two different methods: MRI-TCA1: Calculated using the tumor contact length (TCL) in the axial plane and the longer TCL in either the sagittal or coronal plane, capturing tumor dimensions across two planes. MRI-TCA2: Calculated using the TCL in the axial plane and tumor thickness derived from MRI slice data, reflecting the tumor's contact area within the MRI volume. We compared postoperative prostate-specific antigen (PSA) recurrence-free survival by stratifying patients based on the optimal thresholds of MRI-TCL, MRI-TCA1, MRI-TCA2, pathological-TCL, and pathological-TCA.
Results: Sixteen patients (22.2%) were pathologically positive for EPE. MRI-TCL, MRI-TCA1, and MRI-TCA2 were significantly greater in patients with EPE-positive (EPE+) tumors than in those with EPE-negative (EPE-) tumors (p < 0.0001, p < 0.0001, and p = 0.0026, respectively). No statistically significant differences were found between MRI-TCL and MRI-TCA1 (p = 0.914) or between MRI-TCL and MRI-TCA2 (p = 0.112) in predicting pathological EPE. A significant difference in postoperative PSA recurrence rate was observed in the stratified analysis based on pathological-TCA (p = 0.022).
Conclusion: Both MRI-TCA1 and MRI-TCA2 are clinically accessible and effective parameters for predicting pathological EPE in cT2N0M0 prostate cancer patients. However, neither method demonstrated clear superiority over MRI-TCL. Pathological-TCA was shown to be a significant predictor of both pathological EPE and postoperative PSA recurrence.
Prostate cancer is the most frequently diagnosed tumor of male reproductive system. Clinically, there is a lack of effective treatment drugs for prostate cancer. Previous studies have shown that AMPK inhibitor dorsomorphin was demonstrated to have potent antitumor effects. However, the effect of dorsomorphin on prostate cancer and its molecular mechanism are still unclear. In this study, the effects of dorsomorphin on the invasion and infiltration, epithelial-mesenchymal transition (EMT), and angiogenesis were investigated in two types of prostate cancer cells (DU145 and PC-3). In addition, nude mouse tumorigenic experiments were performed to confirm the antitumor effect of dorsomorphin. We found that dorsomorphin treatment concentration- and time-dependently inhibited the invasion and infiltration of DU145 and PC-3 cells. In addition, dorsomorphin reduced the expression levels of extracellular matrix components and angiogenesis-related proteins (HIF-1α and VEGF). Further study showed that dorsomorphin inhibited matrix deposition by antagonizing the EMT. Our results from nude mouse tumorigenic experiments further demonstrated dorsomorphin's tumor-growth inhibitory effect, whereas its antimetastatic potential is supported by in vitro invasion and EMT assays. Mechanistically, dorsomorphin treatment suppressed TGF-β1 expression and thereby inhibited the phosphorylation and nucleation of Smad2/3 signaling, which plays a key role in the regulation of EMT. Further study showed that dorsomorphin-triggered inactivation of JAK2/STAT3 and sonic hedgehog (Shh) signaling was involved in the inhibition of TGF-β1-mediated EMT. Interestingly, dorsomorphin inhibited the expression and nucleation of Gli1 and Gli3 but not affected the expression of Gli2. Thus, these findings reveal that the new mechanism of AMPK inhibitor dorsomorphin against prostate cancer metastasis is through synergistically antagonizing JAK2/STAT3 and Gli2-independent Shh activation.
Background: Fibroblast growth factor receptor 1 (FGFR1) signaling is activated by fibroblast growth factors (FGFs) during prostate cancer (PCa) progression. However, the mechanisms by which FGFR1 signaling regulates PCa progression are not fully understood. The objective of this study was to investigate the cross talk between autocrine FGF/FGFR1 loop and aerobic glycolysis in progression of advanced PCa. Method: DU145 cells were used as an advanced PCa model. FGFR1 expression was knockdowned by stable expression of anti-FGFR1 shRNA, and lactate dehydrogenase A (LDHA) levels were rescued by ectopic expression of LDHA cDNA. Protein expression was determined using Western blotting and immunohistochemistry. Tumorigenicity of DU145 cells was defined by cell growth, invasion, and survival in both cultures and xenografts in mice. Results: Here, we showed that DU145 cells in cultures expressed both FGF2 and FGFR1, and knockdown of FGFR1 expression or inactivation of FGFR1 signaling reduced LDHA expression or aerobic glycolysis, which was correlated with suppression of both cell proliferation and invasion, and with promotion of apoptosis. Ectopic expression of LDHA cDNA rescued LDHA levels in FGFR1-deficient cells, restoring their aerobic glycolysis, cell growth, and survival. Similarly, the growth rates of xenografted DU145 cells in mice were decreased by the loss of FGFR1 expression but were rescued by the ectopic expression of LDHA. Conclusion: Our data indicate autocrine FGF/FGFR1 signaling regulates aerobic glycolysis in PCa DU145 cells via LDHA, suggesting the potential of targeting FGFs/FGFRs-LDHA for the management of advanced PCa. The regulation of aerobic glycolysis by other growth factors in PCa remains further investigation.
High-intensity focused ultrasound (HIFU) is a noninvasive modality that is gaining prominence for the localized treatment of malignant tumors. Most current HIFU research utilizes mouse tumor models, where selection of appropriate mouse breed is important for conducting thermal ablation experiments on tumors with consistency. In this study, three breeds (NOD/SCID GammaC -/- (NSG), NSG-SGM3 (NSGS), and Homozygote J:NU (Nude); n = 2 per group) originating from Jackson Laboratory were tested for identifying the breed that has sufficient size for conducting HIFU experiments. Tumors were developed using a human PC3 (CRL-1435) prostate cancer cell line and monitored over 5 to 7 weeks. The surface area and volume of the implanted tumors were determined by assuming the tumor having an ellipsoidal shape. At the end of the growth period, NSG mice exhibited 29% larger tumor surface area than NSGS and 58% larger than Nude mice. Similarly, NSG mice had a 55% larger tumor volume than NSGS mice and 100% larger than Nude mice. Therefore, this research established NSG mice as the superior mouse breed for the PC3 cell-induced tumor growth having established size within a reasonable timeline (5-7 weeks). Subsequently, the NSG model with a larger sample size (n = 48) was selected for HIFU ablation, and histopathological analysis revealed a significantly higher number of apoptotic cells in the HIFU-treated tumors compared to controls. This further confirmed the model's suitability for HIFU research. Tumor surface area and volume compared between the tested (n = 2) and selected (n = 48) groups were statistically insignificant (p = 0.78 for surface area and p = 0.60 for volume).
Background: Prostate cancer (PCa) is a prevalent malignancy in men, with increasing incidence and longer wait times for curative surgery, particularly in public health systems. While the impact of surgical wait time (SWT) on oncological outcomes in PCa remains controversial, its influence on patient-reported outcomes has not been thoroughly evaluated. Objective: To assess the impact of SWT on both oncological and psychological outcomes in patients undergoing robot-assisted radical prostatectomy (RARP) for preoperative ISUP grade 2 and 3 PCa. Methods: This retrospective single-center study included patients who underwent RARP for intermediate risk localized PCa between April 2016 and August 2024. Patients were stratified into two groups based on SWT: < 6 months vs. ≥ 6 months. The primary outcome was recurrence-free survival (RFS) for all patients. Secondary outcomes included RFS in a high-risk subgroup defined by pathological features (pT3 stage, seminal vesicle invasion, extracapsular extension, and positive surgical margins), as well as a comparison of functional outcomes between the two groups. Patient-reported outcomes were evaluated using SF-36 (mental and physical components) and the Decision Regret Scale (DRS) at 6 weeks, 3 months, 6 months, and 1 year. Statistical analyses included Kaplan-Meier survival estimates, Cox proportional hazard models, and comparative tests with p < 0.05 considered significant. Results: 218 patients have been included. RFS did not significantly differ between groups (p=0.98), including among high-risk patients (p=1.00). No significant differences were found in extraprostatic extension, seminal vesicle invasion, positive surgical margins, or ISUP upgrading between groups. Similarly, changes in both SF-36 physical and mental and DRS scores showed no statistically significant differences at all time points. Conclusion: In this cohort of patients with intermediate-risk PCa, SWT beyond 6 months did not adversely affect oncological or health-related quality of life outcomes.
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