Castration-resistant Prostate Cancer Research Articles

225Aс-PSMA-617 therapy in metastatic castration-resistant prostate cancer

177Lu-PSMA-617 is a new therapy option for PSMA-positive metastatic castrate-resistant metastatic prostate cancer (mCRPC) with proven efficacy. 225Ac-PCMA-617 is an alpha emitter, making this drug potentially more powerful. Despite the active use of 225Ac-PSMA-617 worldwide, no randomized phase III studies have yet been conducted. The present prospective cohort study presents the experience of 225Ac-PSMA-617 use in the A.F. Tsyb MRRC. Material and Methods. the study included mCRPC patients with prostate-specific membrane antigen (PSMA) overexpression confirmed by PET-CT or SPECT-CT, who received the first course of therapy in 2023. Results. Forty three patients received 1 to 6 (median 2) administrations of 225Ac-PSMA-617, 26 (60 %) of these patients had a history of 177Lu-PSMA-617 therapy, 13 (30 %) had a history of radium chloride [223Ra] therapy, and 10 (23 %) patients had no history of chemotherapy. Five (12 %) had liver metastases at the time of inclusion in the study. PSA reduction of more than 50 % was recorded in 55 % of patients, with biochemical response significantly more frequent in the PSMA-naïve group, 63 % vs 35 %; the number of adverse events was also lower in this group. But no advantage in overall survival (OS) in PSMA-naïve patients was revealed at the present time. Favorable prognosis factors included a history of radium chloride [223Ra] therapy; in contrast, liver metastasis was a negative prognostic factor. the study found no differences in OS among taxane-naïve patients and patients with a history of 1–2 lines of chemotherapy. Continued therapy with androgen receptor targeted agents after initiation of 225Ac-PSMA-617 treatment also showed no effect on OS. Conclusions. 225Ac-PCMA-617 may be effective in 177Lu-PCMa resistance, but there are no data on the increase in overall patient survival when 225Ac-PCMA-617 is administered as first-line radioligand therapy.

Lutetium-177 PSMA radioligand therapy in taxan-naive first- and second-line metastatic castration resistant prostate cancer after first-line ARPI therapy.

Lutetium-177 Prostate-specific membrane antigen (Lu-PSMA) radioligand therapy is EMA-approved for metastatic castration resistant prostate cancer (mCRPC) after androgen receptor pathway inhibition (ARPI) and taxan-based chemotherapy. However, its effect in taxan-naïve patients is under current investigation. We relied on the FRAMCAP database to elaborate Lu-PSMA therapy outcomes of progression-free (PFS) and overall (OS) in taxan-naïve mCRPC patients after previous ARPI treatment. Comparison was made against current standard of care with ARPI or docetaxel, irrespective of the previous used staging modality. Of 269 patients, 11% received Lu-PSMA in first/second-line mCRPC vs. 57% ARPI vs. 33% docetaxel. Mostly no significant baseline differences between Lu-PSMA and ARPI patients were observed, while Lu-PSMA patients were significantly older, received less systematic treatments and ECOG1-2 proportions were higher, relative to docetaxel patients. In PFS (13.3 vs. 8.2 months, hazard ratio [HR]: 0.70, p = 0.16) and OS analyses (68.9 vs. 39.1 months, HR: 0.64, p = 0.2), Lu-PSMA was numerically more favorable than ARPI. In additional multivariable Cox regression models, Lu-PSMA was significant better regarding PFS and OS, relative to ARPI (both p < 0.05). Compared to docetaxel, also significant better PFS (13.3 vs. 8.1 months, HR: 0.46) and OS (68.9 vs. 27.3 months, HR: 0.34, both p < 0.01) was observed for Lu-PSMA treatment. The OS advantage was also observed after multivariable adjustment (p < 0.01). This retrospective single-center study including a substantial proportion of patients with treatment preference for Lu-PSMA suggests that Lu-PSMA therapy provides significantly more favorable PFS and OS outcomes in taxan-naïve mCRPC patients after previous ARPI treatment, relative to ARPI or docetaxel treatment and may be considered as an early mCRPC treatment option.

Comprehensive Genome Profiling Test in Japanese Patients With Castration-Resistant Prostate Cancer: A Single-Center Retrospective Study

Comprehensive Genome Profiling Test in Japanese Patients With Castration-Resistant Prostate Cancer: A Single-Center Retrospective Study

Synergistic Anti-tumorigenic Effects of Cabazitaxel and Usnic Acid Combination on Metastatic Castration-Resistant Prostate Cancer Cells.

Prostate cancer (PC) affects millions of men, causing high mortality rates. Despite the treatment approaches, the options for metastatic castration-resistant prostate cancer (mCRPC), a lethal form of advanced PC, are still limited. Cabazitaxel (Cbx) is the last taxane-derived chemotherapeutic approved for Docetaxel- resistant mCRPC patients. However, its effects are limited due to the activation of several pathways. Therefore, new approaches are needed to increase the efficacy of Cbx. Usnic acid (UA) is a natural product with wellknown anti-tumorigenic and synergistic effects with various chemotherapeutics. Although the cytotoxicity of UA and Cbx has been evaluated on mCRPC cells, the anti-tumorigenic effect of UA combination with any taxane has not been investigated yet. Thus, we aimed to evaluate the possible synergistic effect of Cbx+UA in mCRPC cells. Cell viability and apoptosis were analyzed using WST-1 and Annexin-V. Morphological changes were visualized by fluorescent staining. Finally, cell cycle, mitochondrial health, and ROS levels were determined. Based on WST-1 results, 25 μM UA exhibited significant additive and synergistic effects with the use of Cbx. Annexin V and cell cycle results showed that UA significantly enhanced the Cbx efficacy at increasing doses compared to using only Cbx (**p<0.01). Moreover, combined treatment significantly increased ROS levels and mitochondrial membrane depolarization compared with Cbx alone (**p<0.01). Thus, the results suggest that UA increased the anti-tumorigenic effects of Cbx on mCRPC cells by increasing apoptosis, causing an increase in intracellular ROS and disrupting mitochondrial health. Consequently, combining UA and Cbx offers a new combined therapeutic strategy for mCRPC treatment.

PSMA and SSTR2 Dual-Targeting Theranostic Agents for Neuroendocrine-Differentiated Prostate Cancer (NEPC).

Radioactive prostate-specific membrane antigen (PSMA)-targeting agents are clinically useful for the diagnosis and treatment of patients with PSMA-positive metastatic castration-resistant prostate cancer (mCRPC). Neuroendocrine-differentiated prostate cancer (NEPC), a highly aggressive subtype that is strongly associated with a poor clinical prognosis, may present with reduced PSMA expression and evade detection with PSMA-targeted agents. Several studies have shown elevated uptake of somatostatin receptor 2 (SSTR2) ligands in PSMA-negative NEPC. By combining a SSTR2-targeting peptide, JR11, with previously reported PSMA-targeting ligands, P16-093 and P17-087, [68Ga]Ga-1 and [68Ga]Ga/[177Lu]Lu-2 were designed and synthesized. The cell uptake of [68Ga]Ga-1 was comparable to [68Ga]Ga-P16-093 in PSMA-positive cell lines, while [68Ga]Ga-1 and [68Ga]Ga-2 showed a positive but slightly lower uptake than [68Ga]Ga-DOTA-TATE in SSTR2-positive cell lines. In vivo studies in SSTR2+ or PSMA+ tumor-bearing mice demonstrated that [68Ga]Ga-1 and [68Ga]Ga/[177Lu]Lu-2 showed positive uptake for both SSTR2+ and PSMA+ tumors. These dual-targeting radiotracers are potentially valuable for the diagnosis and radioligand therapy of NEPC.

Harnessing nature's therapeutic potential: A review of natural products in prostate cancer management.

Prostate cancer is the most commonly diagnosed cancer and the second leading cause of cancer-related death among men in the United States. The global burden of this disease is rising, placing significant strain on healthcare systems worldwide. Although definitive therapies like surgery and radiation are often effective, prostate cancer can recur and progress to castration-resistant prostate cancer in some cases. Conventional treatments for prostate cancer often have substantial side effects that can greatly impact patients' quality of life. Therefore, many patients turn to complementary therapies to improve outcomes, manage side effects, and enhance overall well-being. Natural products show promise as complementary treatments for prostate cancer, offering anticancer properties with a low risk of adverse effects. While preclinical research has produced encouraging results, their role in prostate cancer treatment remains controversial, largely due to inconsistent and limited success in clinical trials. This review explores the mechanisms of action of key natural products in prostate cancer management and summarizes clinical trials evaluating their efficacy and safety. It underscores the need for high-quality, rigorously designed, and adequately powered studies to validate the therapeutic potential and safety of these supplements in cancer care. Additionally, we propose future directions to enhance their role in addressing the complex challenges associated with prostate cancer.

Alkaline phosphatase decline and pain response as predictors of overall survival benefit in patients treated with radium-223: a post hoc analysis of the REASSURE study.

Alkaline phosphatase (ALP) declines and pain responses can occur during radium-223 (223Ra) treatment, but their association with treatment outcomes is unclear. For patients with metastatic castration-resistant prostate cancer treated with 223Ra in the REASSURE study, we investigated whether ALP decline (Week 12) and/or pain response (during treatment) are associated with improved overall survival (OS). The Brief Pain Inventory-Short Form (BPI-SF) was used to assess pain at baseline and pain response (in patients with baseline BPI-SF score ≥2). Of 785 patients with baseline and Week 12 ALP measurements, 779 were eligible for the OS analyses. Overall, 80% of patients had an ALP decline. Median OS was longer in patients with than without an ALP decline (18.1 versus 14.2 months; HR 0.74; 95% CI 0.60-0.92). In patients with an ALP decline, there was no clear OS difference between those with versus without a pain response. For patients without ALP decline, median OS was longer in those with versus without a pain response (16.2 versus 10.9 months; HR 0.50; 95% CI 0.32-0.77). Decreases in ALP and/or pain during 223Ra treatment are associated with improved OS. This may help support clinical decisions. ClinicalTrials.gov identifier NCT02141438. Analyses from the radium-223 REASSURE global study suggest that declines in alkaline phosphatase and pain during treatment may predict longer survival in patients with advanced prostate cancer and may help doctors make decisions with their patients.

Comparison of two alternative sequences with cabazitaxel and 177Lu-PSMA-617 in metastatic castration-resistant prostate cancer: A retrospective multicenter study (LuCaS).

Cabazitaxel and 177Lu-PSMA-617 have been shown to improve survival in patients with metastatic castration-resistant prostate cancer (mCRPC) previously treated with docetaxel and androgen receptor pathway inhibitors (ARPI). we aimed to evaluate the impact of sequencing cabazitaxel and 177Lu-PSMA-617 on survival outcomes in patients with mCRPC. This is a retrospective, multicenter, cohort study which included patients with mCRPC who received sequential treatment with 177Lu-PSMA-617 and cabazitaxel between January 2015 and December 2023. Primary outcome was progression-free survival-2 (PFS-2) RESULTS: A total of 68 patients with mCRPC who received sequential 177Lu-PSMA-617 and cabazitaxel were included in the study. The primary outcome, progression-free survival-2 (PFS-2), was similar in patients treated with 177Lu-PSMA-617 first (LU-CA) and those receiving cabazitaxel (CA-LU) first (10.8 and 11.7 months, respectively; p = 0.422). The median overall survival (OS) was also similar in the LU-CA and CA-LU groups (16.6 and 19.9 months, respectively; p = 0.917). The objective response rate (ORR) for 177Lu-PSMA-617 was 23.1 % when used first and 16.1 % after cabazitaxel. ORR for cabazitaxel was 25.6 % and 31.3 % when used as the first agent and when used after 177Lu-PSMA-617, respectively. In conclusion, treatment sequencing between cabazitaxel and 177Lu-PSMA-617 did not significantly affect survival outcomes in patients with mCRPC. These findings suggest that both drugs can be effectively integrated into the mCRPC treatment paradigm without concerns about the effect of sequencing. However, prospective data are needed to optimize sequencing strategies and explore their impact on specific patient subgroups for more personalized care.

Germline and Somatic Genomic Testing for Metastatic Prostate Cancer: ASCO Guideline.

To evaluate evidence on germline and somatic genomic testing for patients with metastatic prostate cancer and provide recommendations. A systematic review by a multidisciplinary panel with patient representation was conducted. The PubMed database was searched from January 2018 to May 2024. Articles were selected for inclusion if they reported on patients with metastatic prostate cancer who received a germline or somatic genomic test and/or made comparisons between those tests, reported detection rates, prognostic information, or treatment implications. A total of 1,713 papers were identified in the literature search. After applying the eligibility criteria, 14 remained: eight systematic reviews and six clinical trials. Patients with metastatic prostate cancer should undergo both germline and somatic DNA sequencing using panel-based assays. These tests can guide the use of poly(ADP-ribose) polymerase inhibitors, which have a survival benefit in metastatic castration-resistant prostate cancer. In addition, germline testing may have screening implications for additional cancers for patients and cascade testing implications for family members. The data supporting when to perform repeat testing and optimal tissue type to use (eg, primary tumor v metastatic biopsy versus circulating tumor DNA [ctDNA] testing) are more limited, but this panel recommends considering retesting in patients whose results were previously negative or uninformative, and to consider either a metastatic biopsy or ctDNA when a significant change in clinical status occurs. Next-generation genomic sequencing findings that are associated with prognostic only (and not predictive) value should not be used to guide treatment outside of a clinical trial.Additional information is available at www.asco.org/genitourinary-cancer-guidelines.

Time to Castration Resistance is Associated With Overall Survival Even After the Achievement of Castration Resistance in Metastatic Prostate Cancer.

Recent clinical trials have shown that patients with metastatic castration-sensitive prostate cancer in real-world settings have different overall survival (OS) rates after stratifying for tumor burden or visceral metastasis. However, some patients with a low tumor burden and without visceral metastasis still have a poor survival. Androgen receptor signaling is still a main therapeutic target of prostate cancer treatment even after the achievement of castration resistance. In this regard, we hypothesized that time to castration resistance can be a prognostic factor of metastatic castration-sensitive prostate cancer even after achieving castration resistance. The current study aimed to assess the novel prognostic factors, particularly time to castration resistance, of prostate cancer in patients at a real-world single institution. The data of 261 patients who were newly diagnosed with metastatic castration-sensitive prostate cancer from January 2007 to December 2023 were retrospectively analyzed. The median OS was 60.7 months, and the median time to castration resistance was 13.1 months. Among 261 patients, 158 developed castration-resistant prostate cancer. A shorter time to castration resistance, the presence of distant lymph node metastasis, ISUP grade group 5, and older age were associated with a shorter OS in patients who developed castration-resistant prostate cancer. A shorter time to castration resistance was significantly associated with a shorter OS regardless of the tumor burden. Further, it was associated with a shorter OS even after the achievement of castration resistance. The study results support the presence of persistent androgen receptor signaling even after achieving castration resistance in prostate cancer, and time to castration resistance can be a biomarker for the activation of androgen receptor signaling regardless of tumor burden.

Exploring B7-H4's role in prostate cancer dormancy post-androgen deprivation therapy: extracellular matrix interactions and therapeutic opportunities.

Prostate cancer (PCa) is mainly managed with androgen deprivation therapy (ADT), but this often leads to a dormant state and subsequent relapse as lethal castration-resistant prostate cancer (CRPC). Using our unique PCa patient-derived xenograft (PDX) dormancy models, we investigated this critical dormant phase and discovered a selective increase in B7-H4 expression during the dormancy period following mouse host castration. This finding is supported by observations in clinical specimens of PCa patients treated with ADT. Differential expression analyses revealed the enrichment of extracellular matrix (ECM)-cell interaction pathways in B7-H4-positive cells. Functional assays demonstrated a crucial role of B7-H4 in maintaining dormancy within the ECM niche. Specifically, B7-H4 expression in LNCaP cells reduced proliferation within dormant ECM in vitro and significantly delayed relapse in castrated hosts in vivo. These results shed light on the dynamic regulation of B7-H4 during PCa dormancy and underscore its potential as a therapeutic target for preventing CRPC relapse. Implications: Our study identified membranous B7-H4 expression during ADT-induced dormancy, highlighting its potential as a therapeutic target for managing dormant prostate cancer and preventing fatal CRPC relapse.

Initial clinical experience with [177Lu]Lu-PNT2002 radioligand therapy in metastatic castration-resistant prostate cancer: dosimetry, safety, and efficacy from the lead-in cohort of the SPLASH trial.

SPLASH (NCT04647526) is a multicenter phase III trial evaluating the efficacy and safety of [177Lu]Lu-PNT2002 radioligand therapy in metastatic castration-resistant prostate cancer (mCRPC). This study leveraged a lead-in phase to assess tissue dosimetry and evaluate preliminary safety and efficacy, prior to expansion into a randomized phase. Here we report those results. Enrolled participants had mCRPC that progressed on one prior androgen receptor pathway inhibitor (ARPI), were prostate-specific membrane antigen (PSMA) PET-positive as determined by a central reader, were chemotherapy-naïve for mCRPC, and had adequate bone marrow and end-organ reserve. Participants received up to 4 cycles of [177Lu]Lu-PNT2002 at 6.8 GBq (± 10%) intravenously per cycle every 8 weeks. Dosimetry (planar + SPECT/CT [n=7]; planar only [n=20]), safety, prostate-specific antigen (PSA) response, objective response rate (ORR), and radiographic progression-free survival (rPFS) per blinded independent central review were assessed. Of 34 individuals screened, 32 underwent PSMA-PET/CT; 27 met all eligibility criteria. Median (range) age was 72 (57-86) years; all participants were enrolled in North America; 40.7% initiated prior ARPI treatment without distant metastases (M0) and 25.9% while hormone sensitive. Nineteen of 27 (70.4%) participants completed all 4 planned cycles. Organs receiving the largest mean (median, range) specific absorbed doses were lacrimal glands at 1.2 (0.9, 0.4-6.7) Gy/GBq (planar only [n=27]), followed by kidneys at 0.73 (0.63, 0.22-1.8) Gy/GBq (planar + SPECT/CT [n=7]; planar only [n=20]). Mean (median, range) tumor specific absorbed dose was 4.3 (2.1, 0.3-33.4) Gy/GBq (approximately 29 Gy/cycle) based on planar + SPECT/CT of 21 lesions in seven participants. [177Lu]Lu-PNT2002 was associated with no treatment-related deaths, few treatment-related grade ≥3 treatment-emergent adverse events (TEAEs), and no discontinuations for unacceptable toxicity. Treatment-related TEAEs occurring in ≥10% of participants included dry mouth (22.2%; all grade 1), fatigue (18.5%; grades 1-2), nausea (18.5%; grades 1-2), and anemia (14.8%; grades 1-3). Median (95% CI) rPFS was 11.5 (9.2-19.1) months, a PSA decline of ≥50% occurred in 42.3% (11/26) of participants, and confirmed ORR for evaluable disease was 50% (5/10). [177Lu]Lu-PNT2002, administered at 6.8 GBq/cycle for 4 cycles, demonstrated a favorable dosimetry and safety profile, as well as promising preliminary efficacy. https://clinicaltrials.gov/, identifier NCT04647526.

Systems-level liquid biopsy in advanced prostate cancer.

Treatment for castration-resistant prostate cancer (CRPC) primarily involves suppression of androgen receptor (AR) activity using androgen receptor signaling inhibitors (ARSIs). While ARSIs have extended patient survival, resistance inevitably develops. Mechanisms of resistance include genomic aberrations at the AR locus that reactivate AR signaling or lineage plasticity that drives emergence of AR-independent phenotypes. Given the diverse mechanisms of ARSI resistance in CRPC, there is a need for more effective monitoring strategies that detect signs of resistance to inform prognosis and guide use of alternative therapies. Liquid biopsy is a blood test that has emerged as a powerful, minimally invasive tool for investigating advanced cancer. In CRPC, liquid biopsy has been shown to reflect genomic and transcriptomic features in tumor tissue and has been utilized to detect an array of resistance signatures. Liquid biopsy is uninhibited by spatial restrictions and allows for longitudinal monitoring of disease progression. However, current clinical liquid biopsy tests provide limited actionable information. This review highlights recent advancements to the understanding of mechanisms driving treatment resistance in CRPC through research-grade liquid biopsy assays. We explore novel methods of disease characterization developed using liquid biopsy and emphasize the clinical potential of a multi-omics molecular profiling approach to comprehensively detect emerging therapeutic resistance. Routine assessment of therapy resistance using a liquid biopsy assay has the potential to enhance prognostication and improve outcomes of men with CRPC.

Gold Nanoparticle Inhibits the Tumor-Associated Macrophage M2 Polarization by Inhibiting m6A Methylation-Dependent ATG5/Autophagy in Prostate Cancer.

Background: This study aims to study how gold nanoparticles (AuNPs) function in the recruitment and polarization of tumor-associated macrophages (TAMs) in hormone-sensitive prostate cancer (HSPC) and castration-resistant prostate cancer (CRPC). Methods: Phorbol ester (PMA)-treated THP-1 cells were cocultured with LNCaP or PC3 cells to simulate TAMs. Macrophage M2 polarization levels were detected using flow cytometry and M2 marker determination. ATG5 expression was detected by western blotting. Luciferase reporter assay was used to analyze the N6-methyladenosine (m6A) site activity of ATG5 3' untranslated regions (3'-UTRs). Methylated RNA immune precipitation (MeRIP)-quantitative polymerase chain reaction (qPCR) was performed to determine the m6A levels at ATG5 3'-UTR. Xenograft mouse models were used to determine the function of AuNPs in vivo. Results: Macrophages exhibited reduced M2 polarization in both HSPC and CRPC cells after AuNP treatment which was prevented by induction of autophagy. AuNP treatment decreased the m6A levels in the 3'-UTR of ATG5. Mutational analysis of potential m6A sites within ATG5 3'-UTR revealed that these sites were required for AuNP regulation, indicating that AuNPs inhibited ATG5 levels in an m6A-dependent manner. The mouse model revealed that AuNPs significantly reduced the M2 polarization of TAMs in an autophagy-dependent manner in vivo. This suggests that AuNPs inhibit tumor growth in vivo partially through targeting M2 TAM. Conclusion: The ATG5/autophagy pathway is inhibited by AuNP treatment in an METTL3/m6A-dependent manner. AuNPs inhibit the TAM M2 polarization in HSPC and CRPC by inhibiting ATG5/autophagy.

Dysregulated key long non-coding RNAs TP53TG1, RFPL1S, DLEU1, and HCG4 associated with epithelial-mesenchymal transition (EMT) in castration-resistant prostate cancer

Dysregulated key long non-coding RNAs TP53TG1, RFPL1S, DLEU1, and HCG4 associated with epithelial-mesenchymal transition (EMT) in castration-resistant prostate cancer

An estrogen receptor β-targeted near-infrared probe for theranostic imaging of prostate cancer.

Estrogen receptor β (ERβ) is aberrantly expressed in castration-resistant prostate cancer (CRPC). Therefore, a diagnostic and therapeutic ERβ probe not only helps to reveal the complex role of ERβ in prostate cancer (PCa), but also promotes ERβ-targeted PCa therapy. Herein, we reported a novel ERβ-targeted near-infrared fluorescent probe D3 with both imaging and therapeutic functions, which had the advantages of high ERβ selectivity, good optical performance, and strong anti-interference ability. In addition, it displayed excellent antiproliferative activity in CRPC cells. Finally, D3 was also successfully applied to the in vivo imaging of ERβ in the prostate cancer mouse model. Thus, this ERβ-targeted near-infrared fluorescent probe can be used as a potential tool for the study of ERβ-targeted diagnostic and therapeutic PCa.

Cynanchum wallichii Wight and CW1 reversed docetaxel resistance effects by inhibiting P-gp and promoting PI3K/Akt-mediated apoptosis in prostate cancer.

Cynanchum wallichii (CW) is a traditional Chinese medicine which is widely used for treating arthrophlogosis, traumatic injury, and other conditions. Herein, we investigate the effects and mechanisms of CW and its bioactive constituent CW1 in reversing docetaxel (DTX) resistance in prostate cancer (PCa) cells. We investigated the reversal effects of CW and its bioactive constituent CW1 on 22Rv1/DTX cells in vitro and in vivo. We also explored the underlying mechanism by evaluating drug sensitivity, cell proliferation, efflux transporter P-glycoprotein (P-gp), and molecular signaling involved in apoptosis-related protein expression. CW and its bioactive constituent CW1 reversed DTX resistance in PCa 22Rv1/DTX cells by directly binding to the efflux transporter P-gp and by inhibiting the expression of P-gp. This significantly increased the intracellular concentration of DTX and inhibited the malignant proliferation of 22Rv1/DTX cells. In addition, DTX + CW/CW1 co-treatment significantly increased the apoptosis effects in 22Rv1/DTX cells by regulating the relative expressions of BAX, Bcl2, cytochrome C, and caspase 3/9. Furthermore, both CW and CW1 enhanced the in vivo therapeutic effect of DTX in the 22Rv1/DTX cell xenograft while alleviating the side effects of liver and kidney damage caused by DTX. Our results suggest that CW and its bioactive constituent CW1 enhance the antitumor activity of DTX by reducing P-gp expression and promoting phosphoinositide 3-kinase/Akt-mediated apoptosis in vitro and in vivo. Our results firstly confirm that CW1, as a natural bioactive substance, holds promise as an adjuvant drug for treating high-load metastatic and castration-resistant PCa.

Doublecortin-like kinase 1 promotes stem cell-like properties through the Hippo-YAP pathway in prostate cancer.

Background: Doublecortin-like kinase 1 (DCLK1) has been revealed to be involved in modulating cancer stemness and tumor progression, but its role in prostate cancer (PCa) remains obscure. Castration-resistant and metastatic PCa exhibit aggressive behaviors, and current therapeutic approaches have shown limited beneficial effects on the overall survival rate of patients with advanced PCa. This study aimed to investigate the biological role and potential molecular mechanism of DCLK1 in the progression of PCa. Methods: The role of DCLK1 in maintaining PCa stem cell-like properties was explored via gain- and loss-of-function studies, including colony formation assays, sphere formation assays and measurement of stemness-related marker expression. A set of transcriptomic data for patients with PCa was downloaded from The Cancer Genome Atlas to analyze the correlations between DCLK1 and Hippo pathway gene expression. The mechanism by which DCLK1 regulates Hippo signaling and cancer stemness was further investigated in vitro by methods such as Western blot analysis, quantitative real-time PCR analysis, immunofluorescence staining, and luciferase reporter assays and in vivo by animal studies. Results: The gain- and loss-of-function studies demonstrated that upregulating DCLK1 promoted but downregulating DCLK1 suppressed aspects of the PCa stem cell-like phenotype, including colony formation, sphere formation and the expression of stemness-related markers (c-Myc, OCT4, CD44, NANOG, SOX2, and KLF4). Importantly, bioinformatics analysis indicated that DCLK1 is closely correlated with the Hippo signaling pathway in PCa. Further in vitro assays revealed that DCLK1 inhibits the Hippo signaling pathway, leading to yes-associated protein (YAP) activation via large tumor suppressor homolog 1 (LATS1). Moreover, the effect of DCLK1 on abolishing stemness traits in PCa was observed after treatment with verteporfin, a small molecule inhibitor of YAP. Consistent with the in vitro findings, the in vivo findings confirmed that DCLK1 promoted the tumorigenicity and stem cell-like traits of PCa cells via Hippo-YAP signaling. Conclusion: DCLK1 promotes stem cell-like characteristics by inducing LATS1-mediated YAP signaling activation, ultimately leading to PCa tumor growth and progression. Thus, our findings identify an attractive candidate for the development of cancer stem cell-targeted therapies to improve treatment outcomes in advanced PCa.

Synergistic combination effect of the PCA-1/ALKBH3 inhibitor HUHS015 on prostate cancer drugs in vitro and in vivo.

Prostate cancer antigen-1/ALKBH3, a DNA/RNA demethylase of 3-methylcytosine, 1-methyladenine (1-meA), and 6-meA, was found in prostate cancer as an important prognostic factor. Additionally, 1-meA has been associated with other cancers. The ALKBH3 inhibitor HUHS015 was found to be effective against prostate cancer both in vitro and in vivo . Herein, we investigated the effect of HUHS015 in combination with drugs for prostate cancer approved in Japan (including bicalutamide, cisplatin, mitoxantrone, prednisolone, ifosfamide, tegafur/uracil, docetaxel, dacarbazine, and estramustine) by treating DU145 cells with around IC 50 value concentrations of these drugs for 3 days. Additionally, the cells were observed for additional 9 days after drug removal. Combination treatment with dacarbazine, estramustine, tegafur/uracil, and HUHS015 showed a slight additive effect after 3 days. After drug washout of them and mitoxantrone, the combined effects and levels were enhanced and sustained, although the effects of each treatment alone declined. HUHS015 combined with cisplatin or docetaxel elicited synergistic and sustained effects. In vivo , combining HUHS015 and docetaxel, the first chemotherapeutic agent for castration-resistant prostate cancer, showed notable effects in the DU145 xenograft model. In conclusion, HUHS015 exhibited a synergistic effect with docetaxel and drugs acting on DNA in vitro , even after drug removal. Since cancer chemotherapy is typically administered during rest periods due to its high toxicity, combining it with an ALKBH3 inhibitor could be a promising strategy for enhancing cancer treatment, as it can elicit an additive effect during treatment, allowing dosage reduction, and synergistically sustain the effect after drug washout during rest periods.

Falls in older adults during treatment for metastatic castration-resistant prostate cancer (mCRPC)

Falls in older adults during treatment for metastatic castration-resistant prostate cancer (mCRPC)