Castration-resistant Prostate Cancer Research Articles

Inhibiting HnRNP L-mediated alternative splicing of EIF4G1 counteracts immune checkpoint blockade resistance in Castration-resistant prostate Cancer.

Immunotherapy with checkpoint inhibitors produced significant clinical responses in a subset of cancer patients who were resistant to prior therapies. However, Castration-resistant prostate cancer (CRPC) is seriously lack of T cell infiltration, which greatly limits the clinical application of immunotherapy, but the mechanism is unclear. In the present study, in silico analyses and experimental data show that HnRNP L was significantly negatively correlated with CD4+ and CD8+ T cells infiltration in patients; besides, we found deficiency of HnRNP L recruites CD4+ and CD8+ T cells infiltration and impairs tumorigenesis. Mechanically, HnRNP L enhanced the translation of c-Myc and then promoted CXCL8 secretion via alternative splicing of EIF4G1. In vivo, inhibition of EIF4G1 by the inhibitor, SBI-0640756, attenuated HnRNP l-induced tumor progression and immunosuppressive activity. And most of all, therapeutic synergy between HnRNP L knockdown and Anti-PD-1 could significantly suppress xenograft prostate cancer growth. In summary, this study revealled the molecular mechanism of HnRNP L regulating the immune infiltration, which provides a new theoretical basis for overcoming the limitation of immunotherapy for CRPC.

Roles of CDK12 mutations in PCa development and treatment.

Prostate cancer (PCa) is one of the most common cancers in men, and cyclin-dependent kinase 12 (CDK12) is emerging as a novel star player in the PCa tumorigenesis and progression to castration-resistant prostate cancer (CRPC). In PCa, CDK12 alterations are mostly loss-of-function mutations featuring intronic polyadenylation (IPA), focal tandem duplications (FTDs), and R-loops formation and transcription-replication conflicts (TRCs). The occurrence of IPA can result in homologous recombination deficiency (HRD) and androgen receptor (AR) variation. FTDs induce neoantigens and increase the expression of the AR, MYC, and other hotspot- associated genes. R-loops lead to TRCs and influence various cellular processes, including gene expression and genome stability. Due to the poor prognosis of CDK12-mutant PCa patients and the mediocre response to classic standard therapies, HRD and increased neoantigen levels have provided clinicians with new insights into alternative systematic treatments for this novel PCa phenotype. In this review, we summarize the roles of CDK12 mutations in PCa and discuss their clinical value, suggesting that CDK12 potentially represents a target for further research and the development of clinical strategies for PCa.

Clinical, Diagnostic and Therapeutic Framework of mHSPC and nmCRPC: A Multidisciplinary Consensus Project of the Italian Society for Uro-Oncology (SIUrO).

The recent evidences provided in metastatic hormone sensitive prostate cancer (nmHSPC) and in nonmetastatic castration resistant (nmCRPC) introduced the possibility to adopt Androgen Receptor Signaling inhibitor (ARSi) alone (both settings) or with chemotherapy (in mHSPC). In daily clinical practice there are some opening questions regarding the inclusion of next generation imaging, mainly PSMA-PET, how integrate local treatment as radiotherapy, how to select patients or drugs in a multiple-choice scenario, and how to manage patients with comorbidities and polypharmacy. These issues led the Italian Society for Uro-Oncology (SIUrO) to develop a consensus project involving all of the most important Italian scientific societies engaged in the multidisciplinary and multiprofessional management of the disease. This paper describes the items and statements approved, with the aim to support clinicians in managing metastatic hormone sensitive and nonmetastatic castration resistant prostate cancer patients.

Incidence and Risk of Thromboembolic and Cardiovascular Adverse Events with PARP Inhibitor Treatment in Patients with Metastatic Castration-resistant Prostate Cancer: A Systematic Review and Safety Meta-analysis

Incidence and Risk of Thromboembolic and Cardiovascular Adverse Events with PARP Inhibitor Treatment in Patients with Metastatic Castration-resistant Prostate Cancer: A Systematic Review and Safety Meta-analysis

ECM-mimicking hydrogel models of human adipose tissue identify deregulated lipid metabolism in the prostate cancer-adipocyte crosstalk under antiandrogen therapy.

Antiandrogen therapies are effectively used to treat advanced prostate cancer, but eventually cancer adaptation drives unresolved metastatic castration-resistant prostate cancer (mCRPC). Adipose tissue influences metabolic reprogramming in cancer and was proposed as a contributor to therapy resistance. Using extracellular matrix (ECM)-mimicking hydrogel coculture models of human adipocytes and prostate cancer cells, we show that adipocytes from subcutaneous or bone marrow fat have dissimilar responses under the antiandrogen Enzalutamide. We demonstrate that androgen receptor (AR)-dependent cancer cells (LNCaP) are more influenced by human adipocytes than AR-independent cells (C4-2B), with altered lipid metabolism and adipokine secretion. This response changes under Enzalutamide, with increased AR expression and adipogenic and lipogenic genes in cancer cells and decreased lipid content and gene dysregulation associated with insulin resistance in adipocytes. This is in line with the metabolic syndrome that men with mCRPC under Enzalutamide experience. The all-human, all-3D, models presented here provide a significant advance to dissect the role of fat in therapy response for mCRPC.

Clinical Trials in Cancer Theranostics with Potential Near-Term Impact on Clinical Practice.

Theranostics has its roots with the first radioiodine therapy for thyroid diseases in about 80 years ago. More recently the field has experienced a remarkable renascence with the regulatory approval of paired imaging and radiopharmaceutical therapy agents in gastroenteropancreatic neuroendocrine tumors and metastatic castration-resistant prostate cancer that are now employed in routine clinical practice. The momentum is strong for identification and testing of new theranostic agents for use in various cancers and finding new clinical incications of the available agents. There are currently numerous preclinical, first-in-human studies, large-scale prospective registries, and clinical trials including randomized trials underway in cancer theranostics that target a variety of germane biological targets. The results of these investigations, if successful, will undoubtedly impact the future of cancer management which is anticipated to improve patient outcome. Multi-targeted theranostics may also provide opportunities for synergistic efficacy to tackle the inherent complexities driven by the heterogeneity of cancer. In this article, we review the currently active recruiting phase 2 and phase 3 clinical trials in cancer theranostics that are targeted to the prostate-specific membrane antigen, gastrin-releasing peptide receptor, and fibroblast activation protein, with the anticipated potential near-term (<5 years) impact on clinical practice.

Neutrophil-to-lymphocyte ratio as a prognostic factor in patients with castration-resistant prostate cancer treated with docetaxel-based chemotherapy: a meta-analysis

BackgroundIn recent years, many studies have illustrated that the neutrophil-to-lymphocyte ratio (NLR) is a prognostic factor of metastatic castration-resistant prostate cancer (mCRPC), but their conclusions are controversial. The aim of this study was to assess the prognostic value of the NLR in patients with mCRPC treated with docetaxel-based chemotherapy.MethodsDatabase searches were conducted in PubMed, EMBASE and the Cochrane Library to retrieve relevant published English-language literature up to 20 February 2023. RevMan 5.4.1 was used to summarize the hazard ratio (HR) and its 95% confidence interval (CI) for overall survival (OS) and progression-free survival (PFS) with subgroup analysis. Finally, Stata software was adopted for sensitivity analysis, and Egger’s test was used to calculate the results of stability to determine whether there was publication bias.ResultsA total of 1,983 mCRPC patients from 14 retrospective cohort studies were included in this meta-analysis. The combined results showed that elevated NLR was significantly associated with worse OS (HR = 1.86, 95% CI: 1.55–2.23, P < 0.00001) and PFS (HR = 1.96 (95% CI: 1.52–2.53), P < 0.00001) in patients with mCRPC treated with docetaxel-based therapy. For subgroup analysis of high NLR, studies performed in Asia and cutoff value > 3 were associated with poorer OS, while cutoff values > 3 were associated with poorer PFS.ConclusionOur results suggest that the neutrophil-to-lymphocyte ratio may be a prognostic factor in patients with mCPRC with docetaxel-based chemotherapy.

Prognostic factors for overall survival in castration-resistant metastatic prostate cancer treated with docetaxel (MeProCSS): results from a German real-world cohort.

To identify prognostic factors for overall survival (OS) and develop a prognostic score in patients receiving docetaxel in metastatic castration-resistant prostate cancer (mCRPC). Retrospective analysis was conducted on mCRPC patients treated with docetaxel at a German tertiary center between March 2010 and November 2023. Prognostic clinical and laboratory factors were analyzed using uni- and multivariable logistic regression. Next, the result of the modified Glasgow Prognostic Score (mGPS), neutrophil-to-lymphocyte ratio (NLR) (cut-off ≥3), the presence of high-volume bone metastases (as defined by CHAARTED criteria), hemoglobin (Hb) (cut off < 13.2 g/dl), Gleason score ≥8, and presence ofvisceral metastases were combined into the Metastasized Prostate Cancer Survival Score (MeProCSS). Patients were then stratified into three prognostic groups. Their OS was assessed by Kaplan-Meier analysis. Median OS for the overall cohort (n = 153) and the first-line cohort (n = 83) was 18 and 21.5 months, respectively. In multivariable analysis, high-volume bone metastases and Hb levels below the norm were significant predictors of shorter OS in the total cohort. The MeProCSS demonstrated an area under curve (AUC) of 0.837 in the overall cohort and 0.946 in first-line cohort. Kaplan-Meier analysis revealed a significant association between lower MeProCSS and longer OS in both the overall (p<0.001) and first-line (p = 0.035) cohort. MeProCSS, consisting of routinely collected parameters prior to the start of chemotherapy, seems to effectively stratify patients with mCRPC into risk groups based on their metastatic burden, nutritional and inflammatory status. This model may guide treatment decisions and reveal a potentially often underestimated or overlooked urgency for additional measures as supportive palliative care in mCRPC patients. Further large and prospective studies are necessary for validation of MeProCSS-also in other systemic PC therapy regimens.

An MRI radiomics model for predicting a prostate-specific antigen response following abiraterone treatment in patients with metastatic castration-resistant prostate cancer

ObjectiveTo establish a combined radiomics-clinical model for the early prediction of a prostate-specific antigen(PSA) response in patients with metastatic castration-resistant prostate cancer(mCRPC) after treatment with abiraterone acetate(AA).MethodsThe data of a total of 60 mCRPC patients from two hospitals were retrospectively analyzed and randomized into a training group(n=48) or a validation group(n=12). By extracting features from biparametric MRI, including T2-weighted imaging(T2WI), diffusion-weighted imaging(DWI), and apparent diffusion coefficient(ADC) maps, radiomics features from the training dataset were selected using least absolute shrinkage and selection operator(LASSO) regression. Four predictive models were developed to assess the efficacy of abiraterone in treating patients with mCRPC. The primary outcome variable was the PSA response following AA treatment. The performance of each model was evaluated using the area under the receiver operating characteristic curve(AUC). Univariate and multivariate analyses were performed using Cox regression to identify significant predictors of the efficacy of abiraterone treatment in patients with mCRPC.ResultsThe integrated model was constructed from seven radiomics features extracted from the T2WI, DWI, and ADC sequence images of the training data. This model demonstrated the highest AUC in both the training and validation cohorts, with values of 0.889 (95% CI, 0.764-0.961) and 0.875 (95% CI, 0.564-0.991). The Rad-score served as an independent predictor of the response to abiraterone treatment in patients with mCRPC (HR: 2.21, 95% CI: 1.01-4.44).ConclusionThe biparametric MRI-based radiomics model has the potential to predict the PSA response in patients with mCRPC following abiraterone treatment.Clinical relevance statementThe MRI-based radiomics model could be used to noninvasively identify the AA response in mCRPC patients, which is helpful for early clinical decision-making.

Abstract B001: Double targeted therapy PSCA-CAR-T cells and PSMA-radioligand in metastatic castration-resistant prostate cancer

Abstract Targeted radioligand therapy (PSMA-RLT) extends survival in advanced castration-resistant prostate cancer (CRPC) (Sartor et al., 2021), yet half of patients experiences limited responses or relapse with additional metastases (Stuparu et al., 2020). Given that metastatic CRPC has a tumor environment lacking immune infiltration and resisting immune checkpoint therapies, combination strategies that actively bring immune cells into the tumor are urgently needed (Choudhury et al., 2024). Prostate stem cell antigen (PSCA) is another promising target, as it is frequently overexpressed in advanced CRPC. PSCA-CAR-T cells, engineered to specifically attack PSCA-expressing tumors, may complement PSMA-RLT by overcoming immune resistance (Dorff et al., 2024; Murad et al., 2021). This study explores the therapeutic potential of combining PSMA-RLT with PSCA-CAR-T cells to strengthen immune response and increase response rates and survival. For this reasons, PC3-PIP human metastatic prostate cancer cells expressing PSMA were transfected to express human PSCA. PSMA and PSCA expression was confirmed by flow cytometry. Double positive PSMA-PSCA cells were inoculated by intracardiac injection in NSG mice under ultrasound guidance. Tumor progression was followed up twice a week by bioluminescence imaging. Mice were randomized before treatment into 5 groups: (1) Control NT (2) 225Ac-PSMA-617 (15 kBq) alone (3) CAR-T (0.2 x 106 cells) alone (4) Combo 225Ac-PSMA-617 (15 kBq) + CAR-T (0.2 x 106 cells) (day 4 post-RLT) (5) Combo 225Ac-PSMA-617 (15 kBq) + CAR-T (0.2 x 106 cells) (day 6 post-RLT). 4 mice per group were used to determine blood toxicity of RLT and 8 mice in each group were followed up until the end point for efficacy study. No blood toxicity related to RLT was observed in treated mice. Compared to control group, the Combo 225Ac-PSMA-617 and PSCA-CAR-T demonstrated a synergistic effect with a significant delay in tumor growth. Comparison between 68Ga-PSMA-11 PET and bioluminescence imaging showed heterogenous localization in 3 mice randomized to Combo groups and CAR-T alone group. In conclusion, our study shows promising results from combining PSMA-RLT with PSCA-CAR-T cell therapy. In a dual prostate cancer expressing in vivo model (PC3-PIP PSMA-PSCA), we observed a delay in tumor growth. However, the increase of survival rates in combo groups compared to CAR-T alone was limited. Additional studies are required to improve overall survival. Thus, we plan to extend our study to test the combination of PSCA-CAR-T with PluvictoTM, a recent FDA approved theranostics agent for metastatic CRPC (Hennrich &amp; Eder, 2022). Moreover, we will modify the expression of PSCA to mimic the heterogeneity expression observed in patients, to validate the performance of the combination. Citation Format: Iveta Fajnorova, Pauline Jeanjean, Ines Camille Azrour, Ava Fakharpour, Venna Jiangyue Liu, Johannes Czernin, Caius Radu, Saul Priceman, Christine Mona. Double targeted therapy PSCA-CAR-T cells and PSMA-radioligand in metastatic castration-resistant prostate cancer. [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Targeted Therapies in Combination with Radiotherapy; 2025 Jan 26-29; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(2_Suppl):Abstract nr B001.

The Safety and Efficacy of Targeted Alpha Therapy, Ac-225 Prostate-Specific Membrane Antigen, in Patients With Metastatic Castration-Resistant Prostate Cancer: A Systematic Review and Meta-Analysis.

Metastatic castration resistance prostate cancer (mCRPC) is a challenging disease with a significant burden of mortality and morbidity. Most of the patients attain resistance to the available treatments, necessitating further novel therapies in this clinical setting. Actinium 225 (225Ac) prostate-specific membrane antigen (PSMA) radioligand therapy has emerged as a promising option and has been utilized for the last decade. Although a few meta-analyses were performed on the efficacy and safety of 225Ac-PSMA RLT in mCRPC patients, several current studies have been added to the literature since the latest meta-analysis. We aimed to gather all individual studies to perform up-to-date meta-analyses. We searched the literature using Pubmed-Medline, Web of Science, Elsevier-Sceince Direct, and Cochrane-Central databases. The data for any PSA decline, over 50% PSA decline, overall survival (OS), progression-free survival (PFS), and toxicity profile were captured from the studies eligible for meta-analysis. We utilized the random effect model to generate pooled estimates. The sixteen eligible studies contained 1102 patients. Sixty-three percent of patients achieved more than 50% PSA decline, while 82% had any PSA decline after the completion of therapy. The pooled mean OS and PFS were 12.72 months (9.52-15.91) and 11.02 months (6.88-15.15), respectively. The most common adverse event was xerostomia, with a pooled proportion of 84%. Grade ≥ 3 anemia, thrombocytopenia, leucopenia, and nephrotoxicity were encountered in 9%, 5%, 4%, and 4% of the patients. 225Ac-PSMA RLT is an efficacious and safe treatment for mCRPC. Future well-designed randomized controlled studies comparing 225Ac-PSMA RLT with other approved therapeutic options would better comprehend the exact role of this therapy in the treatment sequence of mCRPC.

Natural Compounds and Histone Deacetylase Inhibitors: A Combined Approach Against mCRPC Cells

Background: Sodium butyrate (NaBu), a short-chain fatty acid, modulates global gene expression through histone deacetylase (HDAC) inhibition, suppressing proliferation and inducing apoptosis in various cancers. Rutin (RUT), a polyphenolic flavonoid found in many plants, exhibits notable anticancer properties. Combining chemotherapeutic agents with natural polyphenols represents a promising strategy for cancer therapy. This study aims to evaluate, for the first time, the potential effects of NaBu and RUT combination therapy on metastatic castration-resistant prostate cancer (mCRPC) cells. Methods: PC-3 cells were treated with varying concentrations of NaBu, RUT, and their combinations. Cell viability was assessed using the WST-1 assay. Based on combination index values, selected treatments were further analyzed for apoptosis (Annexin V assay), intracellular reactive oxygen species (ROS) production, mRNA expression levels, and changes in cell and nuclear morphology. Results: The combined treatment of NaBu and RUT significantly reduced cell viability compared to individual treatments. Enhanced apoptotic induction and elevated ROS levels were observed in combination-treated cells, alongside notable changes in cellular and nuclear morphology and mRNA expression levels. Conclusions: NaBu and RUT combination therapy exhibits a synergistic anticancer effect in mCRPC cells by inhibiting cell viability, inducing apoptosis, and increasing ROS production. These findings suggest a promising therapeutic approach that warrants further investigation to elucidate the underlying molecular mechanisms and assess its potential in preclinical and clinical settings.

Circular RNA circBNC2 inhibits tumorigenesis by modulating ferroptosis and acts as a nanotherapeutic target in prostate cancer

BackgroundMetastasis is a leading cause of cancer-related death in castration-resistant prostate cancer (CRPC) patients. Circular RNAs (circRNAs) have emerged as key regulators of the metastasis of various cancers. However, the functional effects and regulatory mechanisms of circRNAs in metastatic CRPC (mCRPC) remain largely unknown.MethodsThe expression of circBNC2 in prostate cancer (PCa), CRPC and neuroendocrine prostate cancer (NEPC) tissues was analyzed through bioinformatics analysis. Functional assays, including cell proliferation, migration, invasion and ferroptosis, were conducted in vitro and in vivo. The interactions between circBNC2, miR-4298, and ACSL6 were explored via luciferase reporter assays, RNA immunoprecipitation, and western blotting analysis. In addition, for the first time in PCa, we developed novel nanobowls (NBs) loaded with docetaxel (DTX) and circBNC2 (Dc-NBs) and evaluated the antitumor efficacy of Dc-NBs in a photothermal therapy (PTT) strategy.ResultsWe identified a novel tumor-suppressive circRNA, circBNC2, in human PCa, CRPC and NEPC samples via bioinformatic analysis. CircBNC2 expression was significantly downregulated in PCa tissues and PCa cell lines. Functional assays demonstrated that circBNC2 inhibited PCa cell proliferation and migration both in vitro and in vivo. Mechanistically, circBNC2 acted as a sponge for miR-4298, and ACSL6 was identified as a direct target of the circBNC2/miR-4298 axis. Moreover, we demonstrated that ACSL6 is essential for mediating circBNC2-regulated ferroptosis in PCa cells. More importantly, we demonstrated the nanodelivery of Dc-NBs, which exhibited significant antitumor effects in both subcutaneous and metastatic PCa models.ConclusionThis study revealed the tumor-suppressive role of circBNC2 in mCRPC by driving ferroptosis via the circBNC2/miR-4298/ACSL6 axis. Additionally, we developed an efficient and safe PTT strategy based on a nanodelivery system that codelivers circBNC2 and DTX, highlighting its potential as a novel therapeutic approach for mCRPC.

Association between frailty and specific comorbidities on oncological outcomes in metastatic hormone-sensitive and castration resistant prostate cancer.

Demographic changes will lead to higher proportions of metastatic hormone-sensitive (mHSPC) and castration resistant metastatic prostate cancer (mCRPC) patients with higher frailty index and multiple comorbidities. We relied on an institutional tertiary-care database to explore the effect of frailty (Eastern Cooperative Oncology Group [ECOG]), as well as cardiovascular (CVD) and secondary malignancy (SecCa) comorbidities on overall survival (OS) and time to mCRPC in mHSPC and OS in mCRPC patients with Kaplan-Meyer estimates and Cox regression models. Of 802 mHSPC patients, 61% were ECOG0 vs. 32% ECOG1 vs. 6.5% ECOG≥2. Significant differences in baseline patient and baseline mHSPC characteristics were observed for all three groups (all P ≤ 0.05). In time to mCRPC analyses and OS analyses of mHSPC and mCRPC patients, significant disadvantages were observed for ECOG 1/≥2 patients, relative to ECOG0, even after multivariable adjustment. Moreover, 31% of included patients had history/active CVD, which yielded significant median OS differences in mHSPC patients (95 vs. 63 months, multivariable hazard ratio: HR: 1.77, P < 0.01), but not in mCRPC patients (P = 0.085). After stratification according to SecCa, 14% had a SecCa which led to significant median OS differences in mCRPC patients (50 vs. 37 months, P < 0.01) but not in mHSPC patients (76 vs. 64 months, P = 0.089). Patients with higher frailty index and comorbidities showed significant differences in therapy lines. Frailty and specific comorbidities significantly influence cancer-control outcomes in mHSPC, as well as mCRPC patients, even after controlling for adverse tumor characteristics.

A novel peptide encoded by circSRCAP confers resistance to enzalutamide by inhibiting the ubiquitin-dependent degradation of AR-V7 in castration-resistant prostate cancer

BackgroundThe sustained activation of androgen receptor splice variant-7 (AR-V7) is a key factor in the resistance of castration-resistant prostate cancer (CRPC) to second-generation anti-androgens such as enzalutamide (ENZ). The AR/AR-V7 protein is regulated by the E3 ubiquitin ligase STUB1 and a complex involving HSP70, but the precise mechanism remains unclear.MethodsHigh-throughput RNA sequencing was used to identify differentially expressed circular RNAs (circRNAs) in ENZ-resistant and control CRPC cells. The coding potential of circSRCAP was confirmed by polysome profiling and LC–MS. The function of circSRCAP was validated in vitro and in vivo using gain- and loss-of-function assays. Mechanistic insights were obtained through immunoprecipitation analyses.ResultsA novel ENZ-resistant circRNA, circSRCAP, was identified and shown to be upregulated in ENZ-resistant C4-2B (ENZR-C4-2B) cells, correlating with increased AR-V7 protein levels. circSRCAP is generated via splicing by eIF4A3, forming a loop structure and is exported from the nucleus by the RNA helicase DDX39A. Mechanistically, circSRCAP encodes a 75-amino acid peptide (circSRCAP-75aa) that inhibits the ubiquitination of AR/AR-V7’s co-chaperone protein HSP70 by disrupting the interaction with the E3 ligase STUB1. This process results in the upregulation of AR-V7 expression and promotes ENZ resistance in CRPC cells. Xenograft tumor models further confirmed the role of circSRCAP in CRPC progression and its potential as a therapeutic target for ENZ-resistant CRPC.ConclusionscircSRCAP provides an epigenetic mechanism influencing AR-V7 stability and offers a promising therapeutic target for treating ENZ-resistant CRPC.

Exhalation of Rn-219 by patients treated with Radium-223

BackgroundTreatment with Ra-223 dichloride is approved for the therapy of castration resistant prostate cancer (CRPC) with symptomatic bone metastases and no known visceral metastases in Europe since 2013, and Ra-223 is under discussion for labelling other molecules and nanoparticles. The direct progeny of Ra-223 is Rn-219, also known as actinon, a radioactive noble gas with a half-life of 3.98 s. This Rn-219 can be exhaled by patients while Ra-223 is present in the blood. Hence, direct measurements for assessing the exhalation of Rn-219 were performed for the first time in the context of the non-interventional multicenter study “RAPSODY”, a substudy to the international early access program, which aimed at assessing the radiation exposure of relatives of patients suffering from castration resistant prostate cancer with bone metastases and treated with Ra-223 dichloride in an outpatient setting, in order to investigate if this kind of method is functional and tolerated by the patients.MethodsRn-219 was measured directly in patients’ exhalations using Alphaguard radon monitors (Saphymo, formerly Genitron, Frankfurt, Germany), originally intended for the measurement of Rn-222, and custom-made breath-test kits. Measurements were performed 20–30 min p. i. and 3–4 h p. i. In total, datasets from 21 administrations in 14 patients were obtained.ResultsAlthough 75% of the measurement data 20–30 min p. i. and 35% of the measurement data 3–4 h p. i., respectively, were censored due to exceedance of the upper limit of the Alphaguards’ measurement range in the applied measurement setup, statistical data were derived based on the assumption of lognormal distributions. For measurements 3–4 h p. i., mean activity concentrations of Rn-219 in exhaled breath of approx. 4.4 kBq/l were obtained. In measurements 20–30 min p. i., the expectation value of the activity concentration of approx. 6 kBq/l, derived by statistical methods, was higher.ConclusionsDirect measurements using Alphaguard instruments are suitable for assessing the exhalation of Rn-219 by patients treated with Ra-223. The measurement method is well tolerated by the patients. Rn-219 is present in patients’ exhalations. Our results are in accordance with published data obtained using other, indirect measurement methods.

Discovery of a Potent and Selective GSPT1 Molecular Glue Degrader for the Treatment of Castration-Resistant Prostate Cancer.

The treatment of castration-resistant prostate cancer (CRPC) remains a significant challenge, necessitating the development of new and promising therapeutic strategies. Utilizing molecular glue to degrade previously intractable cancer drivers represents an emerging and promising therapeutic approach to cancer treatment. In this study, we developed a novel CRBN-interacting molecular glue, 7d (XYD049), which exhibits potent and selective degradation of G1 to S phase transition 1 (GSPT1), a well-known untargetable cancer driver in diverse cancer cells. Importantly, 7d exhibits superior efficacy compared to 1 (CC-90009) in degrading GSPT1 in 22Rv1 cells with a DC50 value of 19 nM. It effectively suppresses the growth of 22Rv1 cells with an IC50 value of 0.007 ± 0.004 μM and demonstrates efficacy in inhibiting 22Rv1 tumor growth in mice. Mechanistically, via degradation of GSPT1, 7d downregulates CRPC-related oncogenes in 22Rv1 cells, including AR, AR-V7, PSA, and c-Myc. Thus, our work provides a novel GSPT1 selective degrader with potent effectiveness in targeting Myc-driven CRPC.

Baseline Imaging Derived Factors of Response Following [225Ac]Ac-J591 Therapy in Metastatic Castration-Resistant Prostate Cancer: A Lesion Level Analysis.

Actinium-225 labeled prostate-specific membrane antigen (PSMA) targeted radionuclide therapy has emerged as a potential treatment option in the management of men with metastatic castrate-resistant prostate cancer (mCRPC). This study investigated molecular imaging-derived parameters and compared imaging response of lesions categorized by tumor site. Men with mCRPC treated with [225Ac]Ac-J591 from 2017 to 2022 at our center on two prospective trials (NCT03276572 and NCT04506567) with pre- and post-treatment [68Ga]Ga-PSMA-11 Positron Emission Tomography (PET) imaging studies available were included. SUVpeak of the 3 most- and 3 least-avid lesions of the tumor sites were manually assessed. The median change of the SUVpeak from pre- to post-treatment per tumor site was evaluated using the paired Wilcox test. An objective response (OR) in the follow-up image was defined as complete or partial response using PET Response Criteria in Solid Tumors (PERCIST) 1.0. A total of 46 cases met the criteria for image review; most of them (n = 25, 54.3%) had more than one tumor site category. In total, 445 PSMA PET-positive lesions were assessed: 220 osseous, 163 nodal, 41 visceral, and 21 prostatic lesions. After treatment with [225Ac]Ac-J591, absolute SUVpeak values per tumor site declined significantly (p < 0.05) except for prostatic lesions (p = 1). The PERCIST-OR rate for osseous, nodal, visceral, and prostatic lesions was 53%, 28%, 56%, and 38%, respectively. [225Ac]Ac-J591 is an active treatment in men with mCRPC. Tumor distribution patterns may influence treatment response and potentially prognosis. Our findings warrant further validation in a larger cohort but may be considered in treatment planning and trial design.

Prognostic 18F-flotufolastat PET parameters for outcome assessment of 177Lu-labeled PSMA-targeted radioligand therapy in metastatic castration-resistant prostate cancer.

This retrospective analysis evaluates baseline 18F-flotufolastat positron emission tomography (PET) parameters as prognostic parameters for treatment response and outcome in patients with metastatic castration-resistant prostate cancer (mCRPC) undergoing treatment with [177Lu]Lu-PSMA-I&T. A total of 188 mCRPC patients with baseline 18F-flotufolastat PET scans were included. Tumor lesions were semiautomatically delineated, with imaging parameters including volume-based and standardized uptake value (SUV)-based metrics. Outcome measures included prostate-specific antigen (PSA) response, PSA-progression-free survival (PSA-PFS), and overall survival (OS). Univariate and multivariate regression analyses assessed the impact of baseline imaging and pretherapeutic clinical parameters on outcome. Event time distributions were estimated with the Kaplan-Meier method, and groups were compared with log-rank tests. Significant prognostic parameters for PSA response and PSA-PFS included log-transformed whole-body SUVmax (odds ratio (OR), 3.26, 95% confidence interval (CI), 2.01-5.55 and hazard ratio (HR), 0.51, 95% CI, 0.4-0.66; both p < 0.001) and prior chemotherapy (OR 0.3, 95% CI, 0.12-0.72 and HR 1.64, 95% CI, 1.07-2.58; p = 0.008 and p = 0.028, respectively). For OS, significant prognosticators were the following log-transformed parameters: number of lesions (HR 1.38, 95% CI, 1.24-1.53; p < 0.001), TTV (HR 1.27, 95% CI, 1.18-1.37; p < 0.001), and ITLV (HR 1.24, 95% CI, 1.16-1.33; p < 0.001), with log-transformed TTV (HR 1.15, 95% CI, 1.04-1.27; p = 0.008) remaining significant in multivariate analysis. At baseline, SUV-based 18F-flotufolastat PET metrics (e.g., whole-body SUVmax) serve as significant positive prognosticators for short-term outcomes (PSA response and PSA-PFS). In contrast, volume-based metrics (e.g., TTV) are significant negative prognosticators for long-term outcome (OS), in mCRPC patients treated with [177Lu]Lu-PSMA-I&T.

Role of prostate-specific membrane antigen positron emission tomography/computed tomography (PSMA-PET/CT) in staging

The superiority of prostate-specific membrane antigen (PSMA) positron emission tomography (PET) over conventional staging methods such as computed tomography (CT) and bone scintigraphy has now been demonstrated for almost all clinical stages of prostate cancer. In primary diagnostics, PSMA-PET/CT is therefore the new standard for risk-adapted whole-body staging. At the same time, PSMA-PET/CT provides anew risk-based classification for predicting overall survival across all early and late stages of the disease. However, the clinical implications of this information are not yet fully understood, particularly as data on systemic therapy for metastatic prostate cancer are still based on conventional imaging. For this reason, clinical follow-up is usually still carried out using conventional imaging. The Prostate Cancer Working Group4 criteria will represent an initial consensus on therapy monitoring using PSMA-PET/CT. To monitor treatment response using PSMA PET/CT in metastatic castration resistant prostate cancer, there is already aframework (RECIP1.0) in place. There is no doubt that PSMA PET/CT should be performed prior to PSMA radioligand therapy to optimize patient selection.