Castration-resistant Prostate Cancer Patients Research Articles

7906 Nanoencapsulated Curcumin-Piperine Complex: A Breakthrough In Targeting CYP17A1 For Castration Resistant Prostate Cancer Therapy

Abstract Disclosure: J. Yakubu: None. Nanoencapsulated Curcumin-Piperine Complex: A Breakthrough in Targeting CYP17A1 for Castration Resistant Prostate Cancer Therapy. Jibira Yakubu a,b,c, Oya Taritd, Evangelos Natsaridisd, Amit V. Pandey a,ba Translational Hormone Research Program, Department of Biomedical Research, Faculty of Medicine, b Paediatric Endocrinology, Diabetology and Metabolism, University Children’s Hospital, Inselspital, Bern, c Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland. d Biointerfaces, Institute of Chemistry and Bioanalytics, University of Life Sciences FHNW, Muttenz, Switzerland. Abstract: Androgens play a pivotal role in prostate cell survival and are implicated in both early-stage and advanced, castration-resistant prostate cancer (CRPC). In CRPC patients on CYP17A1 inhibitors, the development of drug resistance and hypertensive crisis through the inhibition of CYP21A2 and or its substrate are a recognized challenge. Given its crucial role in androgen production, CYP17A1 has become a major target for cancer therapies. In this study, we employed a mini-evaporation technique to nanoencapsulate curcumin, exploring its impact on CYP17A1 activity in human adrenal NCI-H295R cells. We performed steroid profiling with LC-MS, as well as gene and protein expression studies. Initial results demonstrated that curcumin nanoparticles exhibited superior efficacy in reducing CYP17A1 activity compared to known drug Abiraterone acetate. Curcumin and piperine combined in nano-capsules greatly increased the inhibitory effects on CYP17A1 activity. Furthermore, ongoing studies include western blot investigation of the drug's interaction with the CYP17A1 protein and cell cycle effects. We confirmed the efficacy of our nano formulation by testing its impact on the growth of androgen-sensitive prostate cancer cell lines. Notably, nanoencapsulation improved curcumin's inhibitory effects on DHEA production via CYP17A1. Surprisingly, the curcumin-piperine nano-capsules enhanced these effects while having no effect on CYP21A2, offering a promising option for prostate cancer treatment. Our study reveals the promise of nanoencapsulated curcumin-piperine as a game-changing method for targeting CYP17A1 for improved prostate cancer therapy. The synergistic benefits observed in our study open new avenues for addressing the difficulties associated with androgen deprivation therapy. Funding: Cancer Research Switzerland grant number: KFS 5557-02-2022 Presentation: 6/3/2024

B-255 Identification of the protein expression of Androgen Receptor variants using Targeted proteomics in clinical Castration Resistant Prostate Cancer models

Abstract Background Castration Resistant Prostate Cancer (CRPC) is a treatment resistant form of prostate cancer (PCa). Currently, there is not a way to identify which patients will develop this resistance before full blown CRPC develops. Therefore, all PCa treatment approaches are similar yet this results in tumor regression in some cases and progression in others. Targeting the androgen receptor (AR) is still the main focus of current therapies even in CRPC. Emergence of AR splice variants (AR-Vs) after initial treatment is thought to be one of the primary mechanisms of resistance. AR-Vs lack the ligand binding domain rendering Androgen Deprivation Therapy (ADT) ineffective in tumors expressing these variants. Recent work has identified the DNA and RNA species of ARVs in CRPC but investigation into whether the protein is translated are unknown. One exception is the approval of an antibody test that detects a specific AR-v, AR-v7, from the blood of PC patients and predicts ADT response. However, there are instances where a patient may not express ARv7 and are still resistant to ADT. This may suggest that other AR-Vs, not currently detected at the protein level, are important predictors for ADT response. Methods The primary goal of this work is to expand the protein identification of known and unknown AR-Vs that may predict response to ADT using targeted liquid chromatography tandem mass spectrometry (LC-MS/MS). We developed the AR-V targeted LC-MS/MS assay by first designing AR splice variants from unique splice regions via RNA-guided sequences translated to amino acid sequences. The AR-variants full amino acid sequences were then in-silico trypsin digested using Expasy software tool that generated tryptic peptides. Blast analysis of the AR-V peptides was performed where no overlap with other human proteins was observed. These AR-V peptide sequences were commercially synthesized along with heavy isotopically analogs to be used as internal standards in the LC-MS/MS method. The method examined 9 peptides and included 2 to 3 MRM transitions per peptide and calibration curves were constructed using unlabeled peptides. Specimens examined consisted of a panel of PCa cell lines (n= 6), CRPC patient derived xenografts tumors (PDX) (n=4) and a negative control cell line (no androgen receptor expression), Cos-1, which served with a dual function and was used as matrix for peptide MRM optimization experiments. Linearity and sensitivity for each peptide included in the method was examined using calibration curves. Results The targeted MRM approached was successfully achieved for the quantification of 9 peptides from 8 proteins in 6 PCa cell lines and 4 PDX tumor specimens. Out of the 8 proteins evaluated, we observed 3 known targets (AR-exon1, AR-V7 and AR-V12) and 4 novel AR-Vs in 22Rv1 PCa cell lines. Additionally, CRPC PDX were assessed where 3 novel AR-Vs were detected. Conclusions These preliminary results using a LC-MS/MS platform show promising identification and quantification of novel AR-Vs that have not been measured before at the protein level. Subsequent analysis of larger cohorts will further elucidate AR-Vs role in PCa treatment resistance mechanisms and possibly assist in future treatment approaches.

PSMA PET/CT for treatment response evaluation at predefined time points is superior to PSA response for predicting survival in metastatic castration-resistant prostate cancer patients

BackgroundIn metastatic castration-resistant prostate cancer (mCRPC), using serum prostate-specific antigen (PSA) levels to evaluate treatment response is not always accurate. This study aimed to assess the efficacy of PSMA PET/CT at specific time points for evaluating treatment response and predicting survival in mCRPC patients, compared to PSA. MethodsSixty mCRPC patients underwent [18F]PSMA-1007 PET/CT at baseline and for treatment response evaluation of either androgen receptor-targeted agents (after 3 months) or chemotherapy (after completion), and were retrospectively analysed. Visual assessment categorised overall response and response of the worst responding lesion as partial response, stable disease, or progressive disease, using the EAU/EANM criteria. Additionally, percentage changes in SUVmax, total tumour volume and total lesion uptake (tumour volume * SUVmean) were calculated. PSA response was defined according to the PCWG3 criteria. Cox regression analysis identified predictors of overall survival. ResultsPSMA PET/CT and PSA response were discordant in 47 % of patients, and PSMA PET/CT response was worse in 89 % of these cases. Overall response on PSMA PET/CT independently predicted overall survival (progression versus non-progression: HR = 4.05, p < 0.001), outperforming PSA response (progression versus non-progression: HR = 2.53, p = 0.010) and other PSMA PET/CT parameters. Among patients with a PSA decline of > 50 %, 31 % showed progressive disease on PSMA PET/CT, correlating with higher mortality risk (progression versus non-progression: HR = 4.38, p = 0.008). No flare in PSMA uptake was observed in this cohort. ConclusionsPSMA PET/CT for assessing treatment response at predefined time points was superior to PSA-based response for predicting overall survival in mCRPC patients treated with androgen receptor-targeted agents and chemotherapy. PSMA PET/CT showed the ability to detect disease progression earlier than PSA levels, which can affect treatment decisions and has the potential to improve patient outcomes. We recommend further research to validate these findings in larger patient cohorts, to extend the number of treatments, and to evaluate cost-effectiveness and impact on patient outcomes.

Importance of PSA Kinetics as a Prognostic Factor in Locally Advanced/Metastatic Prostate Cancer Patients with Prior Androgen Deprivation Therapy

Abstract Background Prostatic cancer ranks 2nd amongst men in worldwide while 4th in Egypt. Many factors are used to predict patients’ survival. PSA kinetics are one of the main prognostic factors used for treatment response in advanced or relapsed cases. However, its application as prognostic marker is lacking in Egyptian clinical settings and research. Aim of Study In this retrospective study, we aimed to assess correlation between PSA kinetics among locally advanced and metastatic prostatic cancer patients and their survival status for prognostic aspects. Methods We conducted a retrospective cohort study at Clinical Oncology department, Ain Shams University hospitals from January 2013 till December 2022 (10 years). All prostate cancer patients who were initially hormonal sensitive locally advanced or metastatic that later developed biochemical failure during follow up period were included in our study. Results Our study included 77 patients with a mean age of 66.4±7.4 years. Three cases were locally advanced while 74 cases were metastatic. The most frequent mode of ADT monotherapy prior biochemical failure was GnRH analogue in 55 cases. Upon disease progression, most of the cases were shifted to abiraterone acetate. The initial median PSA value was 100 (49.1-193.9) ng/ml. It took about 9 (6-14) months (median TTN) with a median declining rate of 10.5 (3.75-35.1) % for their PSA values to reach nadir level of median 1.2 (0.21-5.27) ng/dl. When ADT failed, PSA levels increased again reaching a median value of 8.9 (3.75-35.2) ng/ml. The median PSA velocity after progression was 35.2 (2.8-208) ng/dl/yr while median PSA DT was 3.6 (1.3-7.25) months. Univariate analysis revealed PSA nadir &amp;lt;0.76 ng/dl level (P value= 0.003) and TTN &amp;gt;11 m (p value = 0) significantly associated with longer PFS and improved survival. However, PSA DT &amp;lt; 3.1 (p value=0.017) predicts higher mortality. Meanwhile, multivariate results showed that PSA declining rate (P value= 0.047) and age &amp;gt; 67 years (P value 0.016) were statistically significant as independent factors when associated to PFS. Conclusion TTN &amp;gt; 11 months and PSA nadir &amp;lt;0.76 during initial treatment was associated with prolonged PFS and OS. They were associated with better clinical response to treatment in castration resistant prostate cancer patients. Thus, it could be helpful for decision making of early treatment strategy in castration resistant cases.

Statin use and oncological outcomes in a propensity-matched cohort of nonmetastatic castration resistant prostate cancer patients of the ARAMIS trial

IntroductionWhile observational studies suggest favorable associations between statin use and prostate cancer (CaP) outcomes, data from randomized-controlled trials remain inconclusive. Our study explores the relationship between statin use and survival outcomes in the context of the phase III ARAMIS study, a trial of darolutamide in the treatment of nonmetastatic castration-resistant prostate cancer. MethodsWe reviewed all 1,509 patients in the ARAMIS trial. Statin use was identified at baseline. Statin users were matched 1:2 with nonusers using a propensity score matching model. The primary endpoint was metastasis-free survival (MFS). Kaplan-Meier curves were plotted for MFS comparing statin users and nonusers across ARAMIS trial arms. A multivariate Cox proportional hazards model was fitted using the propensity-matched cohort and incorporating statin use and all covariates. ResultsOf the 1,509 patients in ARAMIS, 334 (22.1%) were statin users. We matched 297 statin users to 550 nonusers. Characteristics appeared well balanced. Among nonusers, 331 (60.3%) and 219 (39.7%) were in the ARAMIS darolutamide and placebo arms, respectively. Among statin users, 179 (60.3%) and 118 (39.7%) were in the ARAMIS darolutamide and placebo arms, respectively. Overall, we found no significant difference in MFS between statin users and nonusers (HR 1.05, 95% CI 0.80–1.38 P = .72). However, we found significant interaction between statin use and ARAMIS trial arm. Specifically, statin use had a stronger association with MFS in the placebo arm (P = 0.024). However, this is likely coincidental and due to the statin-placebo patients having higher nodal positivity than the nonusers-placebo patients (14.3% vs. 5.5%). Statin use was similarly not associated with the secondary outcomes of PSA progression-free survival (P = 0.42), time-to-pain progression (P = 0.85), or overall survival (P = 0.15). ConclusionsIn our secondary analysis of the ARAMIS trial, statin users had similar MFS and secondary outcomes compared to nonusers. These results suggest pursuing further statin synergies with amide-based androgen receptor axis target agents may not be fruitful.

Germline and somatic testing for homologous repair deficiency in patients with prostate cancer (part 1 of 2).

Unfortunately, not all metastatic castration resistant prostate cancer (mCRPC) patients receive available life-prolonging systemic therapies, emphasizing the need to optimize mCRPC treatment selections. Better guidelines are necessary to determine genetic testing in prostate cancer. In this two-part expert opinion-based guide, we provide an expert consensus opinion on the utilization of germline and somatic testing to detect HRR alterations in patients with mCRPC. This guide was developed by a multidisciplinary expert panel that convened in 2023-2024, including representatives from medical oncology, urology, radiation oncology, pathology, medical genomics, and basic science. We argue for the widespread adoption of germline testing in all patients with prostate cancer and for somatic mutations testing in patients at the time of recurrent/metastatic disease. In this first part, we review how genomic testing is performed. We also review how to overcome certain barriers to integrate genetic and biomarker testing into clinical practice.

Therapeutic implications of homologous repair deficiency testing in patients with prostate cancer (Part 2 of 2).

Unfortunately, not all metastatic castration-resistant prostate cancer (mCRPC) patients receive available life-prolonging systemic therapies, emphasizing the need to optimize mCRPC treatment selections. Better guidelines are necessary to determine genetic testing for prostate cancer. In this two-part expert opinion-based guide, we provide an expert consensus opinion on the utilization of germline and somatic testing to detect HRR alterations in patients with mCRPC. This guide was developed by a multidisciplinary expert panel that convened in 2023-2024, including representatives from medical oncology, urology, radiation oncology, pathology, medical genomics, and basic science. In this second part, we highlight how genetic testing can lead to improved, life-prolonging mCRPC therapeutic strategies based on a review of the recent phase III trials and subsequent regulatory approvals for PARP inhibitors in mCRPC.

Efficacy and Toxicity of [177Lu]Lu-PSMA-617 for Metastatic Castration-Resistant Prostate Cancer: Results from the U.S. Expanded-Access Program and Comparisons with Phase 3 VISION Data.

The phase 3 VISION trial demonstrated that [177Lu]Lu-PSMA-617 prolonged progression-free survival and overall survival (OS) in prostate-specific membrane antigen [PSMA]-positive metastatic castration-resistant prostate cancer (mCRPC) patients who progressed on taxane-based chemotherapy and androgen receptor-signaling inhibitors (ARSIs). The U.S. expanded-access program (EAP; NCT04825652) was opened to provide access to [177Lu]Lu-PSMA-617 for eligible patients until regulatory approval was obtained. This study aimed to evaluate the efficacy and safety profile of [177Lu]Lu-PSMA-617 within the EAP and compare the results with those from the VISION trial. Methods: Patients enrolled in the EAP at 4 institutions in the United States with available toxicity and outcome data were included. Outcome measures included OS, a prostate-specific antigen (PSA) response rate (RR) of at least 50%, and incidences of toxicity according to Common Terminology Criteria for Adverse Events version 5.0. Differences in baseline characteristics, outcome data, and toxicity between the EAP and VISION were evaluated using t testing of proportions and survival analyses. Results: In total, 117 patients with mCRPC who received [177Lu]Lu-PSMA-617 within the EAP between May 2021 and March 2022 were eligible and included in this analysis. Patients enrolled in the EAP were more heavily pretreated with ARSI (≥2 ARSI regimens: 70% vs. 46%; P < 0.001) and had worse performance status at baseline (Eastern Cooperative Oncology Group score ≥ 2: 19% vs. 7%; P < 0.001) than VISION patients. EAP and VISION patients had similar levels of grade 3 or higher anemia (18% vs. 13%; P = 0.15), thrombocytopenia (13% vs. 8%; P = 0.13), and neutropenia (3% vs. 3%; P = 0.85) and similar PSA RRs (42% vs. 46%; P = 0.50) and OS (median: 15.1 vs. 15.3 mo; P > 0.05). Conclusion: Patients with PSMA-positive mCRPC who received [177Lu]Lu-PSMA-617 within the EAP were later in their disease trajectory than VISION patients. Patients enrolled in the EAP achieved similar PSA RRs and OS and had a safety profile similar to that of the VISION trial patients.

Abstract A034: DNA repair capacity in metastatic castration-resistant prostate cancer patients using lymphocytes as surrogate markers

Abstract Prostate cancer (PCa) is one of the most commonly diagnosed cancers in men from the United States (US) and Puerto Rico (PR). In 2024, around 35,250 PCa-related deaths will occur in the US, making PCa the second leading cause of cancer-related mortality in men in the US. In Puerto Rican men, PCa represents the first cause of cancer incidence (38%) and mortality (19%). Metastatic castrate-resistant prostate cancer (mCRPC) remains among the most frequent causes of cancer-related mortality in males. Patients with mCRPC become progressively resistant to androgen deprivation therapy, and the median survival for these patients is around two years. Ortiz-Sanchez et al. (2022) previously reported that the nucleotide excision repair (NER) pathway is dysregulated in the lymphocytes from patients with indolent and aggressive PCa; nevertheless, mCRPC cases were not included in the study design. Therefore, this pilot study aimed to evaluate the DNA repair capacity (DRC) in Puerto Rican men with and without mCRPC through the CometChip assay using lymphocytes as surrogate markers. Variations in mean DRC values were expected among the study groups. DRC measurements through the NER pathway were performed in a cohort of 96 participants, including PCa cases (n=71) and controls (n=25). The mean DRC value for the control group was 17.63%, and for the cases, it was 7.90%. When comparing mCRPC (n=16), non-mCRPC (n=55), and controls, significant differences were observed between the controls and each cancer group. However, no significant differences were found between PCa cases stratified by disease aggressiveness. Currently, we are evaluating the functionality of the homologous recombination repair pathway to gain additional insights into the role of DRC in PCa. Our results represent the first effort to apply a phenotypic assay to evaluate the overall DRC in mCRPC. This may improve patient diagnosis and patient stratification in terms of disease progression. Citation Format: Jaime Matta, Jarline Encarnación-Medina, Gilberto Ruiz-Deya, Valerie Rodriguez-Baez, Carmen Ortiz-Sanchez. DNA repair capacity in metastatic castration-resistant prostate cancer patients using lymphocytes as surrogate markers [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr A034.

Personalized dosimetry assessment of [177Lu]Lu-PSMA-617 radioligand therapy in the management of metastatic castration-resistant prostate cancer

Introduction Prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT) is revolutionizing the treatment landscape for metastatic castration-resistant prostate cancer (mCRPC) patients. This study aimed to establish patient-specific radiation dosimetry for [177Lu]Lu-PSMA-617 RLT in Iranian patients with mCRPC. Method Twelve biopsy-proven prostate cancer patients (aged 68.73 ± 5.26 yr) underwent 6.62 ± 0.36 GBq [177Lu]Lu-PSMA-617 RLT. Post-therapy whole-body planar scans were acquired approximately at 4, 48, and 72 h post-administration, alongside a single SPECT/CT around 48 h using Siemens Symbia T2 to obtain cumulated activity. An imaging protocol and dosimetry approach were designed to balance between time efficacy and accuracy in post-therapeutic dosimetry. Using accurate activity calibration, S-values were calculated by importing SPECT/CT images as the source/geometry into the Geant4 application for the tomographic emission (GATE) Monte Carlo (MC) toolkit. The Medical Internal Radiation Dose (MIRD) scheme was followed for subsequent absorbed dose (AD) calculations in organs at risk (OAR) and tumoral lesions using the dose actor and accumulated activities for precise dose estimations. Results Using the MC approach, the mean ADs to the liver, spleen, right and left kidneys, and tumor lesions were 0.11 ± 0.04 Gy/GBq, 0.08 ± 0.03 Gy/GBq, 0.34 ± 0.09 Gy/GBq, 0.34 ± 0.10 Gy/GBq, and 0.83 ± 0.54 Gy/GBq, respectively. Notably, tumoral lesions demonstrated significantly higher ADs, indicating enhanced uptake of radiopharmaceuticals by malignant cells. Conclusions This study indicates that the ADs of OARs and tumoral lesions from [177Lu]Lu-PSMA-617 RLT in patients with mCRPC are consistent with existing literature. The dosimetry findings suggest that increasing the administered activity of [177Lu]Lu-PSMA-617 RLT is feasible and does not pose a significant risk of adverse effects on OARs, as supported by our data. However, to validate the safety and efficacy of higher doses, further clinical follow-up studies are recommended.

Prognostic Significance of Baseline Clinical and [68Ga]Ga-PSMA PET Derived Parameters on Biochemical Response, Overall Survival, and PSA Progression-Free Survival in Metastatic Castration-Resistant Prostate Cancer (mCRPC) Patients Undergoing [177Lu]Lu-PSMA Therapy.

In this study, we sought to identify the clinical baseline characteristics and pre-therapy 68Ga-PSMA PET derived parameters that can have impact on PSA (biochemical) response, OS and PSA PFS in patients with metastatic castration-resistant prostate cancer (mCRPC) who undergo RLT with [177Lu]Lu-PSMA-617. Various pre-treatment clinical and PSMA PET derived parameters were gathered and computed. We used PSA response as the criteria for more than a 50% decrease in PSA level, and OS and PSA PFS as endpoints. We assessed the collected parameters in relation to PSA response. Additionally, we employed univariable Cox regression and Kaplan-Meier analysis with log rank to evaluate the influence of the parameters on OS and PFS. A total of 125 mCRPC patients were included in this study. The median age was 68 years (range: 49-89). Among the cases, 77 patients (62%) showed PSARS, while 48 patients (38%) did not show PSA response. The median OS was 14 months (range: 1-60), and the median PSA-PFS was 10 months (range: 1-56). Age, prior history of chemotherapy, and SUVmax had a significant impact on PSA response (p<0.05). PSA response, RBC count, hemoglobin, hematocrit, neutrophil to lymphocyte ratio (NLR), alkaline phosphatase (ALP), number of metastases, wbPSMA-TV, and wbTL-PSMA significantly affected OS. GS, platelet count, NLR, and number of metastases were found to have a significant impact on PSA PFS. We have identified several baseline clinical and PSMA PET derived parameters that can serve as prognostic factors for predicting PSA response, OS, and PSA PFS after RLT. Based on the findings, we believe that these clinical baseline characteristics can assist nuclear medicine specialists in identifying RLT responders who have long-term survival and PFS.

Microsatellite Instability-High and High Tumor Mutation Burden Frequencies in Urologic Malignancies Off-Label for Immune Checkpoint Inhibitors in Japan: A Retrospective Single-Institutional Cohort.

Objectives Microsatellite instability-high (MSI-H) and high tumor mutation burden (TMB-high) frequencies were investigated to determine the efficacy and adverse events of pembrolizumab in patients with urologic malignancies (or their equivalents) for which immune checkpoint inhibitors (ICIs) are not covered by Japanese insurance. Methods Between February 2019 and April 2024, patients with urologic malignancies (or their equivalents) treated in our department for whom ICIs were not approved by Japanese insurance were screened with an MSI companion diagnostic kit or comprehensive genomic profiling (CGP). The efficacy of pembrolizumab therapy, presence of adverse events, and outcomes were evaluated retrospectively in patients with MSI-H or TMB-high. Results In total, 44 patients were tested, and the median age at testing was 70 years. Castration-resistant prostate cancer (CRPC) was the most common (n = 31). Overall, 49 tests were performed, including 22 MSI companion diagnostic kits and 27 CGP tests. Of the 49 tests, 1 detected MSI-H, 2 detected TMB-high, and 1 detected simultaneous MSI-H/TMB-high, with detection rates of 4.1% and 11.1% for MSI-H and TMB-high, respectively. A patient with MSI-H CRPC and neuroendocrine differentiation achieved a complete response and a prolonged duration of response to pembrolizumab without adverse events. The duration of response to pembrolizumab was shorter ina patient with TMB-high, and a CRPC patient with simultaneously detected MSI-H/TMB-high had to discontinue pembrolizumab early due to immune-related adverse events. Conclusions Despite the potential benefit of pembrolizumab, MSI-H or TMB-high was less frequently detected in urologic malignancies for which ICIs are not covered by Japanese insurance.

1635P Validation of automated bone scan index as a progression endpoint in two phase III studies of metastatic castration resistant prostate cancer (mCRPC) patients

1635P Validation of automated bone scan index as a progression endpoint in two phase III studies of metastatic castration resistant prostate cancer (mCRPC) patients

1602P CBP-1018, Bi-ligand-drug conjugate (Bi-XDC) drug treated for metastatic castration resistant prostate cancer (mCRPC) patients from phase I study results

1602P CBP-1018, Bi-ligand-drug conjugate (Bi-XDC) drug treated for metastatic castration resistant prostate cancer (mCRPC) patients from phase I study results

Correlation of [68Ga]Ga-PSMA PET/CT response and PSA decline in first-line enzalutamide for metastatic castration-resistant prostate cancer patients

Purposeto assess the utility of response monitoring to enzalutamide by using [68Ga]Ga-PSMA PET in mCRPC patients treated with enzalutamide as first-line therapy.Methodspatients underwent [68Ga]Ga-PSMA PET less than 8 weeks before and 3 months after starting enzalutamide. On the basis of EAU/EANM criteria, patients were categorized as PSMA responders (PET-R) or PSMA non-responders (PET-NR), whilst, based on PSA, they were classified as biochemical responders (PSA-R) or non-responders (PSA-NR). Survival analysis was performed using the Cox regression hazard model and the Kaplan-Meier method.Results69 patients were considered fully evaluable. We observed 47.8% of concordance between [68Ga]Ga-PSMA PET and PSA monitoring at 3 months after starting enzalutamide. For discordant cases, the PSA reduction has a weak impact on PFS and a significant impact on OS in PET-NR patients, whilst this change has no impact either for PFS and OS in PET-R ones.Conclusions[68Ga]Ga-PSMA PET could be a useful imaging tool for monitoring response to enzalutamide in mCRPC patients, being more informative than PSA in this setting, and possibly better guiding clinicians in therapeutic decisions.

Prostate Cancer's Silent Partners: Fibroblasts and Their Influence on Glutamine Metabolism Manipulation.

Cancer-associated fibroblast (CAF)s in the tumour microenvironment (TME) modulate the extracellular matrix, interact with cancer cells, and facilitate communication with infiltrating leukocytes, significantly contributing to cancer progression and therapeutic response. In prostate cancer (PCa), CAFs promote malignancy through metabolic rewiring, cancer stem cell regulation, and therapy resistance. Pre-clinical studies indicate that targeting amino acid metabolism, particularly glutamine (Gln) metabolism, reduces cancer proliferation and stemness. However, most studies lack the context of CAF-cancer interaction, focusing on monocultures. This study assesses the influence of CAFs on PCa growth by manipulating Gln metabolism using colour-labelled PCa cell lines (red) and fibroblast (green) in a co-culture system to evaluate CAFs' effects on PCa cell proliferation and clonogenic potential. CAFs increased the proliferation of hormone-sensitive LNCaP cells, whereas the castration-resistant C4-2 cells were unaffected. However, clonogenic growth increased in both cell lines. Gln deprivation and GLS1 inhibition experiments revealed that the increased growth rate of LNCAP cells was associated with increased dependence on Gln, which was confirmed by proteomic analyses. Tissue analysis of PCa patients revealed elevated GLS1 levels in both the PCa epithelium and stroma, suggesting that GLS1 is a therapeutic target. Moreover, the median overall survival analysis of GLS1 expression in the PCa epithelium and stroma identified a "high-risk" patient group that may benefit from GLS1-targeted therapies. Therefore, GLS1 targeting appears promising in castration-resistant PCa patients with high GLS1 epithelium and low GLS1 stromal expression.

The Circulating miR-107 as a Potential Biomarker Up-Regulated in Castration-Resistant Prostate Cancer.

Prostate cancer (PCa) is a prevalent malignancy in men globally. Current diagnostic methods like PSA testing have limitations, leading to overdiagnosis and unnecessary treatment. Castration-resistant prostate cancer (CRPC) emerges in some patients receiving androgen deprivation therapy (ADT). This study explores the potential of circulating microRNA-107 (miR-107) in liquid biopsies as a prognosis tool to differentiate CRPC from non-castration-resistant PCa (NCRPC). We designed a case-control study to evaluate circulating miR-107 in serum as a potential prognosis biomarker. We analyzed miR-107 expression in liquid biopsies and found significantly higher levels (p < 0.005) in CRPC patients, compared to NCRPC. Notably, miR-107 expression was statistically higher in the advanced stage (clinical stage IV), compared to stages I-III. Furthermore, CRPC patients exhibited significantly higher miR-107 levels (p < 0.05), compared to NCRPC. These findings suggest that miR-107 holds promise as a non-invasive diagnostic biomarker for identifying potential CRPC patients.

The Neutrophil-to-Lymphocyte Ratio as a Biomarker in Metastatic Castrate-Sensitive Prostate Cancer Patients Treated with Abiraterone Acetate

Given its known prognostic role, we aimed to investigate the role of neutrophil–lymphocyte ratio (NLR) as a biomarker in metastatic castration-resistant prostate cancer (mCRPC) patients receiving ADT, either as monotherapy or in conjunction with abiraterone acetate (AA) and prednisone. This retrospective cohort study analyzed the LATITUDE study of men with high-risk mCSPC. Patients were assigned to receive either AA, prednisone, and androgen deprivation therapy (ADT) or placebo plus ADT. Using a previously established NLR threshold of 2.5, we evaluated if this could predict clinical response to abiraterone. At baseline, there were no significant differences in NLR values between the treatment groups. Of the known baseline prognostic factors, NLR was associated with albumin levels and Eastern Cooperative Oncology Group performance scores. Moreover, the number of bone metastases was higher in patients with NLR ≥ 2.5. On multivariable analysis, baseline NLR ≥ 2.5 did not predict overall survival, PSA progression-free, or metastasis-free survival. However, changes in PSA and NLR at six months indicated distinct survival patterns between the placebo and AA groups, suggesting the potential for their combined assessment as a prognostic tool. Baseline NLR was not an independent predictor factor for response to AA in the LATITUDE study, though NLR changes at 6 months may predict better survival beyond PSA values alone. Further research is required to better understand in which patients with advanced prostate cancer NLR changes may be a useful prognostic tool.

Prebiotic stachyose inhibits PRDX5 activity and castration-resistant prostate cancer development

Stachyose (STA) is a prebiotic with poor oral bioavailability. In this study, we developed stachyose caproate (C6-STA), as a novel STA derivative, to demonstrate its high adsorption rate via oral administration. Pharmacokinetic analysis reveals that after absorption, the STA derived from C6-STA reaches its highest peak in the blood, liver, and kidney at 20 min, 30 min, and 12–24 h, with approximate levels of 1200 μg/mL, 0.14 μg/mL, and 0.2–0.3 μg/mL, respectively. In addition, the accumulation of STA in prostate tissues of mice with castration-resistant prostate cancer (CRPC) (1.75 μg/mg) is 10-fold higher than that in normal prostate tissues (0.14 μg/mg). The analysis also reveals that C6-STA has t1/2 of 12.8 h and Tmax of 0.25 h, indicating that it has the potential to be used as a promising drug in clinical practice. The toxicological evaluation shows no obvious side effects of C6-STA in mice administered with a 0.2 g/kg intragastric dose. Pharmacodynamic analysis and mechanism investigation of C6-STA show its ability to inhibit peroxiredoxin 5 (PRDX5) enzyme activity, disrupt PRDX5-nuclear factor erythroid 2-related factor 2 (NRF2) interaction, and decrease NAD(P)H quinone dehydrogenase 1 (NQO1) levels. NQO1 decrease further causes the accumulation of quinone radicals, which ultimately leads to the apoptosis of LNCaP cell-derived drug-tolerant persister (DTP) cells and slows CRPC progression. Our study discovered the anti-tumor activity of stachyose and shows that prebiotics have biological functions in vivo besides in the gut. Further investigation of C6-STA, especially in CRPC patients, is warranted.

Therapeutic response and safety of radioligand therapy with 177Lu-PSMA-617 in metastatic castration-resistant prostate cancer patients.

Prostate cancer is one of the most common cancers and leading cause of death due to cancer across the globe. This persuaded researchers to devise innovative treatment modalities that may prove effective, safe, and demonstrate better outcomes in terms of patient morbidity and survival. The advancement in theranostics such as lutetium-177 (177Lu)-PSMA-617 radioligand therapies can target prostate cancer cells causing negligible or no damage to most of the normal tissues in patients. It has been proven to effectively improve the quality of life and progression-free survival. In this study, stage IV metastatic castration-resistant prostate cancer patients were treated with 177Lu-PSMA-617, and the therapeutic response and safety of 177Lu-PSMA-617 radioligand therapy were evaluated six months after the treatment. Additionally, molecular docking studies were also conducted to find the possible mechanism at the molecular level that causes the effectiveness of 177Lu-PSMA-617 in prostate cancer.