Advanced Stage Prostate Cancer Research Articles

Transcriptomic response of prostate cancer cells to carbon ion and photon irradiation with focus on androgen receptor and TP53 signaling

BackgroundRadiotherapy is essential in the treatment of prostate cancer. An alternative to conventional photon radiotherapy is the application of carbon ions, which provide a superior intratumoral dose distribution and less induced damage to adjacent healthy tissue. A common characteristic of prostate cancer cells is their dependence on androgens which is exploited therapeutically by androgen deprivation therapy in the advanced prostate cancer stage. Here, we aimed to analyze the transcriptomic response of prostate cancer cells to irradiation by photons in comparison to carbon ions, focusing on DNA damage, DNA repair and androgen receptor signaling.MethodsProstate cancer cell lines LNCaP (functional TP53 and androgen receptor signaling) and DU145 (dysfunctional TP53 and androgen receptor signaling) were irradiated by photons or carbon ions and the subsequent DNA damage was assessed by immuno-cytofluorescence. Furthermore, the cells were treated with an androgen-receptor agonist. The effects of irradiation and androgen treatment on the gene regulation and the transcriptome were investigated by RT-qPCR and RNA sequencing, followed by bioinformatic analysis.ResultsFollowing photon or carbon ion irradiation, both LNCaP and DU145 cells showed a dose-dependent amount of visible DNA damage that decreased over time, indicating occurring DNA repair. In terms of gene regulation, mRNAs involved in the TP53-dependent DNA damage response were significantly upregulated by photons and carbon ions in LNCaP but not in DU145 cells, which generally showed low levels of gene regulation after irradiation. Both LNCaP and DU145 cells responded to photons and carbon ions by downregulation of genes involved in DNA repair and cell cycle, partially resembling the transcriptome response to the applied androgen receptor agonist. Neither photons nor carbon ions significantly affected canonical androgen receptor-dependent gene regulation. Furthermore, certain genes that were specifically regulated by either photon or carbon ion irradiation were identified.ConclusionPhoton and carbon ion irradiation showed a significant congruence in terms of induced signaling pathways and transcriptomic responses. These responses were strongly impacted by the TP53 status. Nevertheless, irradiation mode-dependent distinct gene regulations with undefined implication for radiotherapy outcome were revealed. Androgen receptor signaling and irradiations shared regulation of certain genes with respect to DNA-repair and cell-cycle.

Positive psychology interventions in patients with prostate cancer: A systematic review.

e17005 Background: Prostate cancer is the most common malignancy in men and often results in psychiatric symptoms due to the direct disease effects, hormonal treatments, functional losses, and psychological responses of patients to the cancer. Positive psychology interventions have shown promise in alleviating psychological symptoms in patients with chronic diseases but are infrequently studied in patients with prostate cancer. Therefore, our systematic review aimed to examine the benefits of positive psychology interventions for patients with prostate cancer. Methods: Using PRISMA guidelines, a systematic literature search was conducted using the Medline, PubMed/Medline, and PsycInfo databases using a combination of MeSH terms and free text words, including publications up to November 2023. Studies were eligible if they included at least one positive psychology therapy intervention and the title or abstract mentioned the inclusion of patients with prostate cancer. Two individuals independently reviewed reports identified by the search to meet the above criteria and performed a quality assessment scale of studies based on standardized criteria that were adapted from those used in prior systematic reviews. The study was pre-registered on the Open Science Framework (OSF) repository. Results: The database searches yielded 1244 initial studies, 10 of which met inclusion criteria. Of the 10 included studies, 2 were randomized clinical trials, 2 were pilot feasibility trials, 3 were single-arm interventional studies, and 3 were cross-sectional studies. Manuscripts focused on older adults, with reported mean ages ranging from 54.5 to 72.0. Positive psychology interventions consisted of mindfulness-based therapies, meditation, hope and resilience therapies, and well-being therapies. Most studies showed a positive effect on improving outcomes for patients with early to advanced stage prostate cancers, including psychological distress, mood disorders, anxiety, quality of life, happiness, and life satisfaction. However, most of the studies were limited by small sample size, qualitative findings, loss to follow-up, and observational data. Most studies also excluded patients with severe psychiatric disorders, who may potentially benefit most from these interventions. Conclusions: This systematic review demonstrates that positive psychology approaches may have benefit in patients with prostate cancer. However, further larger prospective studies and clinical trials are needed to determine whether these interventions have proven benefit in this understudied population.

Role of MicroRNA-21 in Prostate Cancer Progression and Metastasis: Molecular Mechanisms to Therapeutic Targets.

The role of noncoding RNA has made remarkable progress in understanding progression, metastasis, and metastatic castration-resistant prostate cancer (mCRPC). A better understanding of the miRNAs has enhanced our knowledge of their targeting mainly at the therapy level in solid tumors, such as prostate cancer (PCa). microRNAs (miRNAs) belong to a class of endogenous RNA that deficit encoded proteins. Therefore, the role of miRNAs has been well-coined in the progression and development of PCa. miR-21 has a dual nature in its work both as a tumor suppressor and oncogenic role, but most of the recent studies showed that miR-21 is a tumor promoter and also is involved in castration-resistant prostate cancer (CRPC). Upregulation of miR-21 suppresses programmed cell death and inducing metastasis and castration resistant in PCa. miR-21 is involved in the different stages, such as proliferation, angiogenesis, migration, and invasion, and plays an important role in the progression, metastasis, and advanced stages of PCa. Recently, various studies directly linked the role of high levels of miR-21 with a poor therapeutic response in the patient of PCa. In the present review, we have explained the molecular mechanisms/pathways of miR-21 in PCa progression, metastasis, and castration resistant and summarized the role of miR-21 in diagnosis and therapeutic levels in PCa. In addition, we have spotlighted the recent therapeutic strategies for targeting different stages of PCa.

Disparities in treatment patterns and mortality in prostate cancer: Interaction between Black race and end-stage kidney disease.

Black men and men with end-stage kidney disease have lower rates of treatment and higher mortality for prostate cancer. We studied the interaction of end-stage kidney disease (ESKD) with Black race for treatment rates and mortality for men with prostate cancer. We included 516 Black and 551 White men with ESKD before prostate cancer 22,299 Black men, and 141,821 White men without ESKD who were 40 years or older from the Surveillance, Epidemiology, and End-Results-Medicare data (2004-2016). All Black men with or without ESKD and White men with ESKD had higher prostate-specific antigen levels at diagnosis than White men without ESKD. Black men with ESKD had the lowest rates for treatment in both local and advanced stages of prostate cancer (age-adjusted risk ratio: 0.76, 95% Confidence Interval (CI): 0.71-0.82 for local stage and age-adjusted risk ratio: 0.82, 95% CI: 0.76-0.9 for advanced stages) compared to White men without ESKD. Compared to White men without ESKD, prostate cancer-specific mortality was higher in White men with ESKD for both local and advanced stages (age-adjusted hazard ratio: 1.8, 95% CI: 1.2-2.8 and HR: 1.6, 95% CI: 1.2-2.2) and it was higher for ESKD Black men only in advanced stage prostate cancer (age-adjusted hazard ratio: 2.4, 95% CI: 1.5-3.6). Our findings suggest that having a comorbidity such as ESKD makes Black men more vulnerable to racial disparities in prostate cancer treatment and mortality.

Enhancing the anticancer effect of androgen deprivation therapy by monocarboxylate transporter 1 inhibitor in prostate cancer cells.

Tumor initiation and progression necessitate a metabolic shift in cancer cells. Consequently, the progression of prostate cancer (PCa), a leading cause of cancer-related deaths in males globally, involves a shift from lipogenic to glycolytic metabolism. Androgen deprivation therapy (ADT) serves as the standard treatment for advanced-stage PCa. However, despite initial patient responses, castrate resistance emerges ultimately, necessitating novel therapeutic approaches. Therefore, in this study, we aimed to investigate the role of monocarboxylate transporters (MCTs) in PCa post-ADT and evaluate their potential as therapeutic targets. PCa cells (LNCaP and C4-2 cell line), which has high prostate-specific membrane antigen (PSMA) and androgen receptor (AR) expression among PCa cell lines, was used in this study. We assessed the expression of MCT1 in PCa cells subjected to ADT using charcoal-stripped bovine serum (CSS)-containing medium or enzalutamide (ENZ). Furthermore, we evaluated the synergistic anticancer effects of combined treatment with ENZ and SR13800, an MCT1 inhibitor. Short-term ADT led to a significant upregulation in folate hydrolase 1 (FOLH1) and solute carrier family 16 member 1 (SLC16A1) gene levels, with elevated PSMA and MCT1 protein levels. Long-term ADT induced notable changes in cell morphology with further upregulation of FOLH1/PSMA and SLC16A1/MCT1 levels. Treatment with ENZ, a nonsteroidal anti-androgen, also increased PSMA and MCT1 expression. However, combined therapy with ENZ and SR13800 led to reduced PSMA level, decreased cell viability, and suppressed expression of cancer stem cell markers and migration indicators. Additionally, analysis of human PCa tissues revealed a positive correlation between PSMA and MCT1 expression in tumor regions. Our results demonstrate that ADT led to a significant upregulation in MCT1 levels. However, the combination of ENZ and SR13800 demonstrated a promising synergistic anticancer effect, highlighting a potential therapeutic significance for patients with PCa undergoing ADT.

Abstract 466: microRNA regulators of neuroendocrine differentiation in metastatic castration-resistant prostate cancer

Abstract Therapy-induced neuroendocrine prostate cancer (NEPC), an extremely aggressive variant of castration-resistant prostate cancer (CRPC), is increasing in incidence with the widespread use of highly potent androgen receptor (AR)-pathway inhibitors (APIs) via a reversible trans-differentiation process, referred to as neuroendocrine differentiation (NED). The molecular basis of NED is not completely understood leading to a lack of effective molecular markers for its diagnosis. We hypothesized that alterations in key miRNAs drive NED, leading to lineage switching and emergence of NEPC. The aims of our study are: (i) identify key miRNA alterations that occur as PCa cells undergo neuroendocrine differentiation; (ii) develop a miRNA-based classifier for predicting/diagnosing NEPC; (iii) understand the functional role of key miRNA alterations. To systematically investigate the key miRNAs alterations driving therapy induced NED, we performed small RNA-NGS in a retrospective cohort of human metastatic CRPC clinical samples + PDX models with adenocarcinoma features (CRPC-adeno) vs those with neuroendocrine features (CRPC-NE). Further, with the application of machine learning algorithms to sequencing data, we trained a ‘miRNA classifier’ that could robustly classify ‘CRPC-NE’ from ‘CRPC-Adeno’ cases. The performance of classifier was validated in additional cohorts of mCRPC patients acquired from independent sites by employing single model prediction algorithm. We further sought to understand the functional role of these miRNAs by overexpessing in PCa cell lines followed by functional assays. In vivo xenograft studies were performed using PC3 cells overexpressing miR-28/control miRNA. We demonstrate for the first time, that lineage switching to NE states is accompanied by key miRNA alterations. Our analysis, measured using receiver operating characteristic (ROC) curves, demonstrated an area under the curve (AUC) value of 0.8318, confirming the robustness of our classifier in distinguishing CRPC-NE from CRPC-Adeno. Furthermore, we identified a select group of 5 miRNAs that were pivotal in distinguishing between these two prostate cancer subtypes. We focused on miR-28-3p, little studied miRNA in prostate cancer. Our in vitro and in vivo data with prostate cancer cell lines and xenograft model suggests that miR-28-3p acts as a tumor suppressor miRNA in advanced stage prostate cancer. We further found mesenchymal gene Vimentin to be a direct miR-28-3p target. We propose that loss of miR-28-3p promotes epithelial-to-mesenchymal transition (EMT), thereby favoring NED. Our study has important clinical implications and transformative potential as our 'miRNA classifier' can be used as a molecular tool to stratify mCRPC patients into those with/without NED and guide treatment decisions. Further, we identify novel miRNA NED drivers that can be exploited for NEPC therapeutic targeting. Citation Format: Diana Asante, Sandip Nathani, Tae Jin Lee, Ashok Sharma, Sharanjot Saini. microRNA regulators of neuroendocrine differentiation in metastatic castration-resistant prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 466.

Abstract 104: Profiling peripheral blood to predict response to targeted androgen receptor axis therapy in mice

Abstract Background: Targeting the androgen receptor (AR) signaling axis (ARAT) continues to be the mainstay treatment for advanced-stage prostate cancer. Using second-generation antiandrogens like abiraterone acetate (Abi) and apalutamide (Apa) has contributed to the survival of prostate cancer patients. However, resistance to these therapies remains a problem and most of these patients progress to castration-resistant prostate cancer (CRPC). Myeloid-derived suppressor cells (MDSCs) have been shown to drive CRPC. We previously showed that unfavorable responses to androgen deprivation therapy (ADT) or ADT plus Apa were associated with polymorphonuclear MDSCs (PMN-MDSCs) cells enriched in prostate tumors from conditional Pten/Trp53-double knockout (DKO) mice. Here, we explore the association between pre-treatment immune cell subsets blood and antitumor to ARAT therapy DKO mice. Methods: Twenty-eight-week-old DKO mice were surgically castrated and after four weeks were randomized to treatments with vehicle, Apa or Abi for an additional four weeks (n=20). Individual treatment responses were assessed and classified according to tumor burden as follows: high tumor burden (HTB), ≥20% of median; moderate tumor burden (MTB), -20% to 20% of median; or low tumor burden (LTB), ≤-20% of median. Peripheral blood was collected both before and after treatment and analyzed by multi-color flow cytometry panels for lymphoid and myeloid subsets. Blood samples from healthy wildtype and untreated DKO mice with castration-naïve prostate tumors were collected as reference samples. Subsets of PMN-MDSCs and monocytic-MDCSs (m-MDSCs) were represented as % of total abundance and 5 of parental population. revealed a signature that was correlated with treatment responses. Profiles were constructed and the data was used to train supervised learning models to predict treatment responses. Shapely additive explanations (ShAP) were used to determine feature importance. The model was tested and validated on an independent cohort of 20 DKO mice treated with ADT and ADT plus Abi. Results: Moderate prediction from baseline blood could be identified for tumor burden following ARAT using a Naïve Bayes classifier. Model evaluation, using an independent cohort, yielded favorable performance with area under the curve (AUC) mean, 0.707; HTB, 0.627; MTB, 0.750; and LTB, 0.745. The most important features for prediction were identified. Conclusion: Our study revealed that MDSC subsets present in blood were associated with treatment responses to ARAT. Citation Format: Marco A. De Velasco, Yurie Kura, Kazuko Sakai, Yoshitaka Saito, Takafumi Minami, Kazuhiro Yoshimura, Kazutoshi Fujita, Kazuto Nishio, Hirotsugu Uemura. Profiling peripheral blood to predict response to targeted androgen receptor axis therapy in mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 104.

Association between patient ethnicity and prostate cancer diagnosis following a prostate-specific antigen test: a cohort study of 730,000 men in primary care in the UK

BackgroundBlack men have higher prostate-specific antigen (PSA) levels and higher prostate cancer incidence and mortality than White men, while Asian men tend to have lower prostate cancer incidence and mortality than White men. Much of the evidence comes from the USA, and information from UK populations is limited.MethodsThis retrospective cohort study used data on patients registered at general practices in England contributing to the Clinical Practice Research Datalink (CPRD) Aurum dataset. Those eligible were men aged 40 and over with a record of ethnicity and a PSA test result recorded between 2010 and 2017 with no prior cancer diagnosis.The aim was to assess the incidence of prostate cancer following a raised PSA test result in men from different ethnic groups. Additionally, incidence of advanced prostate cancer was investigated. Cancer incidence was estimated from multi-level logistic regression models adjusting for potential confounding factors.Results730,515 men with a PSA test were included (88.9% White). Black men and men with mixed ethnicity had higher PSA values, particularly for those aged above 60 years. In the year following a raised PSA result (using age-specific thresholds), Black men had the highest prostate cancer incidence at 24.7% (95% CI 23.3%, 26.2%); Asian men had the lowest at 13.4% (12.2%, 14.7%); incidence for White men was 19.8% (19.4%, 20.2%). The peak incidence of prostate cancer for all groups was in men aged 70–79. Incidence of prostate cancer diagnosed at an advanced stage was similar between Black and White men.ConclusionsMore prostate cancer was diagnosed in Black men with a raised PSA result, but rates of advanced prostate cancer were not higher in this group. In this large primary care-based cohort, the incidence of prostate cancer in men with elevated PSA levels increases with increasing age, even when using age-adjusted thresholds, with Black men significantly more likely to be diagnosed compared to White or Asian men. The incidence of advanced stage prostate cancer at diagnosis was similar for Black and White men with a raised PSA result, but lower for Asian men.

A prospective study of birth weight and prostate cancer risk and mortality in the Health Professionals Follow-up Study.

Previous studies have observed inconsistent associations between birth weight and aggressive prostate cancer risk. This study aimed to prospectively analyse this association in the Health Professionals Follow-up Study (HPFS). Birth weight was self-reported in 1994, and prostate cancer diagnoses were assessed biennially through January 2017 and confirmed by medical record review. Multivariable Cox proportional hazards regression was used to evaluate the association between birth weight and prostate cancer risk and mortality. Among 19,889 eligible men, 2520 were diagnosed with prostate cancer, including 643 with higher-grade/advanced stage, 296 with lethal, and 248 with fatal disease. Overall, no association was observed for increasing birth weight with risk of overall prostate cancer, lower-grade, and organ-confined disease. However, a borderline statistically significant positive trend was observed for increasing birth weight with risk of higher-grade and/or advanced-stage prostate cancer (adjusted hazard ratio [HRadj] per pound: 1.05; 95% confidence interval [CI]: 0.99-1.11; P-trend = 0.08), but no associations were observed with risk of lethal or fatal disease (HRadj: 0.99, 95% CI: 0.91-1.08; P-trend = 0.83; and HRadj: 0.99, 95% CI: 0.90-1.08; P-trend = 0.82, respectively). No consistent associations were observed between birth weight and prostate cancer risk or mortality in this 22-year prospective cohort study.

Analisis Dinamik Model Sel Kanker Prostat dengan Terapi Vaksin Kuratif

Prostate cancer is a type of cancer that occurs in men and requires an effective therapeutic approach. Treatment of prostate cancer depends on the stage at diagnosis. In advanced stages of prostate cancer can be treated with hormone therapy such as chemotherapy which is then followed by vaccine therapy which aims to help increase the body's immune system response to prostate cancer cells. This model consists of a system of ordinary differential equations with five variables used, including androgen-dependent prostate cancer cells, androgen-independent prostate cancer cells, dendritic cells, effector cells, and curative vaccines. Then two equilibrium point conditions are produced, when there is no vaccine for disease free conditions and endemic conditions , then when the vaccine there are three equilibrium conditions namely disease free , side effects and local existence between prostate cancer cells with vaccine . The results of the stability analysis for each equilibrium point show that when , the condition is global asymptotic, while the condition is stable because the eigenvalue is negative. When for the condition it is unstable because the two roots are positive, then for the condition it is global asymptotic and for the condition it is asymptotically local because all the eigenvalues are negative. The numerical simulations of equilibrium points obtained using the fourth order runge-kutta method according to different q parameter values show that the larger the dendritic cells and effector cells activated, the greater the vaccine that enters the body, resulting in immune cells that will fight prostate cancer cells.

Understanding the molecular regulators of neuroendocrine prostate cancer.

Worldwide, prostate cancer (PCa) remains a leading cause of death in men. Histologically, the majority of PCa cases are classified as adenocarcinomas, which are mainly composed of androgen receptor-positive luminal cells. PCa is initially driven by the androgen receptor axis, where androgen-mediated activation of the receptor is one of the primary culprits for disease progression. Therefore, in advanced stage PCa, patients are generally treated with androgen deprivation therapies alone or in combination with androgen receptor pathway inhibitors. However, after an initial decrease, the cancer recurs for majority patients. At this stage, cancer is known as castration-resistant prostate cancer (CRPC). Majority of CRPC tumors still depend on androgen receptor axis for its progression to metastasis. However, in around 20-30% of cases, CRPC progresses via an androgen receptor-independent pathway and is often presented as neuroendocrine cancer (NE). This NE phenotype is highly aggressive with poor overall survival as compared to CRPC adenocarcinoma. NE cancers are resistant to standard taxane chemotherapies, which are often used to treat metastatic disease. Pathologically and morphologically, NE cancers are highly diverse and often co-exist with adenocarcinoma. Due to the lack of proper biomarkers, it is often difficult to make an early diagnosis of this lethal disease. Moreover, increased tumor heterogeneity and admixtures of adeno and NE subtypes in the same tumor make early detection of NE tumors very difficult. With the advancement of our knowledge and sequencing technology, we are now able to better understand the molecular mediators of this transformation pathway. This current study will give an update on how various molecular regulators are involved in these lineage transformation processes and what challenges we are still facing to detect and treat this cancer.

The GLP-1 receptor is expressed in vivo by human metastatic prostate cancer.

The glucagon-like peptide-1 (GLP-1) receptor agonist, liraglutide, reduces human prostate cancer incidence, and similar GLP-1 receptor agonists reduce in vitro proliferation and in vivo growth of prostate cancer cell lines. Primary human prostate cancer expresses the GLP-1 receptor (GLP-1R) in vitro. Cancer evolves with stage, and whether advanced-stage human prostate cancer expresses GLP-1R is unknown. We hypothesised and aimed to prove that human metastatic castrate-resistant prostate cancer (mCRPC) expresses the GLP-1R in vivo. We hypothesised that mCRPC would thus be detectable by positron emission tomography/computed tomography (PET/CT) using a radiotracer bound to a GLP-1R ligand, as in exendin PET/CT. Men with mCRPC, with more than one prostate-specific membrane antigen (PSMA)-avid lesion on PET/CT scanning (pathognomic in that setting for prostate cancer lesions), were approached to undergo PET/CT with gallium68-Dota-exendin-4. We documented PET/CT PSMA-avid lesions, which were also PET/CT exendin avid, as evidence of in vivo GLP-1R expression. Out of the 24 men referred, three did not meet the inclusion criteria. Seventeen declined, largely because the study offered them no therapeutic benefit. Among the four men imaged, three had no exendin-avid lesions, while one had six osseous PSMA-avid lesions, three of which were also exendin avid. We demonstrated in vivo GLP-1R expression by human mCPRC, detecting PET/CT lesions avid for both PSMA and exendin, in one of four participants. GLP-1R expression may thus occur even in advanced-stage prostate cancer. Our data contribute to growing evidence supporting the testing of GLP-1 receptor agonists for therapeutic benefit in prostate cancer.

The Theranostic Optimization of PSMA-GCK01 Does Not Compromise the Imaging Characteristics of [99mTc]Tc-PSMA-GCK01 Compared to Dedicated Diagnostic [99mTc]Tc-EDDA/HYNIC-iPSMA in Prostate Cancer

PurposeRadiolabeled PSMA-ligands play a major role in today’s nuclear medicine. Since approval of [177Lu]Lu-PSMA-617 for therapy of metastatic prostate cancer, availability of 177Lu became bottleneck of supply due to the high demand. Recently, a theranostic PSMA-ligand, PSMA-GCK01, was developed which can be labeled either diagnostically with 99mTc or therapeutically with 188Re with both nuclides available from well-known generator systems. This novel tracer might aid to overcome aforementioned supply limitations. In this investigation, the biodistribution and general imaging characteristics of [99mTc]Tc-PSMA-GCK01 were compared with the diagnostic reference compound [99mTc]Tc-EDDA/HYNIC-iPSMA in patients with advanced stage prostate cancer. In addition, the binding of both ligands to PSMA was analyzed at the molecular level using molecular docking.ProceduresTwo cohorts (n = 19 vs. n = 21) of patients with metastatic castration-resistant prostate cancer matched for age, tumor stage, and Gleason score underwent a planar gamma camera imaging with [99mTc]Tc-EDDA/HYNIC-iPSMA or [99mTc]Tc-PSMA-GCK01 prior to PSMA-ligand therapy for PSMA-phenotyping. The imaging data were retrospective analyzed for salivary gland, kidney, liver, soft tissue, and tumor uptake on a semi-automated ROI-analysis using HERMES Medical Solutions AB (HMS, Sweden).ResultsThe data sets were semi-automated quantified on a ROI-based analysis. The tumor-to-background presented equal results of [99mTc]Tc-PSMA-GCK01 compared to [99mTc]Tc-EDDA/HYNIC-iPSMA. The physiological PSMA-positive organs like salivary gland presented also equal uptake in counts/MBq (salivary gland median 9.48 [99mTc]Tc-PSMA-GCK01 vs. median 9.11 [99mTc]Tc-EDDA/HYNIC-iPSMA), while liver-to-kidney ratio presented a slight shift to the liver parenchyma using [99mTc]Tc-PSMA-GCK01 (0.83) compared to [99mTc]Tc-EDDA/HYNIC-iPSMA (0.55) with no statistical significance. This is in agreement with the results from the docking study revealing only a minor difference in the docking scores for both ligands.ConclusionsThe novel theranostic tracer [99mTc]Tc/[188Re]Re-PSMA-GCK01 demonstrates comparable general imaging characteristic with the reference compound [99mTc]Tc-EDDA/HYNIC-iPSMA. These results pave the way for the PSMA-targeting imaging and theranostic agents for a broader, rather low-cost, generator applied radio-ligand therapy utilization.

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

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

Health-Related and Psychosocial Factors Associated with Prostate Cancer Stage at Diagnosis among Males Participating in Alberta's Tomorrow Project.

Prostate cancer (PCa) stage at diagnosis is an important predictor of cancer prognosis. In Canada, over one-quarter of males are diagnosed with advanced-stage PCa. Studies have identified several factors associated with PCa stage at diagnosis; however, evidence from Canada is limited. This study aimed to examine associations between sociodemographic characteristics, health history, health practices, and psychosocial factors and PCa stage at diagnosis among males participating in Alberta's Tomorrow Project (ATP), a prospective cohort in Alberta, Canada. The study included males aged 35-69 years who developed PCa until January 2018. Factors associated with PCa stage at diagnosis were examined using partial proportional odds (PPO) ordinal regression models. A total of 410 males were diagnosed with PCa over the study period. A higher number of lifetime prostate-specific antigen tests were associated with earlier-stage PCa (OR 0.91, p = 0.02, 95% CI 0.83-0.99), while higher abdominal circumference (OR 1.02, p = 0.05, 95% CI 1.00-1.03), lower social support (OR 2.34, p < 0.01, 95% CI 1.31-4.17), and having children (OR 2.67, p < 0.01, 95% CI 1.38-5.16) were associated with later-stage disease. This study identified factors previously found in the literature as well as novel factors associated with PCa stage at diagnosis, which can help inform targets for cancer prevention programs to improve PCa prognosis.

Assessing the Potential of Small Peptides for Altering Expression Levels of the Iron-Regulatory Genes FTH1 and TFRC and Enhancing Androgen Receptor Inhibitor Activity in In Vitro Prostate Cancer Models.

Recent research highlights the key role of iron dyshomeostasis in the pathogenesis of prostate cancer (PCa). PCa cells are heavily dependent on bioavailable iron, which frequently results in the reprogramming of iron uptake and storage pathways. Although advanced-stage PCa is currently incurable, bioactive peptides capable of modulating key iron-regulatory genes may constitute a means of exploiting a metabolic adaptation necessary for tumor growth. Recent annual increases in PCa incidence have been reported, highlighting the urgent need for novel treatments. We examined the ability of LNCaP, PC3, VCaP, and VCaP-EnzR cells to form colonies in the presence of androgen receptor inhibitors (ARI) and a series of iron-gene modulating oligopeptides (FT-001-FT-008). The viability of colonies following treatment was determined with clonogenic assays, and the expression levels of FTH1 (ferritin heavy chain 1) and TFRC (transferrin receptor) were determined with quantitative polymerase chain reaction (PCR). Peptides and ARIs combined significantly reduced PCa cell growth across all phenotypes, of which two peptides were the most effective. Colony growth suppression generally correlated with the magnitude of concurrent increases in FTH1 and decreases in TFRC expression for all cells. The results of this study provide preliminary insight into a novel approach at targeting iron dysmetabolism and sensitizing PCa cells to established cancer treatments.

Targeting MALAT1 Augments Sensitivity to PARP Inhibition by Impairing Homologous Recombination in Prostate Cancer.

PARPi are clinically approved for patients with metastatic CRPC carrying mutations in HR genes, but are ineffective for HR-proficient prostate cancer. Herein, we show that oncogenic lncRNA, MALAT1 is frequently overexpressed in advanced stage prostate cancer and plays a crucial role in maintaining genomic integrity. Importantly, we propose a novel therapeutic strategy that emphasizes MALAT1 inhibition, leading to HR dysfunction in both HR-deficient and -proficient prostate cancer, consequently augmenting their susceptibility to PARPi.

Targeting Prostate Cancer Using Bispecific T-Cell Engagers against Prostate-Specific Membrane Antigen.

Prostate cancer (PCa) tops the list of cancer-related deaths in men worldwide. Prostate-specific membrane antigen (PSMA) is currently the most prominent PCa biomarker, as its expression levels are robustly enhanced in advanced stages of PCa. As such, PSMA targeting is highly efficient in PCa imaging as well as therapy. For the latter, PSMA-positive tumors can be targeted directly by using small molecules or macromolecules with cytotoxic payloads or indirectly by engaging the immune system of the host. Here we describe the engineering, expression, purification, and biological characterization of bispecific T-cell engagers (BiTEs) that enable targeting PSMA-positive tumor cells by host T lymphocytes. To this end, we designed the 5D3-αCD3 BiTE as a fusion of single-chain fragments of PSMA-specific 5D3 and anti-CD3 antibodies. Detailed characterization of BiTE was performed by a combination of size-exclusion chromatography, differential scanning fluorimetry, and flow cytometry. Expressed in insect cells, BiTE was purified in monodisperse form and retained thermal stability of both functional parts and nanomolar affinity to respective antigens. 5D3-αCD3's efficiency and specificity were further evaluated in vitro using PCa-derived cell lines together with peripheral blood mononuclear cells isolated from human blood. Our data revealed that T-cells engaged via 5D3-αCD3 can efficiently eliminate tumor cells already at an 8 pM BiTE concentration in a highly specific manner. Overall, the data presented here demonstrate that the 5D3-αCD3 BiTE is a candidate molecule of high potential for further development of immunotherapeutic modalities for PCa treatment.

A biochemistry‐oriented drug design: synthesis, anticancer activity, enzymes inhibition, molecular docking studies of novel 1,2,4-triazole derivatives

In this study, we researched the reactions of 5-(5-bromofuran-2-yl)-4-methyl-1,2,4-triazole-3-thiol and 5-thiophene-(3-ylmethyl)-4R-1,2,4-triazole-3-thiols with some halogen-containing compounds, a number of new compounds were synthesized (1.1–1.5 and 2.1–2.8). These compounds showed excellent to good inhibitory activities on acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes. For obtaining the effects of these compounds on AChE and BChE enzymes were determined spectrophotometrically according to Ellman. IC50 values of these enzymes were ranging between 1.63 and 17.68 nM for AChE and 8.71 and 84.02 nM for BChE. After, prostate cancer is the second leading cause of cancer-related mortality for men over the age of 65 in developed countries. Current treatment options remain limited in the treatment of advanced-stage prostate cancer leading to biochemical recurrence in almost 40% of the patients. Therefore, there is an urgent need for development of novel therapeutic tools for treatment of prostate cancer patients. In this study, we aimed at analyzing the potential of all compounds against prostate cancer cells. We found that, of the tested compounds, 2.1, 2.2 and 2.3 showed significant cytotoxic activities against PC3 prostate cancer cells, although their effect on the viability of normal prostate cells was limited. These findings suggest their selective targeting potential for prostate cancer cells and offer them as candidate therapeutic agents against prostate cancer. The inhibitory activities of some chemical compounds, such as (1.1–1.5 and 2.1–2.8) were assessed by performing the molecular docking study in the presence of AChE, BChE and prostate cancer protein. MM/GBSA methods are calculated binding free energy. Finally, ADME/T analysis was performed to examine the drug properties of the 13 studied molecules. Communicated by Ramaswamy H. Sarma

Clinical Experience with [225Ac]Ac-PSMA Treatment in Patients with [177Lu]Lu-PSMA-Refractory Metastatic Castration-Resistant Prostate Cancer.

For patients with advanced-stage metastatic castration-resistant prostate cancer (mCRPC) who do not respond to [177Lu]Lu-PSMA therapy, there are limited treatment options. Clinical results obtained with [225Ac]Ac-PSMA are promising. We retrospectively analyzed the outcomes of patients treated with [225Ac]Ac-PSMA between December 2018 and October 2022. Methods: We evaluated the treatment results of 23 patients (mean age, 70.3 ± 8.8 y) with mCRPC who were refractory to treatment with [177Lu]Lu-PSMA (2-9 cycles). The safety profile was assessed according to Common Technology Criteria for Adverse Events version 5.0. Treatment efficacy was assessed using prostate-specific membrane antigen PET progression criteria and prostate-specific antigen (PSA) response according to Prostate Cancer Working Group 2 criteria after the first cycle of [225Ac]Ac-PSMA treatment. Results: All patients received androgen-deprivation therapy, whereas 22 (96%) and 19 (83%) patients received chemotherapy and second-generation antiandrogen therapy, respectively. One patient received 4 cycles, 2 received 3 cycles, 8 received 2 cycles, and 12 received 1 cycle of [225Ac]Ac-PSMA. The median interval between cycles was 13 wk (range, 8-28 wk). [225Ac]Ac-PSMA was administered with a mean activity of 7.6 MBq (range, 6.2-10.0 MBq) in each cycle. Patients were at an advanced stage of disease, and tumor burden was very high. Although the best PSA response was observed in 5 patients (26%) after [225Ac]Ac-PSMA treatment, there was at least some level of decline in PSA observed in 11 patients (58%; n = 19). Treatment response was assessed in patients who underwent [68Ga]Ga-PSMA PET/CT imaging. After the first cycle of treatment (n = 18), 50% of patients (n = 9) showed disease progression according to prostate-specific membrane antigen PET progression criteria, and the disease control rate was calculated to be 50%. Median progression-free survival was 3.1 mo, and median overall survival was 7.7 mo. Grade 3 hematologic toxicity occurred in 1 patient, and grade 3 nephrotoxicity was observed in another patient. Parotid SUVmax decreased by 33%, although all patients complained of dry mouth before treatment. Conclusion: We observed that [225Ac]Ac-PSMA therapy was safe and showed potential even in cases with advanced-stage mCRPC in which all other treatment options were completed.