Response In Prostate Cancer Patients Research Articles

Exosomal miR-664a-5p as a therapeutic target biomarker for PARP inhibitor response in prostate cancer.

This study investigated the role of urinary exosomal miR-664a-5p as a potential therapeutic target in prostate cancer (PCa). Small RNA sequencing of urinary exosomes from PCa patients with different responses to PARP inhibitors revealed that miR-664a-5p was significantly upregulated in responsive patients. Overexpression of miR-664a-5p enhanced the sensitivity of PCa cells to PARP inhibitors by directly targeting FOXM1, a transcription factor involved in DNA damage repair, leading to the downregulation of DNA damage response genes. Combined treatment with miR-664a-5p and olaparib synergistically inhibited tumor growth in a PC-3 xenograft mouse model. These findings suggest that urinary exosomal miR-664a-5p is a potential therapeutic biomarker for PARP inhibitor response in PCa patients, and targeting FOXM1 via miR-664a-5p represents a promising strategy for enhancing PARP inhibitor efficacy in PCa treatment.

Prostate Cancer Organoids for Tumor Modeling and Drug Screening.

Prostate cancer (PCa) is the second most common malignancy and the fifth leading cause of cancer death in men worldwide. Despite its prevalence, the highly heterogenic PCa has shown difficulty to establish representative cell lines that reflect the diverse phenotypes and different stages of the disease in vitro and hence hard to model in preclinical research. The patient-derived organoid (PDO) technique has emerged as a groundbreaking three-dimensional (3D) tumor modeling platform in cancer research. This versatile assay relies on the unique ability of cancer stem cells (CSCs) to self-organize and differentiate into organ-like mini structures. The PDO culture system allows for the long-term maintenance of cancer cells derived from patient tumor tissues. Moreover, it recapitulates the parental tumor features and serves as a superior preclinical model for in vitro tumor representation and personalized drug screening. Henceforth, PDOs hold great promise in precision medicine for cancer. Herein, we describe the detailed protocol to establish and propagate organoids derived from isolated cell suspensions of PCa patient tissues or cell lines using the 3D semisolid Matrigel™-based hanging-drop method. In addition, we highlight the relevance of PDOs as a tool for evaluating drug efficacy and predicting tumor response in PCa patients.

MT1G, an emerging ferroptosis-related gene: A novel prognostic biomarker and indicator of immunotherapy sensitivity in prostate cancer.

Prostate cancer is a leading cause of cancer-related deaths in men worldwide. Despite advances in treatment strategies, there is still a need for novel therapeutic targets and approaches. Ferroptosis has emerged as a critical process in the development and progression of several cancers, including prostate cancer (PCA). In this study, we investigate the role of MT1G, a gene implicated in immune responses and ferroptosis, in the pathogenesis of PCA. Our objective is to elucidate its prognostic significance and its impact on the tumor microenvironment, while exploring its potential in enhancing the sensitivity to immune checkpoint inhibitor (ICI) therapy. We utilized a combination of in silico analysis and experimental techniques to investigate the role of MT1G in PCA. First, we analyzed large-scale genomic datasets to assess the expression pattern and prognostic significance of MT1G in PCA patients. Subsequently, we performed functional assays to explore the impact of MT1G in PCA and its potential involvement in modulating immune responses. In addition, we conducted in vivo experiments to evaluate the effect of MT1G on tumor growth and response to ICI therapy. Our analysis revealed that MT1G expression is significantly downregulated in PCA tissues compared to normal prostate tissues and is associated with poor prognosis. Furthermore, MT1G overexpression inhibited the growth of PCA cells in vitro and in vivo. Importantly, we found that MT1G regulates the tumor microenvironment by modulating immune cell infiltration and inhibiting immunosuppressive factors. Furthermore, our study reveals a significant correlation between MT1G expression levels and the response to immune checkpoint inhibitor (ICI) therapy in prostate cancer (PCA) patients, as MT1G upregulation leads to an increase in PDL-1 expression. These findings underscore the potential of MT1G as a promising predictive biomarker for ICI therapy response in PCA patients. Our study elucidates the pivotal role played by MT1G in the pathogenesis of prostate cancer (PCA) and its profound implications for prognosis. Moreover, it raises the intriguing possibility that MT1G could pave the way for novel therapeutic approaches in PCA treatment. This potential arises from its ability to orchestrate immune infiltration within the tumor microenvironment, consequently enhancing sensitivity to immune checkpoint inhibitor (ICI) therapy. Therefore, our findings hold substantial promise for advancing our comprehension of PCA and exploring innovative therapeutic strategies.

Integrating single-cell and bulk RNA sequencing to predict prognosis and immunotherapy response in prostate cancer

Prostate cancer (PCa) stands as a prominent contributor to morbidity and mortality among males on a global scale. Cancer-associated fibroblasts (CAFs) are considered to be closely connected to tumour growth, invasion, and metastasis. We explored the role and characteristics of CAFs in PCa through bioinformatics analysis and built a CAFs-based risk model to predict prognostic treatment and treatment response in PCa patients. First, we downloaded the scRNA-seq data for PCa from the GEO. We extracted bulk RNA-seq data for PCa from the TCGA and GEO and adopted “ComBat” to remove batch effects. Then, we created a Seurat object for the scRNA-seq data using the package “Seurat” in R and identified CAF clusters based on the CAF-related genes (CAFRGs). Based on CAFRGs, a prognostic model was constructed by univariate Cox, LASSO, and multivariate Cox analyses. And the model was validated internally and externally by Kaplan–Meier analysis, respectively. We further performed GO and KEGG analyses of DEGs between risk groups. Besides, we investigated differences in somatic mutations between different risk groups. We explored differences in the immune microenvironment landscape and ICG expression levels in the different groups. Finally, we predicted the response to immunotherapy and the sensitivity of antitumour drugs between the different groups. We screened 4 CAF clusters and identified 463 CAFRGs in PCa scRNA-seq. We constructed a model containing 10 prognostic CAFRGs by univariate Cox, LASSO, and multivariate Cox analysis. Somatic mutation analysis revealed that TTN and TP53 were significantly more mutated in the high-risk group. Finally, we screened 31 chemotherapeutic drugs and targeted therapeutic drugs for PCa. In conclusion, we identified four clusters based on CAFs and constructed a new CAFs-based prognostic signature that could predict PCa patient prognosis and response to immunotherapy and might suggest meaningful clinical options for the treatment of PCa.

Identification and validation of cancer-associated fibroblast-related subtypes and the prognosis model of biochemical recurrence in prostate cancer based on single-cell and bulk RNA sequencing.

Cancer-associated fibroblasts (CAFs) are an essential component of the tumor immune microenvironment that are involved in extracellular matrix (ECM) remodeling. We aim to investigate the characteristics of CAFs in prostate cancer and develop a biochemical recurrence (BCR)-related CAF signature for predicting the prognosis of PCa patients. The bulk RNA-seq and relevant clinical information were obtained from the TCGA and GEO databases, respectively. The infiltration scores of CAFs in prostate cancer patients were calculated using the MCP counter and EPIC algorithms. The single-cell RNA sequencing (scRNA-seq) was downloaded from the GEO database. Subsequently, univariate Cox regression analysis was employed to identify prognostic genes associated with CAFs. We identified two subtypes (C1 and C2) of prostate cancer that were associated with CAFs via non-negative matrix factorization (NMF) clustering. In addition, the BCR-related CAF signatures were constructed using Lasso regression analysis. Finally, a nomogram model was established based on the risk score and clinical characteristics of the patients. Initially, we found that patients with high CAF infiltration scores had shorter biochemical recurrence-free survival (BCRFS) times. Subsequently, CAFs in four pairs of tumors and paracancerous tissues were identified. We discovered 253 significantly differentially expressed genes, of which 13 had prognostic significance. Using NMF clustering, we divided PCa patients into C1 and C2 subgroups, with the C1 subgroup having a worse prognosis and substantially enriched cell cycle, homologous recombination, and mismatch repair pathways. Furthermore, a BCR-related CAFs signature was established. Multivariate COX regression analysis confirmed that the BCR-related CAFs signature was an independent prognostic factor for BCR in PCa. In addition, the nomogram was based on the clinical characteristics and risk scores of the patient and demonstrated high accuracy and reliability for predicting BCR. Lastly, our findings indicate that the risk score may be a useful tool for predicting PCa patients' sensitivity to immunotherapy and drug treatment. NMF clustering based on CAF-related genes revealed distinct TME immune characteristics between groups. The BCR-related CAF signature accurately predicted prognosis and immunotherapy response in prostate cancer patients, offering a promising new approach to cancer treatment.

HB-300, a novel arenavirus-based cancer immunotherapy in patients with metastatic castration-resistant prostate cancer.

TPS5108 Background: Prostate cancer is the most frequent type of malignant neoplasia in men. Immunotherapy targeting self-antigens in prostate cancer is evolving and requires overcoming multiple mechanisms that mediate immune tolerance. Sipuleucel-T, a cell-based therapy recognizing prostatic acid phosphatase (PAP) protein, is approved for treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) and induced PAP-specific T cell responses correlating with overall survival (OS). Poxvirus vectors encoding prostate-specific antigen (PSA) increased PSA-specific T cell levels and were associated with OS benefit, although not confirmed in a Phase 3 study. Arenaviral vectors used in preclinical tumor models could overcome self-tolerance by inducing strong self-antigen specific CD8 T cell responses. In humans, arenaviral vectors encoding HPV16 E7E6 fusion protein (HB-200) induced unprecedented E6E7-specific CD8 T cell levels in patients with recurrent/metastatic HPV16+ cancers. Preliminary clinical activity and favorable safety and tolerability were observed in these heavily pre-treated, checkpoint inhibitor-resistant patients (ref: Fu et al. ASCO 2022; NCT04180215). It is therefore hypothesized that HB-300, a live-attenuated arenaviral vector therapy encoding the self-antigens PAP and PSA, will induce substantially stronger T cell responses in prostate cancer patients than previously tested active immunization approaches. Methods: This is a Phase 1/2 open-label clinical study of HB-300 in ~ 70 patients with advanced mCRPC. A 3+3 Dose Escalation will be followed by a dose-expansion to confirm the recommended Phase 2 dose (RP2D). HB-300 consists of HB-302 (Pichinde virus based) alternating with HB-301 (LCMV based) vectors, administered IV every 3 weeks (Q3W) for 5 doses then Q6W. The program’s entry into the clinic with a mini dose-escalation was supported by the submission of a data master file along with the HB-300 Investigational New Drug application, based on arenavirus vector platform data collected in the HB-200 program. Trial inclusion criteria include male participants age ≥ 18; documented mCRPC (adenocarcinoma without neuroendocrine or small cell features); receipt of at least 1 androgen deprivation therapy and no prior chemotherapy regimens (docetaxel in the castration-sensitive setting is allowed); ≥1 measurable lesion; ECOG PS 0-1. Exclusions are uncontrolled pain or symptoms; active auto-immune disease; immunosuppression; active central nervous system or liver metastasis; and active infection. Phase 1 primary objectives include safety/tolerability and determination of RP2D, secondary objectives include preliminary efficacy, and exploratory assessments include antigen-specific T cell response and circulating tumor cell analysis. Clinical trial# NCT05553639. Clinical trial information: NCT05553639 .

Cuproptosis Regulates Microenvironment and Affects Prognosis in Prostate Cancer.

Current immunotherapy for prostate cancer is still in the stage of clinical trials. This delay is thought to be caused by an unclear regulatory mechanism of the immune microenvironment, which makes it impossible to distinguish patients suitable for immunotherapy. Cuprotosis may be related to the heterogeneity of immune microenvironment, which was regarded as a new copper-dependent cell death mode, was proposed, and gain attention. We explored for the first time the relationship between cuprotosis and the immune microenvironment of prostate cancer and constructed cuprotosis score. RNA sequencing data sets for prostate cancer were downloaded from public databases. Consensus clustering was applied to distinguish cuprotosis phenotype based on the expression of cuproptosis-related genes (CRGs) identified as prognostic factors. Genomic phenotypes of CRG clusters were depicted via consensus clustering. Cuprotosis score was established on the basis of differentially expressed genes (DEGs) identified as prognostic factors via principal component analysis. Cuprotosis score = the first principal component of prognostic factors + the second principal component of prognostic factors. The value of cuproptosis score in predicting prognosis and immunotherapy response was evaluated. PDHA1 (HR = 3.86, P < 0.001) and GLS (HR = 1.75, P = 0.018) were risk factors for prognosis of prostate cancer patients, while DBT (HR = 0.66, P = 0.048) was a favorable factor for prognosis of prostate cancer patients. CRG clusters had different prognosis and immune cell infiltration. So as gene clusters. Prostate cancer patients with low cuprotosis score showed better prognosis for biochemical relapse-free survival. Cuprotosis score is accompanied with high immune score and Gleason score. As cuprotosis genes, PDHA1, GLS, and DBT were identified as independent prognostic factors of prostate cancer. Cuprotosis score was established via principal component analysis of PDHA1, GLS, and DBT, which can be used as a predictor of prognosis and immunotherapy response of prostate cancer patients, and can characterize immune cells infiltration in tumors. Cuproptosis was involved in the regulation of immune microenvironment, which may depend on the effect of tricarboxylic acid cycle. Our study provided clues to reveal the relationship between copper death and immune microenvironment, highlighted the clinical significance of cuproptosis, and provided a reference for the development of personalized immunotherapy.

MP73-16 SUV VARIATION ON PSMA PET/CT CORRELATES WITH BIOCHEMICAL RESPONSE IN PATIENTS WITH PROSTATE CANCER UNDERGOING HIGH-INTENSITY FOCUSED ULTRASOUND (HIFU) FOCAL THERAPY

You have accessJournal of UrologyCME1 Apr 2023MP73-16 SUV VARIATION ON PSMA PET/CT CORRELATES WITH BIOCHEMICAL RESPONSE IN PATIENTS WITH PROSTATE CANCER UNDERGOING HIGH-INTENSITY FOCUSED ULTRASOUND (HIFU) FOCAL THERAPY Egesta Lopci, Giovanni Lughezzani, Vittorio Fasulo, Davide Maffei, Emmanuella Nana Yaa Dede Adjaye, Alberto Saita, Piergiuseppe Colombo, Rodolfo Hurle, Marzo Katia, Roberto Peschechera, Alessio Benetti, Silvia Zandegiacono, Luisa Pasini, Paolo Casale, Luca Balzarini, Arturo Chiti, Giorgio Guazzoni, Nicolò Maria Buffi, and Massimo Lazzeri Egesta LopciEgesta Lopci More articles by this author , Giovanni LughezzaniGiovanni Lughezzani More articles by this author , Vittorio FasuloVittorio Fasulo More articles by this author , Davide MaffeiDavide Maffei More articles by this author , Emmanuella Nana Yaa Dede AdjayeEmmanuella Nana Yaa Dede Adjaye More articles by this author , Alberto SaitaAlberto Saita More articles by this author , Piergiuseppe ColomboPiergiuseppe Colombo More articles by this author , Rodolfo HurleRodolfo Hurle More articles by this author , Marzo KatiaMarzo Katia More articles by this author , Roberto PeschecheraRoberto Peschechera More articles by this author , Alessio BenettiAlessio Benetti More articles by this author , Silvia ZandegiaconoSilvia Zandegiacono More articles by this author , Luisa PasiniLuisa Pasini More articles by this author , Paolo CasalePaolo Casale More articles by this author , Luca BalzariniLuca Balzarini More articles by this author , Arturo ChitiArturo Chiti More articles by this author , Giorgio GuazzoniGiorgio Guazzoni More articles by this author , Nicolò Maria BuffiNicolò Maria Buffi More articles by this author , and Massimo LazzeriMassimo Lazzeri More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003341.16AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Focal therapy (FT) for localized prostate cancer (PCa) offers minimally invasive localized ablative treatment while minimizing treatment-related toxicity compared to standard radical options. Recent advances in PCa imaging with PSMA PET/CT offer new opportunities to detect PCa foci and monitor response to treatment. The current study is designed to evaluate the role of PSMA PET/CT for response assessment in PCa patients candidate to High-Intensity Focused Ultrasound (HIFU) focal therapy. METHODS: The present analyses was conducted in patients enrolled in an ongoing, prospective, single-center cohort study of patients treated with HIFU FT for localized PCa. Inclusion criteria: PSA<20 ng/mL, radiological stage≤T2bN0M0, ISUP grade 1-3, PSMA PET/CT at baseline and at response evaluation. Follow up included: PSA at 3, 6 and 12 months; PSMA PET/CT between 6-12 months post treatment. Biochemical response and PET response were statistically correlated: SUVmax and SUVratio to background of the target lesions were used as semi-quantitative parameters for PSMA PET/CT, together with their variations before and after HIFU FT (i.e. ΔSUVmax and ΔSUVratio). RESULTS: Overall, 23 patients met inclusion criteria for the analysis. Median age was 67 years (IQR 63-72), initial PSA (iPSA) was 5.9 ng/mL (IQR 5.2-8.7) and prostate volume was 40 mL (IQR 35.8-50.8). ISUP score was 1 in 16 (70%) patients and 2 in the remaining 7 (30%). Median SUVmax and SUVratio before treatment resulted 3.4 (IQR 2.6-6.3) and 1.4 (IQR 1.1-1.8), respectively. At 3 months post-HIFU, 35% of the patients obtained a PSA response≥50%; whereas at 6 months and 12 months, PSA responses were 35% and 36%, respectively. Median SUVmax and SUVratio post-treatment resulted 2.5 (IQR 1.7-3.4) and 0.9 (IQR 0.7-1.0), respectively, proving a statistically significant reduction compared to baseline values (p=0.048 and 0.0051, respectively). Median ΔSUVmax -22% and ΔSUVratio resulted-30%. There was a statistically significant correlation of ΔSUVmax and PSA response at 12 months post-HIFU (p=0.021) (Figure). CONCLUSIONS: PSMA-PET may be a useful tool for monitoring response in PCa patients undergoing HIFU FT. Moreover, the SUV variation can predict biochemical response at 12 months post-treatment completion. Source of Funding: None © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e1041 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Egesta Lopci More articles by this author Giovanni Lughezzani More articles by this author Vittorio Fasulo More articles by this author Davide Maffei More articles by this author Emmanuella Nana Yaa Dede Adjaye More articles by this author Alberto Saita More articles by this author Piergiuseppe Colombo More articles by this author Rodolfo Hurle More articles by this author Marzo Katia More articles by this author Roberto Peschechera More articles by this author Alessio Benetti More articles by this author Silvia Zandegiacono More articles by this author Luisa Pasini More articles by this author Paolo Casale More articles by this author Luca Balzarini More articles by this author Arturo Chiti More articles by this author Giorgio Guazzoni More articles by this author Nicolò Maria Buffi More articles by this author Massimo Lazzeri More articles by this author Expand All Advertisement PDF downloadLoading ...

Frequencies of an Immunogenic HER-2/neu Epitope of CD8+ T Lymphocytes Predict Favorable Clinical Outcomes in Prostate Cancer

HER-2/neu is the human epidermal growth factor receptor 2, which is associated with the progression of prostate cancer (PCa). HER-2/neu-specific T cell immunity has been shown to predict immunologic and clinical responses in PCa patients treated with HER-2/neu peptide vaccines. However, its prognostic role in PCa patients receiving conventional treatment is unknown, and this was addressed in this study. The densities of CD8+ T cells specific for the HER-2/neu(780-788) peptide in the peripheral blood of PCa patients under standard treatments were correlated with TGF-β/IL-8 levels and clinical outcomes. We demonstrated that PCa patients with high frequencies of HER-2/neu(780-788)-specific CD8+ T lymphocytes had better progression-free survival (PFS) as compared with PCa patients with low frequencies. Increased frequencies of HER-2/neu(780-788)-specific CD8+ T lymphocytes were also associated with lower levels of TGF-β and IL-8. Our data provide the first evidence of the predictive role of HER-2/neu-specific T cell immunity in PCa.

EZH2 as a Prognostic Factor and Its Immune Implication with Molecular Characterization in Prostate Cancer: An Integrated Multi-Omics in Silico Analysis.

Prostate cancer (PCa) is a type of potentially fatal malignant tumor. Immunotherapy has shown a lot of potential for various types of solid tumors, but the benefits have been less impressive in PCa. Enhancer of zeste homolog 2 (EZH2) is one of the three core subunits of the polycomb repressive complex 2 that has histone methyltransferase activity, and the immune effects of EZH2 in PCa are still unclear. The purpose of this study was to explore the potential of EZH2 as a prognostic factor and an immune therapeutic biomarker for PCa, as well as the expression pattern and biological functions. All analyses in this study were based on publicly available databases, mainly containing Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), UCSCXenaShiny, and TISIDB. We performed differential expression analysis, developed a prognostic model, and explored potential associations between EZH2 and DNA methylation modifications, tumor microenvironment (TME), immune-related genes, tumor mutation burden (TMB), tumor neoantigen burden (TNB), and representative mismatch repair (MMR) genes. We also investigated the molecular and immunological characterizations of EZH2. Finally, we predicted immunotherapeutic responses based on EZH2 expression levels. We found that EZH2 was highly expressed in PCa, was associated with a poor prognosis, and may serve as an independent prognostic factor. EZH2 expression in PCa was associated with DNA methylation modifications, TME, immune-related genes, TMB, TNB, and MMR. By gene set enrichment analysis and gene set variation analysis, we found that multiple functions and pathways related to tumorigenesis, progression, and immune activation were enriched. Finally, we inferred that immunotherapy may be more effective for PCa patients with low EZH2 expression. In conclusion, our study showed that EZH2 could be a potentially efficient predictor of prognosis and immune response in PCa patients.

A novel signature based on pyroptosis-related genes for predicting prognosis and treatment response in prostate cancer patients.

Background: Pyroptosis is a form of programmed cell death accompanied by specific inflammatory and immune responses, and it is closely related to the occurrence and progression of various cancers. However, the roles of pyroptosis-related genes (PRGs) in the prognosis, treatment response, and tumor microenvironment (TME) of prostate cancer (PCa) remain to be investigated. Methods: The mRNA expression data and clinical information of PCa patients were obtained from the Cancer Genome Atlas database (TCGA) and the cBioPortal for Cancer Genomics website, and the 52 PRGs were obtained from the published papers. The univariate, multivariate, and LASSO Cox regression algorithms were used to obtain prognostic hub PRGs. Meanwhile, qRT-PCR was used to validate the expression of hub genes between PCa lines and normal prostate epithelial cell lines. We then constructed and validated a risk model associated with the patient's disease-free survival (DFS). Finally, the relationships between risk score and clinicopathological characteristics, tumor immune microenvironment, and drug treatment response of PCa were systematically analyzed. Results: A prognostic risk model was constructed with 6 hub PRGs (CHMP4C, GSDMB, NOD2, PLCG1, CYCS, GPX4), and patients were divided into high and low-risk groups by median risk score. The risk score was confirmed to be an independent prognostic factor for PCa in both the training and external validation sets. Patients in the high-risk group had a worse prognosis than those in the low-risk group, and they had more increased somatic mutations, higher immune cell infiltration and higher expression of immune checkpoint-related genes. Moreover, they were more sensitive to cell cycle-related chemotherapeutic drugs and might be more responsive to immunotherapy. Conclusion: In our study, pyroptosis played a significant role in the management of the prognosis and tumor microenvironment of PCa. Meanwhile, the established model might help to develop more effective individual treatment strategies.

Pro-Survival Factor EDEM3 Confers Therapy Resistance in Prostate Cancer.

Prostate cancer is the most common cancer in men, and it is primarily driven by androgen steroid hormones. The glycosylation enzyme EDEM3 is controlled by androgen signalling and is important for prostate cancer viability. EDEM3 is a mannosidase that trims mannose from mis-folded glycoproteins, tagging them for degradation through endoplasmic reticulum-associated degradation. Here, we find that EDEM3 is upregulated in prostate cancer, and this is linked to poorer disease-free survival. Depletion of EDEM3 from prostate cancer cells induces an ER stress transcriptomic signature, and EDEM3 overexpression is cyto-protective against ER stressors. EDEM3 expression also positively correlates with genes involved in the unfolded protein response in prostate cancer patients, and its expression can be induced through exposure to radiation. Importantly, the overexpression of EDEM3 promotes radio-resistance in prostate cancer cells and radio-resistance can be reduced through depletion of EDEM3. Our data thus implicate increased levels of EDEM3 with a role in prostate cancer pathology and reveal a new therapeutic opportunity to sensitise prostate tumours to radiotherapy.

Abstract 1289: Systemic immune response of prostate cancer patients to alpha-emitting radiotherapy

Abstract Targeted alpha therapy (TAT) is a type of radiotherapy (RT) that uses alpha-emitting radionuclides. These radionuclides have a natural affinity for areas of bone metastases (i.e., radium-223, Ra-223) or can label specific tumour targets (i.e., prostate-specific membrane antigen). Conventional photon irradiation (i.e., external beam) can activate or suppress immune responses. The resulting immune response is dictated by the release of soluble markers such as cytokines (i.e., IL-6) and damage associated molecular patterns, DAMPs (calreticulin). Less is known about the immune response induced by alpha-emitters. With increased interest in using TAT for cancer patients, it is important to gain a more in depth knowledge regarding the immune response of alpha emitters. Aim: Explore the systemic immune response of prostate cancer (PCa) patients to alpha-emitting RT by studying circulating cytokines, checkpoint molecules, matrix metalloproteinases (MMPs) and DAMPs. Methods: The cohort comprised of 43 patients with metastatic castration-resistant PCa treated with up to six four-weekly injections of the alpha emitter, Ra-223. We measured longitudinal changes in 61 plasma markers using the Luminex assay. The plasma markers included cytokines, checkpoint molecules and DAMPs. Results: Ra-223 induced longitudinal changes in 14 plasma markers over the course of treatment (T2-T6) compared with pre-treatment levels (T1). Most of the observed RT-induced changes occurred after four injections of Ra-223 (T5), where 9 of the 14 plasma markers changed significantly. The table summarises T5 findings (presented as mean concentration, pg/ml; statistical analysis using Wilcoxon matched-pairs signed rank test). Conclusion: Our data demonstrates that alpha-emitting RT induces systemic immune responses that can be measured in the plasma of patients. Given the diverse role of these markers, further study is needed to explore the biological implications of these systemic changes on patient outcome. Changes in plasma markers in patients treated with Ra-223 T1 T5 P value IL-8 6.7±0.9 9.7±1.3 0.0009 IL-2R 293.5±42.9 364.5±69.7 0.0247 IP-10 18.4±2.3 21.8±2.5 0.0243 RANTES 2668.8±173.4 2944.7±164.6 0.0455 BTLA 549.9±153.5 527.7±265.2 0.0319 CD137 49.6±8.9 39.1±13.5 0.0099 Calreticulin 7868±3514.9 9238.4±808.5 0.0386 RAGE 63.9±4.7 52.3±5.1 0.0014 MMP1 66.1±7.5 84.9±12.6 0.0245 Citation Format: Sapna Lunj, Hitesh Mistry, YeePei Song, Kamlesh Patel, Hannah Nightingale, Tim Smith, Peter Hoskin, Catharine West, Ananya Choudhury. Systemic immune response of prostate cancer patients to alpha-emitting radiotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1289.

Cancers and Benign Processes on 68Ga PSMA PET-CT Imaging Other than Prostate Cancer

Background Imaging plays an important role in the evaluation of prostate cancer patients. In recent years, much attention has been focused on gallium 68 prostate-specific membrane antigen positron emission tomography-computed tomography ( 68 Ga PSMA PET-CT) in prostate cancer patients and has been widely used for staging, restaging, and therapy response for these patients. The aim of this study was to report 68 Ga PSMA PET-CT in other cancers and benign processes incidentally detected on 68 Ga PSMA PET-CT in patients with prostate cancer. Materials and Methods A total of 600 68 Ga PSMA PET-CT scans were performed for initial staging, restaging, detection of suspected recurrence, and therapy response in prostate cancer patients between December 2018 and June 2020. A total of 38 patients with histopathologically proven prostate cancer were included in the current study with other malignancies and benign processes. Mainly histopathology in most of cases and clinical and radiological follow-up in few cases after PET/CT scanning served as the standard of reference. Results A total of 38 patients (age range: 52–85 years; mean age: 68.6) with prostate cancer final histopathology results were included in the study. A total of 51 lesion sites were evaluated in 38 patients. Forty-one lesion regions of these 51 regions were based on histopathological diagnosis, whereas 10 of them were based on clinical follow-up and conventional radiological follow-up as differential criteria. Thirty of 51 lesion regions were evaluated as malignant and 21 were benign lesions. The most common 68 Ga PSMA ligand avid malignancy was lung adenocarcinoma (6/38). Conclusions Prostate-specific membrane antigen (PSMA) is a cell surface glycoprotein and mainly expressed in prostate epithelium. 68 Ga PSMA PET-CT imaging is very sensitive and specific imaging modality in prostate cancer patients. However, other malignancies and some benign processes may also have 68 Ga PSMA ligand avidity and some prostate cancer metastases may imitate other malignancies.

HERV-K and HERV-H Env Proteins Induce a Humoral Response in Prostate Cancer Patients.

A higher expression of human endogenous retroviruses (HERVs) has been associated with several malignancies, including prostate cancer, implying a possible use as a diagnostic or prognostic cancer biomarker. For this reason, we examined the humoral response against different epitopes obtained from the envelope protein of HERV-K (HERV-K env-su19–37, HERV-K env-su109–126), HERV-H (HERV-H env-su229–241, HERV-H env387–399) and HERV-W (HERV-W env-su93–108, HERV-W env-su248–262) in the plasma of patients affected by prostate cancer (PCa), and compared to that of benign prostate hyperplasia (BPH) and a borderline group of patients with atypical small acinar proliferation (ASAP) and prostate intraepithelial neoplasia (PIN) and healthy controls. A significant antibody response was observed against HERV-K env-su109–126 (p = 0.004) and HERV-H env-su229–241 (p < 0.0001) in PCa patients compared to HCs, BPH and borderline cohorts, whilst no significance difference was found in the antibodies against HERV-W env-su93–108 and HERV-W env-su248–262 in patients with PCa. Our results provided further proof of the association between HERV-K and PCa and added new evidence about the possible involvement of HERV-H in PCa pathogenesis, highlighting their possibility of being used as biomarkers of the disease.

The tumor microenvironment and immune responses in prostate cancer patients.

The landscape of cancer treatment has been transformed over the past decade by the success of immune-targeting therapies. However, despite sipuleucel-T being the first-ever approved vaccine for cancer and the first immunotherapy licensed for prostate cancer in 2010, immunotherapy has since seen limited success in the treatment of prostate cancer. The tumour microenvironment of prostate cancer presents particular barriers for immunotherapy. Moreover, prostate cancer is distinguished by being one of only two solid tumours where increased T cell-infiltration correlates with a poorer, rather than improved, outlook. Here, we discuss the specific aspects of the prostate cancer microenvironment that converge to create a challenging microenvironment, including myeloid-derived immune cells and cancer-associated fibroblasts. By exploring the immune microenvironment of defined molecular subgroups of prostate cancer, we propose an immunogenomic subtyping approach to single-agent and combination immune-targeting strategies that could lead to improved outcomes in prostate cancer treatment.

Investigation of Chromosome 1 Aberrations in the Lymphocytes of Prostate Cancer and Benign Prostatic Hyperplasia Patients by Fluorescence in situ Hybridization.

PurposeRadiotherapy is one of the most common treatments for prostate cancer. Finding a useful predictor of the therapeutic outcome is crucial as it increases the efficacy of treatment planning. This study investigated the individual susceptibility to radiation based on chromosome 1 aberration frequency measured by the FISH (fluorescence in situ hybridization) method.Patients and MethodsWhole blood samples were collected from 27 prostate cancer (PCa) patients and 32 subjects with benign prostatic hyperplasia (BPH), who were considered as a control group. Samples were irradiated with 2 Gy of x-rays, cultured, harvested, and used in the FISH procedure.ResultsAfter irradiation, significantly higher levels of all studied chromosome 1 aberrations (except for deletions) in the group of PCa patients were revealed. Furthermore, in the lymphocytes of cancer patients, nearly five-fold higher frequencies of acentric fragments were observed compared to the BPH group. The highest individual radiosensitivities for all estimated biomarkers were seen in PCa patient cells who reported cancer incidence in the immediate family (CIF+).ConclusionThe differences in chromosome 1 aberrations between PCa and BPH demonstrate that lymphocytes taken from patients with prostate cancer have higher radiosensitivity which might be related to hereditary or familiar inclinations. Therefore, this technique may find future application in searching biomarkers of the cellular radiotherapy response in prostate cancer patients.

Blood-Derived Biomarkers of Diagnosis, Prognosis and Therapy Response in Prostate Cancer Patients.

Prostate cancer is among the most frequent cancers in men worldwide. Despite the fact that multiple therapeutic alternatives are available for its treatment, it is often discovered in an advanced stage as a metastatic disease. Prostate cancer screening is based on physical examination of prostate size and prostate-specific antigen (PSA) level in the blood as well as biopsy in suspect cases. However, these markers often fail to correctly identify the presence of cancer, or their positivity might lead to overdiagnosis and consequent overtreatment of an otherwise silent non-progressing disease. Moreover, these markers have very limited if any predictive value regarding therapy response or individual risk for therapy-related toxicities. Therefore, novel, optimally liquid biopsy-based (blood-derived) markers or marker panels are needed, which have better prognostic and predictive value than the ones currently used in the everyday routine. In this review the role of circulating tumour cells, extracellular vesicles and their microRNA content, as well as cellular and soluble immunological and inflammation- related blood markers for prostate cancer diagnosis, prognosis and prediction of therapy response is discussed. A special emphasis is placed on markers predicting response to radiotherapy and radiotherapy-related late side effects.

Contrasting Circulating Tumor Cells and Free Circulating DNA Responses in Men Treated for Prostate Cancer after Primary Versus Salvage Radiotherapy

Purpose: To investigate the relationships between circulating tumor cells (CTCs), free circulating DNA (fcDNA) and biochemical response in prostate cancer patients treated primarily versus salvage radiotherapy (RT). Methods and Materials: Blood was collected prospectively from patients, enrolled in two institutional Phase II trials for primary and salvage RT. Three blood samples were collected at: (i) prior to treatment [RT or androgen deprivation therapy (ADT)], (ii) last week of RT, and (iii) three months post-RT. CTCs were quantified in 31 samples from 12 primary patients and 30 samples from 12 salvage patients; fcDNA were analyzed in 11 primary (28 samples) and 5 (9 samples) salvage patients. CTCs were visualized by immunofluorescence after microfilter capture and fcDNA was quantified using real-time Polymerase chain reaction (PCR). CTCs and fcDNA were correlated with early biochemical response by subdividing patients into early favorable and unfavorable response at 3 months after RT. Results: For those treated primarily, there was a direct correlation with CTC counts and prostate specific antigen (PSA) pre-RT that changed to a reciprocal relationship 3 months post-RT. CTCs increased significantly (p=0.03) at 3 months after primary RT in the biochemical favorable patients, while no significant association was observed for fcDNA. Correspondingly, post-RT fcDNA levels were inversely related to CTC counts. In salvage patients, the number of CTCs was related to pre-RT PSA, but it was not correlated to RT response. In post-RT series, a significant direct correlation was observed between CTCs and PSA. Conclusion: Our preliminary studies suggest that RT affects CTC counts, which are thus associated with prostate cancer biochemical response. A larger cohort with longer follow-up will be needed to establish the association with more recognized treatment endpoints.

Monitoring Radiotherapeutic Response in Prostate Cancer Patients Using High Throughput FTIR Spectroscopy of Liquid Biopsies.

Radiation therapy (RT) is used to treat approximately 50% of all cancer patients. However, RT causes a wide range of adverse late effects that can affect a patient’s quality of life. There are currently no predictive assays in clinical use to identify patients at risk of normal tissue radiation toxicity. This study aimed to investigate the potential of Fourier transform infrared (FTIR) spectroscopy for monitoring radiotherapeutic response. Blood plasma was acquired from 53 prostate cancer patients at five different time points: prior to treatment, after hormone treatment, at the end of radiotherapy, two months post radiotherapy and eight months post radiotherapy. FTIR spectra were recorded from plasma samples at all time points and the data was analysed using MATLAB software. Discrimination was observed between spectra recorded at baseline versus follow up time points, as well as between spectra from patients showing minimal and severe acute and late toxicity using principal component analysis. A partial least squares discriminant analysis model achieved sensitivity and specificity rates ranging from 80% to 99%. This technology may have potential to monitor radiotherapeutic response in prostate cancer patients using non-invasive blood plasma samples and could lead to individualised patient radiotherapy.