Resistant Prostate Cancer Research Articles

The prognostic implications of macrophage polarization in advanced and therapy-resistant prostate cancer

Abstract Tumor-associated macrophages (TAMs) are components of the spatial microenvironment of many solid neoplasms. In prostate cancer (PCa), TAMs are linked to a poor prognosis. PCa is characterized by enhanced tumor lipid production and TAM lipid accumulation. However, the interplay between lipid-producing tumor cells and TAM lipid uptake has yet to be determined. Human prostate tumor tissue microarrays were evaluated for TAM (CD68+) and M2/M1 (CD206+/CD86+) levels correlated with tumor aggressiveness by multiplex immunohistochemistry. Standard PCa cells 22rv1, PC3 and DU145 were used to develop chemoresistant sublines which were validated using dose-response viability assays and immunoblotting for resistance-associated markers and lipid-producing enzymes. Cancer cell-derived extracellular vesicles (EVs) were isolated from cell culture supernatants by size exclusion chromatography and were incubated with U937-derived macrophages, followed by flow cytometric evaluation of M1 and M2 markers. Proteomic evaluation of human prostate tumors indicates that CD68+ TAMs correlate with aggressive, metastatic PCa. Furthermore, a higher M2-to-M1 ratio also correlates with metastatic disease compared to normal or localized tumors. Chemoresistant PCa cells exhibited an enhanced lipogenic phenotype compared to naive cells and the over-production of lipids was linked to EV-mediated reprogramming of macrophages toward an M2-like phenotype. These findings indicate that alternative activation of macrophages is linked to aggressive, therapy resistant PCa. Moreover, our data suggest that tumor lipid metabolism may influence tumor-associated macrophage phenotype and function through EV-mediated intercellular signaling. Puerto Rico Science Research and Technology Trust

The KDM5B and KDM1A lysine demethylases cooperate in regulating androgen receptor expression and signalling in prostate cancer.

Histone H3 lysine 4 (H3K4) methylation is key epigenetic mark associated with active transcription and is a substrate for the KDM1A/LSD1 and KDM5B/JARID1B lysine demethylases. Increased expression of KDM1A and KDM5B is implicated in many cancer types, including prostate cancer (PCa). Both KDM1A and KDM5B interact with AR and promote androgen regulated gene expression. For this reason, there is great interested in the development of new therapies targeting KDM1A and KDM5B, particularly in the context of castrate resistant PCa (CRPC), where conventional androgen deprivation therapies and androgen receptor signalling inhibitors are no longer effective. As there is no curative therapy for CRPC, new approaches are urgently required to suppress androgen signalling that prevent, delay or reverse progression to the castrate resistant state. While the contribution of KDM1A to PCa is well established, the exact contribution of KDM5B to PCa is less well understood. However, there is evidence that KDM5B is implicated in numerous pro-oncogenic mechanisms in many different types of cancer, including the hypoxic response, immune evasion and PI3/AKT signalling. Here we elucidate the individual and cooperative functions of KDM1A and KDM5B in PCa. We show that KDM5B mRNA and protein expression is elevated in localised and advanced PCa. We show that the KDM5 inhibitor, CPI-455, impairs androgen regulated transcription and alternative splicing. Consistent with the established role of KDM1A and KDM5B as AR coregulators, we found that individual pharmacologic inhibition of KDM1A and KDM5 by namoline and CPI-455 respectively, impairs androgen regulated transcription. Notably, combined inhibition of KDM1A and KDM5 downregulates AR expression in CRPC cells. Furthermore, combined KDM1A and KDM5 inhibition impairs PCa cell proliferation and invasion more than individual inhibition of KDM1A and KDM5B. Collectively our study has identified individual and cooperative mechanisms involving KDM1A and KDM5 in androgen signalling in PCa. Our findings support the further development of KDM1A and KDM5B inhibitors to treat advanced PCa. Further work is now required to confirm the therapeutic feasibility of combined inhibition of KDM1A and KDM5B as a novel therapeutic strategy for targeting AR positive CRPC.

Abstract 442: Developing a lipogenesis inhibitor for prostate cancer

Abstract Background: Prostate cancer (PC) is the single most common and second most lethal cancer in men. Despite therapeutic advances in androgen receptor (AR)-targeting agents, progression to lethal, drug-resistant, castration-resistant prostate cancer (CRPC) remains a major clinical problem. Thus, there is an unmet need for novel treatment approaches and novel, druggable therapeutic targets in metastatic CRPC. Profiling of PC patient samples shows increases in two master regulators of lipogenesis-sterol regulatory binding proteins 1 and 2 (SREBP1 and SREBP2)-and their transcriptional targets. Overexpression of SREBP1 and SREBP2 and their target genes has been associated with tumor aggressiveness, poor clinical outcomes, and drug resistance in PC. The activation and nuclear translocation of SREBPs is tightly regulated by SREBP cleavage-activating protein (SCAP). We propose targeting SCAP will simultaneously block the activation and subsequent activity of all three SREBPs and that this represents a promising therapeutic strategy to treat CRPC. Methods: To increase our understanding of SREBP biology in PC cells, we defined the cistrome of SREBPs across multiple PC cell lines via ChIP-Seq. We compared the transcriptomic profiles of genetic targeting of SREBP via siRNA and pharmacological targeting via the novel SCAP inhibitor, SCAPi. We evaluated the effect of SCAPi on cell viability, cell invasion, and AR-signaling in multiple PC cell lines using immunoblotting, luciferase reporters, flow cytometry, MTT, and invasion assays. Additionally, we will evaluate the anticancer activity and safety profile of our novel SCAPi using CDX mouse models. Results: We found that inhibition of SCAP via siRNA and via SCAPi both yielded similar gene signatures, particularly the perturbation of cell cycle and lipogenesis genes. SCAPi dramatically reduces cell viability, migration, invasion, and expression of both AR- and SREBP-target genes in multiple PC cell lines. Through flow cytometry (Annexin V) and western blots (cleaved PARP) we found SCAPi induces apoptosis within 48 hours in PC cells. Pilot studies in tumor-bearing mice show SCAPi significantly increases survival without inducing animal weight loss. Conclusions: There is a critical need for novel targets in PC, and dysregulated lipogenesis is an untargeted oncogenic pathway. Our work furthers the field’s understanding of hijacked lipogenesis in PC and paves the way for a first-in-class inhibitor of lipogenesis to treat lethal PC. Citation Format: Dallin Lowder, Jin Na Shin, Maria E. Ruiz-Echartea, Darlene Skapura, Jenny Deng, Aleksandra Rusin, Christel Davis, Erik Ehli, Cristian Coarfa, Michael Ittmann, Salma Kaochar. Developing a lipogenesis inhibitor for prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 442.

Abstract 1754: Targeting the mitochondrial protein MAGMAS increases sensitivity to docetaxel in neuroendocrine prostate cancer cells

Abstract Metastatic prostate cancer (PCa) is the leading cause of PCa-associated deaths and one of the leading causes of cancer mortality in men. Novel therapeutics, such as Prostate Specific Membrane Antigen (PSMA) ligand therapy, are emerging as effective treatment strategies for metastatic prostate cancer. However, neuroendocrine differentiated (NED) metastatic PCa, which lacks the PSMA antigen, is deprived of effective biomarkers for disease treatment. Magmas, a 13.8 kDa mitochondrial protein, imports nuclear-encoded mitochondrial proteins into the mitochondrial matrix. Magmas is overexpressed in several aggressive tumors, such as breast cancer, glioblastoma, and prostate cancer. When overexpressed, Magmas plays a role as a cytoprotective protein by acting as a reactive oxygen species (ROS) scavenger that maintains sufficient ROS levels to promote cell proliferation, but below the threshold levels that could lead to apoptosis. This study was designed to investigate the pro-survival and therapy-resistance functions of Magmas in PCa cells expressing NED markers. Predictively, we observed that the docetaxel (DTX)-resistant PC3-DR and DU145-DR PCa cell lines expressed significantly higher levels of Magmas compared to their drug-sensitive parental cell lines. We hypothesized that inhibiting Magmas reduces the aggressive properties of highly proliferative DTX- resistant metastatic PCa cell lines and re-sensitize them to DTX. Magmas knockdown in DTX-sensitive and DTX-resistant PC3 and DU145 cells in the presence of increasing DTX treatments enhanced sensitivity to DTX. Consistent with these results, pharmacological inhibition of Magmas with the novel BT#9 inhibitor in combination with increasing DTX concentrations also enhanced sensitivity to DTX in these cell lines. Additional studies using clonogenic assays, cell migration/invasion assays, and tumorsphere formation assays are currently underway to further establish Magmas as a potential therapeutic target to attenuate the aggressive properties of chemoresistant PCa cells. Lastly, we will investigate the diagnostic potential of Magmas as a biomarker for NED and BT#9 as an imaging/therapeutic-specific agent for NED. Citation Format: Alfonso M. Durán, Christian H. Yoo, Jennifer D. Tran, Krystal Santiago, Adil S. Mohammed, Carlos A. Casiano, Frankis A. Almaguel. Targeting the mitochondrial protein MAGMAS increases sensitivity to docetaxel in neuroendocrine prostate cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1754.

The Management of Metastatic Castrate-Sensitive Prostate Cancer: From Guidelines to Real-World Practice.

This commentary highlights 2 international studies on real-world treatment trends and patterns among patients with metastatic castration-sensitive and resistant prostate cancer and how interventions targeting physicians and patients can bridge the gap between evidence-based medicine and real-world practice.

Abstract 1789: Pre-clinical studies to advance anti-ROR1 CAR-T cell therapy for metastatic prostate cancer

Abstract Background: Alterations in WNT signaling are frequently associated with tumorigenesis and metastasis in many cancers including prostate cancer (PCa). The Wnt ligand, WNT5A, is required for normal prostate gland development and is increased in bone metastatic, castration resistant PCa (CRPC) patients. WNT5A signaling is mediated in part through ROR1, a non-canonical Wnt receptor and fetal oncoprotein for which the therapeutic inhibitory antibody, Zilovertamab, has been developed. Its safety has been clinically proven in trials for chronic lymphocytic leukemia (CLL) and metastatic breast cancer. We sought to investigate Zilovertamab-based anti-ROR1 therapies for metastatic prostate cancer.Our Hypothesis is that WNT5A may activate a stem-cell-like program via ROR1 which leads to therapy resistance in metastatic prostate cancer. The anti-ROR1 biologic, Zilovertamab, may inhibit this mechanism of resistance. The expression of ROR1 on CRPC and NEPC tumors and its lack of expression on normal adult tissues makes it a promising CART cell target. Methods: We used the patient-derived xenograft (PDX), PCSD13, small cell bone metastatic prostate cancer model and the neuroendocrine PCa cell lines, PC3 and DU145, to test the effect of Zilovertamab and Zilovertamab-CART cells in vitro using the real time cell viability, proliferation, and cell cycle tracking assays in an Incucyte S3. We used in vivo bioluminescence and tumor caliper measurements to monitor effects in vivo. Results: Studies using RNASeq, qRT-PCR, FACS and Westerns showed high expression of ROR1 in PC3, DU145, and in PCSD13. CRISPR-Cas9 Knock out of ROR1 in PC3 and DU145 cells showed increased inhibition of proliferation at lower docetaxel concentrations. Treatment of PCSD13 PDX in vivo with Zilovertamab increased docetaxel-mediated tumor growth inhibition. Mice bearing PC3 xenografts injected intravenously with Zilovertamab anti-ROR1 CAR-T cells showed durable, tumor ablation in 67% of mice compared to 22% of mice injected with activated T cells from the same donor and 0% of untreated mice. Survival of mice at Day 70 injected with CART was 78% compared to 0% of mice injected with control donor T cells and 0% of untreated mice. Zilovertamab antibody could inhibit Zilovertamab CART cell tumor cell killing. Conclusions: ROR1 was expressed at high levels on castration resistant small cell PCa and neuroendocrine PCa cell lines and PDX models. Zilovertamab synergized with docetaxel to inhibit tumor growth in patient derived xenograft in vivo and in organoid cultures. Zilovertamab-based CART cells durably eradicated ROR1+ prostate cancer xenograft tumors. These studies supported the recently launched Phase 1b clinical trial of Zilovertamab plus docetaxel in metastatic CRPC patients. Clinical development of GMP Zilovertamab CART cells for a clinical trial in CLL is in progress and may lead to rapid progression to a clinical trial for metastatic CRPC and NEPC. Citation Format: Christina A.M. Jamieson, Jamillah Murtadha, Christopher S. Oh, Michelle Muldong, Evodie Koutouan, JOngwook Kim, Niloofar Etemadfard, Hae Soo Choo, Navyaa Sinha, Sanghee Lee, Christina Wu, Gabriel Pineda, Kathleen Lennon, Karl Willert, Catriona H. Jamieson, Terry Gaasterland, Rana Mckay, Christopher J. Kane, Thomas J. Kipps, Anna A. Kulidjian, Nicholas A. Cacalano, Charles Prussak. Pre-clinical studies to advance anti-ROR1 CAR-T cell therapy for metastatic prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1789.

Abstract 2475: Bromodomain inhibitor: MT1 and its potential role in modulation of prostate cancer progression

Abstract Bromodomains (BD) are epigenetic readers of histone acetylation involved in chromatin remodeling and transcriptional regulation of protooncogene cellular myelocytomatosis (c- Myc) and other genes. Because c-Myc cannot be directly targeted by small molecular inhibitors due to disordered alpha helical structure, epigenetic targeting of c-Myc by BD inhibitors is an attractive therapeutic strategy for diseases such as prostate cancer (PC) associated with increased c-Myc upregulation with advancing disease. We studied the efficacy of MT1, a novel bivalent BD inhibitor that is 100-fold more potent than the first in class BD inhibitor JQ1, at inhibiting PC growth. We tested the effect on viability by MT-1 on PC cell lines, 3D spheroids derived from clinically annotated drug resistant patient derived xenografts (PDX), mice PDX models and corroborated the molecular mechanism of MT1 down regulation of Myc leading to downstream Myc-dependent up regulation of Protein Kinase D1 (PrKD) substrate phosphorylation by western blot. MT-1 inhibited growth of PC in castration sensitive (LNCaP) and resistant PC cells (PC-3). MT-1 treatment upregulated PrKD expression and phosphorylation of known PrKD substrates: threonine 120 (Thr-120) residues in beta-catenin and the serine 216 in Cell Division Cycle 25 (CDC25C) in PC-3 cells. Moreover, MT-1 was effective in inhibition of 3D spheroids growth at IC 50 between 0.27-0.92µM in Abiraterone, Enzalutamide, Docetaxel, Cabazitaxel metastatic castrate resistant PCa patient-derived tumor 3D spheroids. Additionally, MT1 was effective in inhibiting the tumor growth in PDX mice model. A combined intra-peritoneal administration of MT-1 with another c-Myc inhibitor (3JC48-3), an obligate c-Myc and MYC-associated protein X (MAX) heterodimerization inhibitor, increased the efficacy of inhibiting the PDX growth in mice. This study provides strong pre-clinical in vitro and in vivo evidence for advancing MT- 1 as a novel c-Myc targeting drug in PC. The MT-1 drug development will likely be highly impactful as c-Myc is dysregulated in three fourths of men with advanced PC. Citation Format: Sanjeev Shukla, Mohammed Al-Toubat, Allison H. Feibus, Ahmed Elshafei, Carlos Riveros, Nathalie Meurice, Justyna Gleba, Jonathan Chardon-Robles, Adam M. Kase, John A. Copland III, Joachim L. Petit, Teruko Osumi, K.C. Balaji. Bromodomain inhibitor: MT1 and its potential role in modulation of prostate cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2475.

Abstract 2307: Targeted cell-free DNA methylation signature in metastatic castration-resistant prostate cancer

Abstract Background: DNA methylation of cytosines in CpG sites serves as an important epigenetic regulator for gene expression. In prostate cancer (PC), differences in DNA methylation regions have been observed between normal and tumor cells. However, acquiring the samples to study these patterns can be challenging through standard biopsies. Therefore, liquid biopsies provide a minimally invasive method which can be utilized to investigate the methylome of PC patients. In this study, we used liquid biopsies from a well-defined group of PC patients to examine cell-free DNA (cfDNA) methylation signatures and determine their clinical significance in metastatic castration-resistant prostate cancer. Methods: Plasma was prospectively collected from a cohort 108 PC patients representing localized PC (n=24), metastatic hormone-sensitive PC (mHSPC) (n=28), and metastatic castration resistant PC (mCRPC) (n=37 pre-, n=19 post- mCRPC treatments). cfDNA from the patient plasma was used for an enzymatic methylation sequencing (EM-seq) that targeted a panel of genes (n=441) implicated in prostate cancer biology. Methylation status at CpG islands of these genes were examined using Twist targeted cfDNA methylation assay. The Bismark program was used for methylation calling. Differentially methylated regions (DMRs) across various patient outcomes were assessed by linking the CpG methylation data from target genes to the associated clinical data. Results: We identified DMRs in 305 out of the 411 target genes in the plasma epigenome when comparing the mCRPC to non-mCRPC states (localized PC and mHSPC) (false discovery rate, FDR < 0.2). From these 305 genes, we found that in patients experiencing only PSA relapse after failure of mHSPC (biochemical mCRPC) versus patients with clinical progression (clinical mCRPC), 261 out of the 305 genes had DMRs (p <0.05). We also compared DMRs before and after 3-months of treatment in the mCRPC state and found that 175 out of the 305 genes showed significant changes after 3-months of mCRPC-specific treatment. Furthermore, from these 175 genes, 24 genes showed significant methylation differences when comparing patients with and without disease progression during mCRPC treatment and 20 genes showed significant differences when comparing patients with neuroendocrine features to those with common adenocarcinoma of PC at the mCRPC state (p<0.05). These differentially methylated genes include RUNX3, FOXA2, HIC1 and MYCN. Conclusions: cfDNA-based liquid biopsies provide a minimally invasive method to investigate the methylome of mCRPC patients. Our observations that cfDNA methylation was correlated with disease progression provide evidence that DMRs across a select panel of genes may serve as predictive biomarker for poor response to therapy and survival. Citation Format: Jodie Wong, Yijun Tian, Amir Bitaraf, Claire Hanson, Matthew Larson, Jennifer Lloyd, Julia Batten, Neeraj Agarwal, Umang Swami, Anna Neibling, Jonathan Tward, Benjamin Maughan, Sumati Gupta, Manish Kohli, Liang Wang. Targeted cell-free DNA methylation signature in metastatic castration-resistant prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2307.

PD04-10 PRE-CLINICAL STUDIES TO ADVANCE ZILOVERTAMAB-BASED ANTI-ROR1 DUAL SPECIFICITY CAR T-CELL THERAPY FOR METASTATIC PROSTATE CANCER.

PD04-10 PRE-CLINICAL STUDIES TO ADVANCE ZILOVERTAMAB-BASED ANTI-ROR1 DUAL SPECIFICITY CAR T-CELL THERAPY FOR METASTATIC PROSTATE CANCER.

PD21-03 THIRTY-YEAR OUTCOMES FOR MEN WITH PROSTATE CANCER ON WATCHFUL WAITING. NATION-WIDE POPULATION-BASED STUDY

You have accessJournal of UrologyCME1 Apr 2023PD21-03 THIRTY-YEAR OUTCOMES FOR MEN WITH PROSTATE CANCER ON WATCHFUL WAITING. NATION-WIDE POPULATION-BASED STUDY Eugenio Ventimiglia, Christian Corsini, Pär Stattin, and Hans Garmo Eugenio VentimigliaEugenio Ventimiglia More articles by this author , Christian CorsiniChristian Corsini More articles by this author , Pär StattinPär Stattin More articles by this author , and Hans GarmoHans Garmo More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003287.03AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: To model long-term outcomes for men with prostate cancer (PCa) on watchful waiting. METHODS: We developed and applied a state transition model based on data from 11,648 men with PCa managed with watchful waiting (WW) and registered in Prostate Cancer data Base Sweden (PCBaSe). For each man, we calculated the estimated remaining lifetime (ERL) at PCa diagnosis using a previously validated model including both Charlson Comorbidity Index (CCI) and a novel drug comorbidity index (DCI). We analysed the incidence of transition from WW to next treatment state; androgen deprivation therapy, castration resistant PCa, and death from PCa or other causes, stratified according to ERL. We then estimated the duration of time spent in the WW state and the proportion of wen who transitioned to CRPC or PCa death for each combination of PCa baseline risk category and ERL RESULTS: Median (IQR) age at diagnosis was 76 (72-81) years. A majority of men (62%) had no comorbidities (CCI=0, n=7246). Low-risk PCa was diagnosed in 3328 (28%) men, whereas higher-risk PCa (Gleason ≥3+4 or PSA>20 ng/ml or local stage T3) in 40% men. Median ERL was 10.5 years (IQR 7.9-13.5). Men in the low-risk PCa risk category managed with WW had shorter ERL (43 % below the median ERL value) vs. men with higher-risk PCa (61% below the median ERL value). Among men with ERL above median, 58% of men with low-risk PCa were still in the WW state 10 years after diagnosis vs 38% in the higher-risk PCa. At 30 years after diagnosis among men with ERL above median, the proportion of PCa death was 17% for low-risk PCa death and 23% for higher-risk PCa. CONCLUSIONS: One out of two men on watchful waiting had an ERL of at least 10 years, and ten years after diagnosis more than half of these men were still on watchful waiting. Death from other causes was the most common outcome for these men, even for men with higher-risk disease at diagnosis. Source of Funding: None © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e590 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Eugenio Ventimiglia More articles by this author Christian Corsini More articles by this author Pär Stattin More articles by this author Hans Garmo More articles by this author Expand All Advertisement PDF downloadLoading ...

MP20-07 NPTX1 IS A NOVEL SERUM BIOMARKER INDUCED BY ARPI TREATED PROSTATE CANCER AND ENRICHED IN LINEAGE PLASTICITY WITH BRN2 HIGH

You have accessJournal of UrologyCME1 Apr 2023MP20-07 NPTX1 IS A NOVEL SERUM BIOMARKER INDUCED BY ARPI TREATED PROSTATE CANCER AND ENRICHED IN LINEAGE PLASTICITY WITH BRN2 HIGH Takeshi Namekawa, Joshua Scurll, Maxim Kobelev, Dwaipayan Ganguli, Olena Sivak, Martin Gleave, Vancouver, Canada, Eva Corey, Colm Morrissey, and Amina Zoubeidi Takeshi NamekawaTakeshi Namekawa More articles by this author , Joshua ScurllJoshua Scurll More articles by this author , Maxim KobelevMaxim Kobelev More articles by this author , Dwaipayan GanguliDwaipayan Ganguli More articles by this author , Olena SivakOlena Sivak More articles by this author , Martin GleaveMartin Gleave More articles by this author , Vancouver Vancouver More articles by this author , Canada Canada More articles by this author , Eva CoreyEva Corey More articles by this author , Colm MorrisseyColm Morrissey More articles by this author , and Amina ZoubeidiAmina Zoubeidi More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003245.07AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Androgen receptor (AR) pathway inhibition is the first-line therapy for metastatic prostate cancer (PCa). However, tumors invariably develop resistance to ARPI. We previously identified a transcription factor Brain-2 (BRN2), encoded by the gene POU3F2, as a master driver of NEPC which is an aggressive form of AR-independent phenotypes treatment resistant PCa. In this study, we identified a surrogate biomarker of BRN2 activity to monitor the progression of treatment resistant PCa. METHODS: To identify BRN2 serum marker, we analyzed BRN2 ChIPseq data from 2 NEPC and 2 neural-type lung squamous cell carcinoma (nLUSC) cell lines with a focus on shared BRN2 peaks. Annotated peaks from enhancers (EnhancerAtlas) and promoters (genes within 20kb) were selected for secreted proteins and were ranked by correlation with BRN2 expression in PCa patients. Validation of protein expression was performed by western blot. R-PLEX Assay kit was used to measure concentrations in culture media from NCI-H660 cells and in serum from mice with NCI-H660 xenograft or PDX tumors and from human PCa patients. RESULTS: We identified 51 candidate serum biomarkers for BRN2 activity (or expression?) using the methods described above. These biomarkers were ranked based on their expression and correlation with BRN2 expression in PCa patient samples across four public data sets. NPTX1 was identified as the top biomarker of BRN2 expression. We further validated association of NPTX1 and BRN2 expression by BRN2 overexpression in MR42D and 22Rv1, indicating that BRN2 positively regulates NPTX1 expression. Next, we showed that NPTX1 is present in culture media from NCI-H660 cells, and that NPTX1 serum concentration positively correlated with tumor volume in mice with NCI-H660 xenografts and with NPTX1 mRNA expression in LuCaP PDX models. Importantly, evaluation of patients’ samples showed that NPTX1 levels were high in 26/35 CRPC serum samples vs levels in serum of healthy volunteers, and that the NPTX1 serum levels were highest in 4/6 patients with high POU3F2 tumor expression. CONCLUSIONS: We identified and validated NPTX1 as a serum marker that can be readily detected in serum from NEPC patients with BRN2high tumours. Source of Funding: U.S. Army Medical Research and Development Command(W81XWH1810689) © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e277 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Takeshi Namekawa More articles by this author Joshua Scurll More articles by this author Maxim Kobelev More articles by this author Dwaipayan Ganguli More articles by this author Olena Sivak More articles by this author Martin Gleave More articles by this author Vancouver More articles by this author Canada More articles by this author Eva Corey More articles by this author Colm Morrissey More articles by this author Amina Zoubeidi More articles by this author Expand All Advertisement PDF downloadLoading ...

PD04-07 THE BIVALENT BROMODOMAIN INHIBITOR; MT-1 INHIBITS PROSTATE CANCER GROWTH

You have accessJournal of UrologyCME1 Apr 2023PD04-07 THE BIVALENT BROMODOMAIN INHIBITOR; MT-1 INHIBITS PROSTATE CANCER GROWTH Sanjeev Shukla, Mohammed Al-Toubat, Carlos Riveros, Allison H. Feibus, Ahmed El-shafie, Adam M. Kase, John A. Copland, Joachim L. Petit, Nathalie Meurice, Justyna Gleba, Jonathan Chardon-Robles, Teruko Osumi, and K. C. Balaji Sanjeev ShuklaSanjeev Shukla More articles by this author , Mohammed Al-ToubatMohammed Al-Toubat More articles by this author , Carlos RiverosCarlos Riveros More articles by this author , Allison H. FeibusAllison H. Feibus More articles by this author , Ahmed El-shafieAhmed El-shafie More articles by this author , Adam M. KaseAdam M. Kase More articles by this author , John A. CoplandJohn A. Copland More articles by this author , Joachim L. PetitJoachim L. Petit More articles by this author , Nathalie MeuriceNathalie Meurice More articles by this author , Justyna GlebaJustyna Gleba More articles by this author , Jonathan Chardon-RoblesJonathan Chardon-Robles More articles by this author , Teruko OsumiTeruko Osumi More articles by this author , and K. C. BalajiK. C. Balaji More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003228.07AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Bromodomains (BD) are epigenetic readers of histone acetylation involved in chromatin remodeling and transcriptional regulation of protooncogene cellular myelocytomatosis (c-Myc) and other genes. Because c-Myc cannot be directly targeted by small molecular inhibitors due to disordered alpha helical structure, epigenetic targeting of c-Myc by BD inhibitors is an attractive therapeutic strategy for advanced prostate cancer (PC) associated with increased c-Myc upregulation . We studied the efficacy of MT1, a novel bivalent BD inhibitor that is 100-fold more potent than the first in class BD inhibitor JQ1, at inhibiting PC growth METHODS: We tested the effect on viability by MT-1 on PC cell lines, 3D spheroids derived from clinically annotated drug resistant patient derived xenografts (PDX), mice PDX models and corroborated the molecular mechanism of MT1 down regulation of Myc leading to downstream Myc-dependent up regulation of Protein Kinase D1 (PrKD) substrate phosphorylation by western blot. RESULTS: MT-1 inhibited growth of PC in castration sensitive (LNCaP) and resistant PC cells (PC-3). MT-1 treatment upregulated PrKD expression and phosphorylation of known PrKD substrates: threonine 120 (Thr-120) residues in beta-catenin and the serine 216 in Cell Division Cycle 25 (CDC25C) in PC-3 cells. Moreover, MT-1 was effective in inhibition of 3D spheroids growth at IC50 between 0.27-0.92µM in Abiraterone, Enzalutamide, Docetaxel, Cabazitaxel metastatic castrate resistant PCa patient-derived tumor 3D spheroids. Additionally, MT1 was effective in inhibiting the tumor growth in PDX mice model. A combined intra-peritoneal administration of MT-1 with another c-Myc inhibitor (3JC48-3), an obligate c-Myc and MYC-associated protein X (MAX) heterodimerization inhibitor, increased the efficacy of inhibiting the PDX growth in mice. CONCLUSIONS: This study provides strong pre-clinical in vitro and in vivo evidence for advancing MT-1 as a novel c-Myc targeting drug in PC. The MT-1 drug development will likely be highly impactful as c-Myc is dysregulated in three fourths of men with advanced PC. Source of Funding: None © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e144 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Sanjeev Shukla More articles by this author Mohammed Al-Toubat More articles by this author Carlos Riveros More articles by this author Allison H. Feibus More articles by this author Ahmed El-shafie More articles by this author Adam M. Kase More articles by this author John A. Copland More articles by this author Joachim L. Petit More articles by this author Nathalie Meurice More articles by this author Justyna Gleba More articles by this author Jonathan Chardon-Robles More articles by this author Teruko Osumi More articles by this author K. C. Balaji More articles by this author Expand All Advertisement PDF downloadLoading ...

MP67-09 RELATIONSHIP BETWEEN SKIN CANCER AND AGGRESSIVE PROSTATE CANCER: RESULTS FROM THE SEARCH DATABASE

You have accessJournal of UrologyCME1 Apr 2023MP67-09 RELATIONSHIP BETWEEN SKIN CANCER AND AGGRESSIVE PROSTATE CANCER: RESULTS FROM THE SEARCH DATABASE John m. Masterson, Jaruda Ithisuphalap, Durham NC, Emilie J. Fowler, Christopher L. Amling, William J. Aronson, Matthew R. Cooperberg, Lourdes Guerrios-Rivera, San Juan, Puerto Rico, Christopher J. Kane, Zachary Klaassen, Martha K. Terris, and Stephen J. Freedland John m. MastersonJohn m. Masterson More articles by this author , Jaruda IthisuphalapJaruda Ithisuphalap More articles by this author , Durham NCDurham NC More articles by this author , Emilie J. FowlerEmilie J. Fowler More articles by this author , Christopher L. AmlingChristopher L. Amling More articles by this author , William J. AronsonWilliam J. Aronson More articles by this author , Matthew R. CooperbergMatthew R. Cooperberg More articles by this author , Lourdes Guerrios-RiveraLourdes Guerrios-Rivera More articles by this author , San JuanSan Juan More articles by this author , Puerto RicoPuerto Rico More articles by this author , Christopher J. KaneChristopher J. Kane More articles by this author , Zachary KlaassenZachary Klaassen More articles by this author , Martha K. TerrisMartha K. Terris More articles by this author , and Stephen J. FreedlandStephen J. Freedland More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003330.09AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Skin cancer and prostate cancer (PC) are the two most cancers in men. Some data suggest sun exposure and Vitamin D levels inversely correlate with PC. We tested the association between pre-surgery skin cancer presence and outcomes after radical prostatectomy (RP) for PC in a large multi-center cohort. METHODS: We retrospectively reviewed data from men treated by RP from 1988-2020 at 9 VA hospitals. We excluded Black (n=2,743), other (n=299), and missing (n=69) race as skin cancers in these groups was very low. Men were segregated as melanoma, non-melanoma, and no skin cancer. Baseline features across groups were compared. Cox models were used to test the association between skin cancer groups and biochemical recurrence (BCR), metastasis, and castration resistant PC (CRPC). For PC specific mortality (PCSM), competing risk models were used to account for death from other causes. RESULTS: 6,817 men met inclusion: 557 had skin cancer (497 non-melanoma; 60 melanoma). Men with skin cancer were older (median 67 vs 65 yrs), had surgery more recently (median 2011-2 vs. 2006), were slightly less likely to have cT2, and more likely to have grade group 3-5 than men without skin cancer (all p<0.05). On univariable analyses, non-melanoma was unrelated to BCR, metastasis, and CRPC (HRs 0.98-1.05; all p>0.1) (Table 1). Melanoma was linked with numerically fewer poor outcomes (HR 0.46-0.75 and not calculable for PCSM due to no events), though none of these associations were significant. On multivariable analyses, the null associations between non-melanoma and outcomes remained, though all HRs were <1 (0.79-0.94). For melanoma, all HRs remained in the direction of lower risk (HRs 0.16-0.73), though results were not significant (Table 1). CONCLUSIONS: Our results suggest presence of non-melanoma skin cancer is unrelated to PC outcomes after RP, though a very modest association cannot be ruled out. While the numeric direction of reduced aggressiveness (all HRs <1) is in line with our hypothesis that Vitamin D levels associated with sun exposure may reduce PC aggressiveness, the lack of significance suggests any effects, if real, are modest at best. Alternatively, the more strongly, but still null, inverse associations with melanoma warrants further study given our sample only included 60 men with melanoma. Source of Funding: None © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e946 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information John m. Masterson More articles by this author Jaruda Ithisuphalap More articles by this author Durham NC More articles by this author Emilie J. Fowler More articles by this author Christopher L. Amling More articles by this author William J. Aronson More articles by this author Matthew R. Cooperberg More articles by this author Lourdes Guerrios-Rivera More articles by this author San Juan More articles by this author Puerto Rico More articles by this author Christopher J. Kane More articles by this author Zachary Klaassen More articles by this author Martha K. Terris More articles by this author Stephen J. Freedland More articles by this author Expand All Advertisement PDF downloadLoading ...

Apalutamid for treatment of nonmetastatic castration-resistant prostste cancer – case study

A special form of prostate cancer is non-metastatic castration-resistant prostate cancer. Patients with this form have rising prostate-specific antigen and castrate testosterone levels, with no radiological findings of metastatic disease on computed tomography and bone scan. The phase III trials demonstrated apalutamide, darolutamide or enzalutamide to be associated with a significantly longer median metastasis-free survival. The featured description presents one case of man with non-metastatic castration- resistant prostate cancer who was treated with apalutamide.

PSMA-PET Guided Treatment in Prostate Cancer Patients with Oligorecurrent Progression after Previous Salvage Treatment

Prostate Specific Membrane Antigen-Positron Emission Tomography (PSMA-PET) is used to select recurrent prostate cancer (PCa) patients for metastases-directed therapy (MDT). We aimed to evaluate the oncologic outcomes of second-line PSMA-guided MDT in oligo-recurrent PCa patients. we performed a retrospective analysis of 113 recurrent PCa after previous radical prostatectomy and salvage therapies with oligorecurrent disease at PSMA-PET (≤3 lesions in N1/M1a-b) in three high-volume European centres. Patients underwent second-line salvage treatments: MDT targeted to PSMA (including surgery and/or radiotherapy), and the conventional approach (observation or Androgen Deprivation Therapy [ADT]). Patients were stratified according to treatments (MDT vs. conventional approach). Patients who underwent MDT were stratified according to stage in PSMA-PET (N1 vs. M1a-b). The primary outcome of the study was Progression-free survival (PFS). Secondary outcomes were Metastases-free survival (MFS) and Castration Resistant PCa free survival (CRPC-FS). Kaplan-Meier analyses assessed PFS, MFS and CRPC-FS. Multivariable Cox regression models identified predictors of progression and metastatic disease. Overall, 91 (80%) and 22 (20%) patients were treated with MDT and the conventional approach, respectively. The median follow-up after PSMA-PET was 31 months. Patients who underwent MDT had a similar PFS compared to the conventional approach (p = 0.3). Individuals referred to MDT had significantly higher MFS and CRPC-FS compared to those who were treated with the conventional approach (73.5% and 94.7% vs. 30.5% and 79.5%; all p ≤ 0.001). In patients undergoing MDT, no significant differences were found for PFS and MFS according to N1 vs. M1a-b disease, while CRPC-FS estimates were significantly higher in patients with N1 vs. M1a-b (100% vs. 86.1%; p = 0.02). At multivariable analyses, age (HR = 0.96) and ADT during second line salvage treatment (HR = 0.5) were independent predictors of PFS; MDT (HR 0.27) was the only independent predictor of MFS (all p ≤ 0.04) Conclusion: Patients who underwent second-line PSMA-guided MDT experienced higher MFS and CRPC-FS compared to men who received conventional management.

The epigenetic function of androgen receptor in prostate cancer progression.

Androgen and androgen deprivation (castration) therapies, including androgen receptor antagonists, are clinically used to treat patients with prostate cancer. However, most hormone-dependent prostate cancer patients progress into a malignant state with loss of hormone-dependency, known as castration (drug)-resistant prostate cancer (CRPC), after prolong androgen-based treatments. Even in the CRPC state with irreversible malignancy, androgen receptor (AR) expression is detectable. An epigenetic transition to CRPC induced by the action of AR-mediated androgen could be speculated in the patients with prostate cancer. Androgen receptors belongs to the nuclear receptor superfamily with 48 members in humans, and acts as a ligand-dependent transcriptional factor, leading to local chromatin reorganization for ligand-dependent gene regulation. In this review, we discussed the transcriptional/epigenetic regulatory functions of AR, with emphasis on the clinical applications of AR ligands, AR protein co-regulators, and AR RNA coregulator (enhancer RNA), especially in chromatin reorganization, in patients with prostate cancer.

The comprehensive analysis of relationship between gut microbiome and treatment outcome of androgen deprivation therapy (ADT)-based treatment in patients with metastatic castration-sensitive and -resistant prostate cancer.

213 Background: Preclinical and clinical data from various types of cancer show that the gut microbiome can affect the outcome of treatments with immune checkpoint inhibitors or cytotoxic chemotherapies. However, the relationship between the microbiome and treatment outcomes in prostate cancer has remained unclear. Here, we present a comprehensive analysis of the relationship between the gut microbiome and treatment outcomes from a nationwide genome screening project (MONSTAR-SCREEN 1) in patients with metastatic castration-sensitive and -resistant prostate cancer (mCSPC and mCRPC). Methods: We performed 16S rRNA gene sequencing of fecal DNA from 73 mCSPC and 83 mCRPC patients before treatment. The microbiome data were compared using the Wilcoxon-Mann-Whitney test or Fisher’s exact test. Survival status and therapeutic efficacy of ADT based treatment were prospectively collected and estimated using the Kaplan-Meier method, and the log-rank test was used to compare survival in different strata. Results: Fecal samples from mCRPC had more Klebsiella and Enterobacteriaceae than those from mCSPC, whereas mCSPC had more Akkermansia and Bifidobacterium compared to mCRPC. Prior and concurrent usage of anti-biotics did not affect diversity of the amplicon sequence variants (ASVs), KEGG orthology and metabolism pathway representation. Anti-biotics also did not influence time to treatment failure (TTF) in mCRPC (HR:0.81, 95%CI:0.36–1.78) and mCSPC (HR:1.35, 95%CI:0.55–3.34). mCRPC had more diverse KEGG orthology compared to mCSPC ( p=0.0009), however, no statistical differences were observed in the ASV ( p=0.77) and metabolism pathway representation ( p=0.35) between mCRPC and mCSPC. High ASV tended to be associated with longer TTF rather than low ASV in both mCRPC (Adjusted HR:0.63, 95%CI:0.34–1.10) and mCSPC (Adjusted HR:0.66, 95%CI:0.31–1.40). mCRPC patients with high AVS also showed significant longer PSA-progression free survival than patients with low ASV (HR:053, 95%CI:0.28–0.99). Conclusions: This investigation revealed significant differences in the microbiome status of mCRPC compared to mCSPC. These differences and diversity might influence the outcomes of ADT based treatment in prostate cancer.

Racial differences in survival and healthcare resource utilization among Medicaid-insured adults with metastatic castration-resistant prostate cancer.

29 Background: Prostate cancer (PC) disproportionately affects Black or African American (BAA) men in the United States (US), but racial disparities in outcomes are not well understood. This study analyzed racial disparities in OS, healthcare resource utilization (HRU), and PC treatments in Medicaid-insured metastatic castration resistant PC (mCRPC) patients. Methods: This retrospective longitudinal cohort study evaluated de-identified data from the Centers for Medicare and Medicaid Services 100% Medicaid data files from 01/01/2010 – 12/31/2018. The study included adult patients with a diagnosis of PC and metastasis, and a claim for at least one of the following drugs prior to 9/30/2018, which is specific to mCRPC (date defined index): ≥1 claim for cabazitaxel, mitoxantrone, enzalutamide, radium-223, or sipuleucel-T, ≥1 claim for abiraterone acetate before June 2017, ≥1 claim for docetaxel at least 90 days after initiation of hormone therapy, or evidence of castration resistance. Patients were required to be continuously enrolled for ≥6 months pre-index (i.e., baseline period) and ≥3 months post-index. Outcomes were assessed from the index date to the earliest of end of continuous enrollment, data availability, or death. A multivariable Cox proportional hazards model of OS, and a multivariable Poisson model of HRU were implemented and controlled for age, plan type, region, median state income, residence in a state with Medicaid expansion, index year, Charlson comorbidity index, baseline HRU, baseline PC treatments, and clinical characteristics. Results: The study included 1,095 mCRPC patients (320 [29%] White [W], 278 [25%] BAA, 190 [17%] Hispanic [H], 307 [28%] Other races [O]). H had the highest mean age of 69 years, followed by 68 years for O, and 63 years for both W and BAA. Median unadjusted OS was 46.7 months in H, 40.5 months in BAA, 35.3 months in O, and 32.3 months in W. After adjustment, H had significantly lower risk of death vs. W (hazard ratio [95% confidence interval (CI)]: 0.62 [0.42, 0.90]) and BAA had comparable survival to W (0.85 [0.62, 1.16]). BAA had significantly fewer PC-related outpatient (OP) visits vs. W (adjusted incidence rate ratios [IRR] [95% CI]: 0.67 [0.48, 0.93]), but significantly more PC-related emergency room (ER) visits (5.03 [2.03, 12.47]) per patient per year. Race cohorts differed in the proportions of patients treated with novel hormonal therapy (70% W, 63% BAA, 58% H, 67% O) and chemotherapy use (29% BAA, 26% H, 24% W, 19% O). Conclusions: Among Medicaid-insured adult mCRPC patients, H were more likely to live longer than W patients, while BAA and W patients had similar OS. BAA patients had a higher rate of PC-related ER visits but fewer PC-related OP visits as compared to W, showing differential use of PC-related healthcare resources.

A phase 2 randomized open-label study of oral darolutamide monotherapy vs. androgen deprivation therapy in men with hormone-naive prostate cancer (EORTC-GUCG 1532).

160 Background: Darolutamide is androgen-receptor (AR) inhibitor with low blood–brain barrier penetration and limited potential for clinically relevant drug–drug interactions. Darolutamide has been shown to increase overall survival in combination with androgen deprivation therapy (ADT) in patients with newly diagnosed metastatic hormone sensitive prostate cancer (PC) and, in combination with docetaxel, in men with non-metastatic castration resistant PC. This phase 2 study assessed the efficacy and safety of DARO as a monotherapy without ADT in patients with non-castrate testosterone (T) levels (≥230 ng/dL). Methods: This was a 24-wk, open-label, randomized study of patients with hormone-naïve, histologically confirmed prostate cancer (all stages, with a max of 4 metastatic lesions) requiring hormonal treatment, an ECOG PS score of 0, and a life expectancy &gt;1 y. All patients received DARO 600 mg bid or commercially available LHRH analogue. The primary endpoint is PSA response defined as a ≥ 80% decline at week 24 relative to baseline, in the DARO study arm. The ADT arm is used as an internal control. Secondary endpoints included changes in T levels, safety/tolerability, and quality of life. Results: Among 61 men enrolled, the median (range) age was 72 y (53-86y); 49.2% had metastases; 14.8% and 62.3% had undergone prostatectomy or radiotherapy before study entry. The median (range) of PSA at baseline was 8.9 ng/mL (2.2-333.8). In the DARO arm, the evaluable population with available PSA values at baseline and week 24 consisted of 21 patients. The PSA response rate (&gt;80% PSA decline at wk 24) was 100%, with a median (range) decrease of -99.6% (-94.3, -100) at wk 24 in the DARO arm. Serum T levels increased by a median (range) of 43.4% (5.7-144.0) at wk 24, compared with baseline. In the DARO arm, 45.2% of men reported drug-related AEs (mostly Grade 1 or 2). Most frequent treatment-emergent AEs included gynaecomastia (19.4%), fatigue (12.9%), and hot flush (12.9%). 3.1% of men experienced SAEs, none of which were drug related. HR-QoL measures and ADT arm results will be presented as internal reference. Conclusions: DARO monotherapy (600 mg bid) was associated with significant PSA response in nearly all men with hormone-naïve prostate cancer. Testosterone level changes and most common AEs (gynecomastica, fatigue and hot flush) were consistent with potent AR inhibition. Clinical trial information: NCT02972060 .

Plasma proteome landscape and impact of the circulatory proteome on clinical outcomes in metastatic prostate cancer.

237 Background: We performed plasma-based high-plex proteomic profiling for identifying classifiers of clinical outcomes in metastatic prostate cancer (PC). Olink Explore NGS-based proteome profiling platform was used for high-precision analysis of 736 cancer associated plasma proteins in plasma samples from non-metastatic stage prostate cancer (PC), metastatic hormone-sensitive PC (mHSPC) and metastatic castrate resistant PC (mCRPC) states. Methods: Plasma was collected prospectively in a cohort of 108 PC patients (24 with non-metastatic PC; 28 mHSPC; 56 mCRPC of which 37 patients were collected before starting any mCRPC treatments). Proteomic data were generated with Proximity Extension Assay (PEA) on the Olink platform from 100 µL plasma per sample. Levels of 736 cancer-associated protein assays were denoted as normalized protein expression (NPX) units through a QC and normalization process developed and provided by Olink. Data generation of NPX consists of normalization to the extension control, log2 -transformation, and level adjustment using the plate control (plasma sample). Temporal trends of differentially expressed assays in non-metastatic PC, mHSPC and mCRPC states were identified using linear mixed effects model (FDR with Benjamini-Hochberg (BH) adjustment; q-value&lt;0.05, R version 4.1.2.). Clinical outcomes included in mCRPC state overall survival (calculated as time from turning mCRPC to death) and in mHSPC early failure of ADT-based therapies defined as progression within 12.5 months. Cox proportional hazard regression was performed for proteins associated with mHSPC and mCRPC states and clinical endpoint of interest. Results: After BH adjustments, 105 protein assays were differentially expressed across non-metastatic, mHSPC and mCRPC states of which 73 assays differed between non-metastatic and metastatic states (q&lt;0.05). 83/105 assays differed between mHSPC and mCRPC states (q&lt;0.05). Of the 83 plasma proteins, 77 were over-expressed in mCRPC. 19/37 mCRPC patients who had collections performed before mCRPC treatments had died. The median time to death was 29 months (Range: 1.9-119 mths). After adjustment for serum Alkaline phosphatase (ALP) levels in these 37 mCRPC patients 32/77 were significantly associated with overall survival. After performing an enrichment analysis the oxidative phosphorylation pathway with specific proteins assays (IMMT, COX5B and FXN, p = 5.1e-4, FDR = 2.55 e-2) were significantly overexpressed in patients with poor survival. Conclusions: A global plasma proteomic profiling of cancer related proteins revealed significant differences in expression in different states of cancer progression. Overexpressed proteins related to oxidative phosphorylation pathway in mCRPC in specific are associated with poor survival.