Castration Resistance Research Articles

Abstract 5295: Combined loss of tristetraprolin (TTP) and PTEN leads to aggressive prostate cancer and hypersensitivity to nuclear factor kappa B (NFkB) inhibition

Abstract We have reported that loss of tristetraprolin (TTP, gene name ZFP36), an RNA binding protein which modulates mRNA stability increased NFκB activation and is associated with higher rates of disease recurrence in prostatectomy series. Given TTP loss occurs in early prostate cancer we sought to examine the clinical and biological impact of TTP loss combined with PTEN loss, which also occurs in early prostate cancer. IHC revealed an increased risk of relapse with loss of one gene alone and a significantly higher risk of relapse with loss of both TTP and PTEN, (HR 4.50, p=0.04 on MVA adjusting for standard clinicopathologic factors). These findings were confirmed by analysis of RNA profiles of two publicly available prostatectomy series. Engineering ZFP36 deletion specific to prostate luminal cells in vivo induced high-grade prostatic intraepithelial neoplasia (HG-PIN), and when combined with PTEN deletion (P:Z) resulted in rapid progression to invasive adenocarcinoma associated with increased proliferation and development of micrometastases. Combined loss of PTEN and ZFP36 in mice significantly reduced overall survival (53.4 (P:Z+/-) and 49.6 (P:Z-/-) weeks versus 66.9 weeks in PTEN-/- (p<0.0001). Further, surgical castration of mice demonstrated that combined loss of ZFP36 and PTEN significantly accelerated progression to castration resistance versus PTEN alone (median survival, 56.1 (P:Z+/-) and 53.9 (P:Z-/-) weeks versus all PTEN-/- mice still alive by 70 weeks). Ex vivo analysis of organoid growth of the tumors revealed presence of budding with PTEN-/- with ZFP36-/- and almost none with PTEN-/-. These findings were recapitulated with GEMM-derived allograft tumor growth with tumor sizes 20 weeks after castration being 200mm3 in PTEN-/- versus 900mm3 with [PTEN-/- + TTP-/-] versus 600mm3 for PTEN-/- and 1200mm3 for [PTEN-/- + TTP-/-] after sham castration (all comparisons p < 0.05). When the PTEN/ZFP36 null allograft was treated with the NFκB inhibitor dimethylaminoparthenolide (DMAPT, D), tumor sizes 36 days after treatment were: vehicle - 2000mm3, castration (C) - 1500mm3; D alone - 600mm3; C + D - 500mm3 (all comparisons p<0.05; except D vs C + D; p=0.07). These findings were supported by cell death assays of organoid models for the GEMMs. The hypersensitivity of PTEN/ZFP36 null cell line to DMAPT was seen with dose response curves with DMAPT LD50 being 4.52 μM PTEN-/-; 0.76 μM [PTEN -/- + TTP-/-] and 8.66 μM for [PTEN-/- + TTP-/- + silenced p65]. In conclusion, combined loss of PTEN and TTP results in prostate cancer that is clinically more aggressive than PTEN loss alone and this was corroborated by GEMM models. Namely, PTEN/TTP null tumors were more aggressive, minimally responsive to castration, demonstrated activation of NFκB and hypersensitivity to DMAPT. This work supports the planned clinical trials of DMAPT in castration resistant prostate cancer Citation Format: Christopher J. Sweeney, Katherine Morel, Anis Hamid, Leigh Ellis. Combined loss of tristetraprolin (TTP) and PTEN leads to aggressive prostate cancer and hypersensitivity to nuclear factor kappa B (NFkB) inhibition [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 5295.

Abstract 6160: Tie2-mediated AMPK activation by ferritin-based protein C nanoparticles inhibits advanced prostate cancer development through induction of vasodilation

Abstract Prostate cancer (PCa) is one of the most common malignancies and the second-leading cause of cancer-related mortality in men in Western countries. Androgen deprivation therapy (ADT) is an initial systemic therapy for advanced PCa, but almost all cancer eventually becomes castration resistant. Recently, we introduced ferritin-based protein C nanoparticles (PCNs), known as TFG and TFMG, which enhance normalization of the tumor vasculature. However, the exact underlying mechanism how PCNs induces AMP-activated protein kinase (AMPK) activation and anti-tumor activity in castration-resistant prostate cancer (CRPC) remains unknown. Here, we investigated the role of PCNs for CRPC development in endothelial cells. We found that TFMG inhibits prostate cancer castration resistance by activating AMPK through the Tie2-mediated signaling pathway. TFMG treatment increased AMPK phosphorylation at Thr172 and acetyl-CoA carboxylase (ACC) at Ser79 in EA.hy926 cells. TFMG treatment also significantly increased the phosphorylation of endothelial nitric oxide synthase (eNOS) with inducing nitric oxide (NO) production in EA.hy926 cells. In addition, TFMG treatment induced the vasodilatory effect in isolated rat mesenteric resistance arteries (MRAs), which was blocked by NO synthase inhibitor L-NAME. Interestingly, these effects were all abolished by pretreatment with Compound C (an AMPK inhibitor), rebastinib (selective Tie2 Inhibitor), AMPK knockdown using siRNA, or dominant negative AMPKα recombinant adenovirus. Finally, we found that TFMG functionally abrogates CRPC development in mouse model. In summary, TFMG exerted vasodilatation through activating Tie2/AMPK/eNOS signaling in endothelial cells, which leads to the overcoming vasoconstriction induced ADT. This study provides the potential value of TFMG in vasodilation of blood vessels leading suppression of CRPC development. Citation Format: You Mie Lee, Ji-Hak Jeong, Hyunha Jang, Jihye You. Tie2-mediated AMPK activation by ferritin-based protein C nanoparticles inhibits advanced prostate cancer development through induction of vasodilation [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 6160.

Abstract 2297: Profound anti-tumor efficacy of dual CDK7 and PD1 blockade in novel syngeneic prostate cancer models

Abstract Background: Anti-PD1 immune checkpoint blockade (ICB) has largely failed as a monotherapy for metastatic prostate cancer likely due to inadequate tumor neoantigen load and inadequate T cell filtration (TILs). Strategies to increase TILs that can be tested in novel syngeneic mouse models are needed in order to fulfill this critical medical need. CDK7 is a major regulator of the cell cycle that is under investigation as a novel therapeutic target. CDK7 inhibition can trigger robust anti-tumor immunity by causing genomic instability and DNA damage in lung cancer mouse models. Herein, we characterize our novel syngeneic mouse models and report on the anti-tumor activity of CDK7 alone and in combination with anti-PD1 ICB as an immunotherapeutic strategy. Methods: We generated two models of prostate cancer organoids and syngeneic mouse models. APC and PTEN are tumor suppressor genes commonly lost in metastatic prostate cancer and are emerging as a putative mechanism of resistance to immunotherapy. The MPA and MPP models were established by ex-vivo Lenti-Cas9-sgRNA knock-out of APC or PTEN from the prostate organoids grown in 3D cultures established from the prostate of a MYCT/TP53-/- GEMM. Results: Organoids from the MPA and MPP models form orthotopic high grade prostate adenocarcinoma from 2 to 3 weeks post-implantation and spontaneously develop lung metastases 10-12 weeks after orthotopic implantation. In addition, the MPA model developed immediate castration resistance and neuroendocrine transformation following hormone deprivation in vivo. By contrast, the MPP tumors significantly regressed after in vivo androgen deprivation. Baseline immunoprofiling of the MPA and MPP orthotopic tumors showed increased infiltration from monocytic MDSCs and expression of T cell exhaustion markers. Treatment of the MPA and MPP orthotopic models with YKL-5-124, a CDK7 inhibitor, led to substantial in vivo tumor growth inhibition, which was further augmented by the addition of anti-PD-1 ICB. Immunoprofiling of tumors treated with combined YKL-5-124 and PD-1 blockade showed activation of CD4+ and CD8+ T cells, and a decrease in the Treg, B cell and NK cell population. Conclusions: The MPA and MPP orthotopic models recapitulate the biology and immune suppressive microenvironment of advanced prostate cancer and provide useful tools for immunotherapy drug development. Combination of CDK7 inhibition with anti-PD-1 blockade profoundly inhibited in vivo orthotopic tumor growth in both MPA and MPP model, providing a rationale for exploring CDK7 in combination with PD-1 checkpoint immunotherapy as a novel therapeutical strategy for advanced prostate cancer. Funding Acknowledgements: DRW is funded through 2018YI2295 Prostate Cancer Foundation Young Investigator Award and PC160944 Department of Defense Physician Research Career Development Award. Citation Format: David Wise, Luiza Doro Pereira, Jiansheng Wu, Victor R. Adorno Febles, Jonathan Melamed, Fang-Ming Deng, Hua Zhang, Kwok-Kin Wong. Profound anti-tumor efficacy of dual CDK7 and PD1 blockade in novel syngeneic prostate cancer models [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 2297.

Abstract 2411: Di-ganglioside GD2 expression and role in promoting tumorigenicity in prostate cancer

Abstract Background & Significance: Prostate cancer (PCa) is the second leading cause of cancer deaths (~34,000 in 2021 (ACS)) in American men. Castration resistance and resistance to the next-gen androgen receptor (AR) targeted drugs are major challenges. Castration resistance involves multiple mechanisms, including androgen-independent signaling by androgen receptor (AR)- or its variants, and lineage plasticity (LP) with AR-indifferent neuroendocrine (NE) differentiation. Identifying new vulnerabilities across these multitude mechanisms could provide new therapeutic avenues against castration-resistant PCa (CRPC). The cell-surface di-ganglioside GD2 is overexpressed in neural crest cell tumors such as neuroblastoma & melanoma and chimeric (Dinutuximab) or humanized (Naxitamab) anti-GD2 antibodies are now FDA-approved for high-risk neuroblastoma therapy. GD2 expression is reported in other cancers such as breast cancer and glioma and is linked to cancer stem cell behavior. While limited prior studies have detected GD2 expression in PCa cell lines or tumor tissues, nothing is known about the functional role of GD2 in PCa. Objectives: We hypothesized that GD2 overexpression in PCa could play a pro-tumorigenic role and that linkage of GD2 overexpression with CRPC progression may reveal the potential of targeting GD2 for CRPC therapy. Study Design & Results: Immunohistochemical analysis of PCa patient and patient-derived xenograft tissue microarrays (TMAs) revealed GD2 expression in a subset of tumor cells. Fluorescence-activated cell sorter analysis of PCa cell lines showed strong constitutive GD2 expression on murine CRPC cell line RM-1 (derived from mutant Ras and c-Myc overexpressing prostatic epithelial cells) and human PCa line 22Rv1 (overexpresses wild-type AR and ARv7 splice variant). GD2 expression was induced de novo upon induction of lineage plasticity in GD2-negative LNCaP C4-2 prostate adenocarcinoma cell line by shRNA knockdown (KD) of RB1 or TP53. High GD2 expression was also induced when C4-2B cells were made enzalutamide resistant (C4-2BER). Induction of GD2 expression correlated with increased expression of rate-limiting GD2 biosynthetic pathway enzyme GD3 synthase (GD3S). CRISPR-Cas9 mediated stable GD3S knockout (KO) in the RM1 cell line led to the loss of GD2 expression. The GD3S-KO RM1 cells exhibited reduced proliferation, migration, invasion, and tumor sphere forming ability compared to the control cells. Intratibial injections in castrated male C57BL/6 mice showed a significant reduction in tumor development by GD3S KO RM1 cells compared to control cells. Conclusions: Our studies demonstrate that GD2 is expressed in a subset of prostate cancers. Cell line-based studies show that GD2 expression promotes pro-tumorigenic traits. Future studies will assess the biological roles of GD2 in PCa and the potential of targeting GD2+ CRPC with antibody-based approved therapeutic agents. Citation Format: Aaqib M. Bhat, Bhopal C. Mohapatra, Insha Mushtaq, Sukanya Chakraborty, Samikshan Dutta, Sameer Mirza, Matthew D. Storck, Subodh M. Lele, Ming-Fong Lin, Bruce J. Trock, Karen S. Sfanos, Colm Morrissey, Eva Corey, Jonathan Melamed, Leah Cook, Kaustubh Datta, Jane Meza, Jawed Siddiqui, Surinder K. Batra, Vimla Band, Hamid Band. Di-ganglioside GD2 expression and role in promoting tumorigenicity in prostate cancer [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 2411.

Abstract 1579: Increased stromal-oriented MAOB expression associated with poor clinical outcomes promotes prostate cancer progression

Abstract Background. Stromal fibroblasts, the predominant cell type within the tumor microenvironment, plays a critical regulatory role in prostate cancer (PC) by engaging in stromal-epithelial interactions to dictate cancer initiation, growth, and progression. Monoamine oxidase B (MAOB) catalyzes oxidative deamination of biogenic and dietary monoamines and generates hydrogen peroxide as a by-product, which can predispose stromal cells to a reactive, cancer-promoting state with elevated production of extracellular matrix molecules, growth factors, cytokines, and chemokines. This study investigated the clinical relevance and previously unrecognized function of stromal MAOB in PC. Methods. The stromal MAOB expression levels were determined in PC clinical specimens by immunohistochemistry and in publicly available multi-omics cancer datasets, which were associated with different clinical parameters. The human prostatic stromal fibroblast PrSC cells engineered for stable overexpression or knockdown of MAOB were co-cultured with a panel of human PC cells in 2-D or 3-D fashion, followed by examination of cancer cell behavior by cell proliferation, migration, and invasion assays. MAOB-knockdown PrSC cells were co-inoculated with luciferase-tagged PC cells as subrenal tissue recombinant xenografts into mice for assessment of MAOB’s impact on tumor growth by bioluminescence imaging. Results. MAOB expression was induced in the stroma associated with primary PC compared to normal prostatic tissues of clinical samples, which was corroborated by the same MAOB expression trend in three matched pairs of patient-derived fibroblasts. Following the analysis of three independent clinical cohorts, increased stromal MAOB levels were shown to be correlated with higher Gleason scores, castration resistance, survival, and appearance of neuroendocrine differentiation as evidenced by CHGA expression in the adjacent epithelia. Co-culturing MAOB-overexpressing PrSC cells with several human PC cell lines (C4-2, PC-3, DU145 and C4-2BENZR) accelerated cancer cell proliferation, migration, and invasion. Conversely, these cancer cell phenotypes were suppressed in the presence of MAOB-knockdown PrSC cells. Additionally, C4-2 tumor xenografts when co-inoculated with MAOB-knockdown PrSC grew to a substantially smaller size in mice, which was paralleled by reduced Ki-67 index and reactive stromal marker αSMA expression in the tumor and stromal compartments respectively, compared to controls. Conclusion. Our results suggest that the elevated MAOB expression in PC stromal cells is associated with poor clinical outcomes and further contributes to adjacent PC growth, which provides new insights into understanding the stromal support of PC pathogenesis and progression. Funding provided by the NIH/NCI grant R01CA258634 and WSU CPPS startup fund (to B.W). Citation Format: Tainjie Pu, Jing Wang, Chia-Hui Chen, Tzu-Ping Lin, Boyang Wu. Increased stromal-oriented MAOB expression associated with poor clinical outcomes promotes prostate cancer progression [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 1579.

Abstract 5655: Brefeldin A mediates integrated stress response and in combination with Navitoclax induces apoptosis in prostate cancer cells

Abstract Introduction and Objectives: Metastatic castration resistance prostate cancer is a lethal disease. New AR-axis-targeted agent are available, but they will eventually become ineffective. Brefeldin A, an endoplasmic reticulum (ER) protein transport inhibitor, has been shown to cause ER stress. Navitoclax is a BH3 mimetic drug that targets anti-apoptotic proteins (BCL2 and BCLXL) and induces apoptosis in some solid tumors. Here, we investigated the efficacy of Brefeldin A combined with navitoclax on prostate cancer cells. Materials and Methods: We assessed the effect of combination therapy for prostate cancer cells using MTS assay, qRT-PCR, luciferase assay, and western blot. Results: Combination therapy with Brefeldin A and navitoclax synergistically decreased cell viability in prostate cancer cells. Mechanistically, Brefeldin A induced MCL1 degradation and, combined with navitoclax, drove apoptosis. Further, integrated stress response was at least in part involved in Brefeldin A-induced MCL1 degradation. Conclusions: Combination therapy with Brefeldin A and navitoclax shows synergistic anti-tumor effects in prostate cancer cells. These results suggest that Brefeldin A might still be effective in prostate cancer if used with navitoclax. Citation Format: Akira Ohtsu, Seiji Arai, Tatsuhiro Sawada, Yoshiyuki Miyazawa, Yoshitaka Sekine, Kazuhiro Suzuki. Brefeldin A mediates integrated stress response and in combination with Navitoclax induces apoptosis in prostate cancer cells [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 5655.

Abstract 3113: Molecular and pharmacological profiling of a novel prostate cancer-derived xenograft panel to identify resistance mechanisms and new therapeutic options

Abstract Prostate Cancer (PCa) is the most frequently diagnosed cancer in men and remains one of the leading causes of cancer death worldwide. It is a highly heterogenous and complex disease, presenting serious challenges to preclinical drug development and biomedical research. Prostate normal development, growth and function, as well as most of its pathological drifts, are associated to androgen receptor (AR) pathway regulation. Most patients subjected to androgen deprivation therapy (ADT) respond well to the treatment, however they usually progress into intractable castration-resistant PCa (CRPC) within 2 to 3 years. Therefore, understanding the mechanisms of castration resistance underlying PCa progression is key to develop future therapies. Patient-Derived Xenografts (PDX) are mouse models that recapitulate the disease more faithfully than any other in vivo model in terms of histopathologic, genomic and metastatic features, facilitating the translation of preclinical results in the clinical setting. PCa PDXs are challenging to develop, and only few are available to the scientific community. This lack of relevant preclinical models is a major limitation in PCa research. In particular, the development of PCa PDX models from castration-resistant tumors to explore new treatments against CRPC is a requirement. To fill this gap, XenTech and Gustave Roussy Institute are collaborating to develop a panel of PCa PDX models. In the framework of the MATCH-R clinical trial (NCT02517892), in which patients with disease progression under treatment are enrolled and switched to new targeted therapy based on the genetic alterations identified in biopsies, 8 PCa PDXs have been developed from metastatic lesions biopsy. In addition, we developed a PCa PDX model from circulating tumor cells (CTCs) obtained by leukapheresis at diagnosis. These 9 models, plus 4 PCa PDXs previously developed at XenTech, increases our PCa PDX panel to 13 models. All models were characterized at molecular level by whole exome and RNA sequencing and pharmacologically for response to standards of care, physical castration and response to the androgen receptor inhibitor enzalutamide. This PDX collection is a valuable preclinical tool to identify pivotal mechanisms underlying acquired resistance to current therapies and develop novel treatment strategies against PCa and CRPC. Citation Format: Laura Brulle-Soumare, Ludovic Bigot, Katell Mevel, Enora Le Ven, Luc Friboulet, Benjamin Besse, Françoise Farace, Jean Gabriel Judde, Stefano Cairo, Yohann Loriot, Olivier Déas. Molecular and pharmacological profiling of a novel prostate cancer-derived xenograft panel to identify resistance mechanisms and new therapeutic options [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 3113.

Abstract 6398: Functional characterization of Androgen Receptor splice variants in breast cancer invasion and metastasis

Abstract Introduction: A growing body of evidence suggests the prognostic and therapeutic value of Androgen Receptors (AR) in Breast Cancer (BrCa), particularly Triple Negative BrCa (TNBC). The splice variants of AR (ARVs); notably full-length AR (AR-fl) of ~110 kDa and a C-terminally Ligand Binding Domain (LBD) truncated AR isoform (AR-V7) of ~67 kDa are present in a variety of tissues. The ligand-independent AR-V7 is constitutively expressed and confers castration resistance in prostate cancer. With the irrefutable role of ARVs in BrCa, we evaluated their expression profile in cell lines with their prevalence and clinicopathological correlation in BrCa patients from India. Methods: Breast Cancer cell lines MDA-MB-231, MCF7, and MDA-MB-453 were procured from American Type Culture Collection. Thirty-eight de novo cases of Breast Cancer undergoing surgical intervention at a tertiary healthcare center in India were recruited. Tumor and adjacent benign tissue were collected after informed consent. The ARVs expression at transcriptomic and proteomic levels was evaluated by qRT-PCR and western blotting & Immunohistochemistry (IHC) respectively. For functional annotation, ARVs were knocked down in vitro using differently targeting siRNAs facilitated by Lipofectamine 3000 based transfection. There was a strong complementarity observed in western blotting and IHC. Results: All the ARVs were significantly higher in MDA-MB-453 followed by MCF7 and MDA-MB-231 cells. The expression ratio of AR-V7 versus AR-fl is, however, elevated in highly aggressive TNBC cell line MDA-MB-231. 67% of patients recruited were immunostained positive for AR (n=38). A majority of patients were of Luminal phenotype (37%) expressing both the prominent ARVs. One-third of the TNBC fraction were AR positive. Following the TNBC cell line, a subset of patients' samples also exhibited a substantial upregulation of AR-V7 compared to AR-fl. These patients had poor prognoses and aggressive features. The siRNA knockdown of all the ARVs resulted in decreased invasion and Epithelial-mesenchymal transition (EMT). Interestingly knocking down of ARVs barring AR-V7, restored invasiveness suggesting the compensatory behavior of AR-V7. Conclusion: Our work demonstrates the presence of ARVs in BrCa with a particular focus on the AR-V7. The LBD truncated AR-V7 potentiates the growth in BrCa cell lines and patients. This study further encourages the ARVs expression screening with AR positive BrCa for a prognostic biomarker of aggressive phenotype and therapeutic resistance. Citation Format: Tryambak Pratap Srivastava, Ruby Dhar, Anurag Srivastava, SVS Deo, Rajinder Parshad, Subhradip Karmakar. Functional characterization of Androgen Receptor splice variants in breast cancer invasion and metastasis [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 6398.

The Extracellular Matrix Stiffening: A Trigger of Prostate Cancer Progression and Castration Resistance?

Simple SummaryProstate cancer is a malignancy that affects a high number of men all over the world. When indolent, prostate cancer can remain silent for years without needing medical intervention. However, aggressive prostate cancer can grow fast, resist treatment, and cause morbidity and ultimately death. Uncovering mechanisms of prostate cancer disease progression and therapy resistance is important to develop new treatments that help patients live longer and healthier. The extracellular matrix, which provides physical support for tissues and organs, is emerging as an important mediator of disease, especially in cancer. In this review, we examine how extracellular matrix alteration, primarily through stiffening, can affect prostate cancer disease course. We look at mechanisms that involve the androgen receptor, which lies at the center of the disease transcriptional landscape, as well as alternative pathways that are androgen receptor-independent.Despite advancements made in diagnosis and treatment, prostate cancer remains the second most diagnosed cancer among men worldwide in 2020, and the first in North America and Europe. Patients with localized disease usually respond well to first-line treatments, however, up to 30% develop castration-resistant prostate cancer (CRPC), which is often metastatic, making this stage of the disease incurable and ultimately fatal. Over the last years, interest has grown into the extracellular matrix (ECM) stiffening as an important mediator of diseases, including cancers. While this process is increasingly well-characterized in breast cancer, a similar in-depth look at ECM stiffening remains lacking for prostate cancer. In this review, we scrutinize the current state of literature regarding ECM stiffening in prostate cancer and its potential association with disease progression and castration resistance.

Assessment of Androgen Receptor Splice Variant-7 as a Biomarker of Clinical Response in Castration-Sensitive Prostate Cancer.

Therapies targeting the androgen receptor (AR) have improved the outcome for patients with castration-sensitive prostate cancer (CSPC). Expression of the constitutively active AR splice variant-7 (AR-V7) has shown clinical utility as a predictive biomarker of AR-targeted therapy resistance in castration-resistant prostate cancer (CRPC), but its importance in CSPC remains understudied. We assessed different approaches to quantify AR-V7 mRNA and protein in prostate cancer cell lines, patient-derived xenograft (PDX) models, publicly available cohorts, and independent institutional clinical cohorts, to identify reliable approaches for detecting AR-V7 mRNA and protein and its association with clinical outcome. In CSPC and CRPC cohorts, AR-V7 mRNA was much less abundant when detected using reads across splice boundaries than when considering isoform-specific exonic reads. The RM7 AR-V7 antibody had increased sensitivity and specificity for AR-V7 protein detection by immunohistochemistry (IHC) in CRPC cohorts but rarely identified AR-V7 protein reactivity in CSPC cohorts, when compared with the EPR15656 AR-V7 antibody. Using multiple CRPC PDX models, we demonstrated that AR-V7 expression was exquisitely sensitive to hormonal manipulation. In CSPC institutional cohorts, AR-V7 protein quantification by either assay was associated neither with time to development of castration resistance nor with overall survival, and intense neoadjuvant androgen-deprivation therapy did not lead to significant AR-V7 mRNA or staining following treatment. Neither pre- nor posttreatment AR-V7 levels were associated with volumes of residual disease after therapy. This study demonstrates that further analytical validation and clinical qualification are required before AR-V7 can be considered for clinical use in CSPC as a predictive biomarker.

Establishment of a Novel Combined Nomogram for Predicting the Risk of Progression Related to Castration Resistance in Patients With Prostate Cancer

Background: The emergence of castration resistance is fatal for patients with prostate cancer (PCa); however, there is still a lack of effective means to detect the early progression. In this study, a novel combined nomogram was established to predict the risk of progression related to castration resistance. Methods: The castration-resistant prostate cancer (CRPC)-related differentially expressed genes (DEGs) were identified by R packages “limma” and “WGCNA” in GSE35988-GPL6480 and GSE70768-GPL10558, respectively. Relationships between DEGs and progression-free interval (PFI) were analyzed using the Kaplan–Meier method in TCGA PCa patients. A multigene signature was built by lasso-penalized Cox regression analysis, and assessed by the receiver operator characteristic (ROC) curve and Kaplan–Meier curve. Finally, the univariate and multivariate Cox regression analyses were used to establish a combined nomogram. The prognostic value of the nomogram was validated by concordance index (C-index), calibration plots, ROC curve, and decision curve analysis (DCA). Results: 15 CRPC-related DEGs were identified finally, of which 13 genes were significantly associated with PFI and used as the candidate genes for modeling. A two-gene (KIFC2 and BCAS1) signature was built to predict the risk of progression. The ROC curve indicated that 5-year area under curve (AUC) in the training, testing, and whole TCGA dataset was 0.722, 0.739, and 0.731, respectively. Patients with high-risk scores were significantly associated with poorer PFI (p < 0.0001). A novel combined nomogram was successfully established for individualized prediction integrating with T stage, Gleason score, and risk score. While the 1-year, 3-year, and 5-year AUC were 0.76, 0.761, and 0.762, respectively, the good prognostic value of the nomogram was also validated by the C-index (0.734), calibration plots, and DCA. Conclusion: The combined nomogram can be used to predict the individualized risk of progression related to castration resistance for PCa patients and has been preliminarily verified to have good predictive ability.

Clinical annotations for prostate cancer research: Defining data elements, creating a reproducible analytical pipeline, and assessing data quality.

Routine clinical data from clinical charts are indispensable for retrospective and prospective observational studies and clinical trials. Their reproducibility is often not assessed. We developed a prostate cancer-specific database for clinical annotations and evaluated data reproducibility. For men with prostate cancer who had clinical-grade paired tumor-normal sequencing at a comprehensive cancer center, we performed team-based retrospective data collection from the electronic medical record using a defined source hierarchy. We developed an open-source R package for data processing. With blinded repeat annotation by a reference medical oncologist, we assessed data completeness, reproducibility of team-based annotations, and impact of measurement error on bias in survival analyses. Data elements on demographics, diagnosis and staging, disease state at the time of procuring a genomically characterized sample, and clinical outcomes were piloted and then abstracted for 2261 patients (with 2631 samples). Completeness of data elements was generally high. Comparing to the repeat annotation by a medical oncologist blinded to the database (100 patients/samples), reproducibility of annotations was high; T stage, metastasis date, and presenceand date of castration resistance had lower reproducibility. Impact of measurement error on estimates for strong prognostic factors was modest. With a prostate cancer-specific data dictionary and quality control measures, manual clinical annotations by a multidisciplinary team can be scalable and reproducible. The data dictionary and the R package for reproducible data processing are freely available to increase data quality and efficiency in clinical prostate cancer research.

Targeting cyclin-dependent kinase 7-association between CDK7 and pMED1 expression in prostate cancer tissue.

Cyclin-dependent kinase (CDK) 7-mediated phosphorylation of Mediator-complex subunit 1 (MED1) enhances androgen receptor (AR) activity in prostate cancer (PCa). Hyperactive AR-signalling plays a key role for the development of castration resistance. Several CDK7 inhibitors are currently under investigation in Phase I/II trials addressing solid tumours, including PCa. Aim of this study was to characterize the CDK7/phospho-(p)MED1 axis in human tissue. Immunohistochemistry was performed on 595 PCa samples including 394 primary tumour foci obtained by radical prostatectomy (RP), 64 advanced or recurrent tumours obtained by palliative transurethral resection of the prostate (pTUR), 65 lymph node metastases (LNM), 35 distant metastases (DM) and 36 benign samples. CDK7 is expressed in 79.3% of PCa tissues and protein levels are significantly higher in LNM, pTUR and DM and lower in benign tissues compared to primary tumours. CDK7 and pMED1 expression show strong positive correlation. High expression of CDK7 associated with shorter 5-year biochemical recurrence-free-survival (63.0% vs. 85.0%) and reduced survival persists when adjusted for T-Stage, nodal status, resection boundaries, grade group and pre-operative prostate-specific antigen in multivariate Cox-regression (hazard ratio 4.30; 95% CI, 1.43 to 12,40, P = 0.007). High CDK7 and pMED1 levels correlate with nuclear AR expression. CDK7 positive tumours harbour higher Ki67 expression indices and show more frequently positive ERG (ETS-related gene)-status. In conclusion, CDK7 is frequently expressed in human PCa and predicts disease recurrence after RP. Therapeutical inhibition of CDK7 might be a promising approach in treatment of advanced PCa.

PD07-04 PRE-CLINICAL STUDIES FOR ADVANCING CIRMTUZUMAB-BASED ANTI-ROR1 THERAPIES IN METASTATIC PROSTATE CANCER

You have accessJournal of UrologyCME1 May 2022PD07-04 PRE-CLINICAL STUDIES FOR ADVANCING CIRMTUZUMAB-BASED ANTI-ROR1 THERAPIES IN METASTATIC PROSTATE CANCER Michelle Muldong, Sanghee Lee, Theresa Mendoza, Danielle Burner, Christina Wu, Jamillah Murtadha, Evodie Koutouan, Naomi Pineda, Gabriel Pineda, Kathleen Lennon, Hao Pham, Karl Willert, Nicholas Cacalano, Catriona Jamieson, Terry Gaasterland, Christopher Kane, Anna Kulidjian, and Christina Jamieson Michelle MuldongMichelle Muldong More articles by this author , Sanghee LeeSanghee Lee More articles by this author , Theresa MendozaTheresa Mendoza More articles by this author , Danielle BurnerDanielle Burner More articles by this author , Christina WuChristina Wu More articles by this author , Jamillah MurtadhaJamillah Murtadha More articles by this author , Evodie KoutouanEvodie Koutouan More articles by this author , Naomi PinedaNaomi Pineda More articles by this author , Gabriel PinedaGabriel Pineda More articles by this author , Kathleen LennonKathleen Lennon More articles by this author , Hao PhamHao Pham More articles by this author , Karl WillertKarl Willert More articles by this author , Nicholas CacalanoNicholas Cacalano More articles by this author , Catriona JamiesonCatriona Jamieson More articles by this author , Terry GaasterlandTerry Gaasterland More articles by this author , Christopher KaneChristopher Kane More articles by this author , Anna KulidjianAnna Kulidjian More articles by this author , and Christina JamiesonChristina Jamieson More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002526.04AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Increased levels of the Wnt ligand, WNT5A, are correlated with bone metastatic, castrate resistant PCa (CRPC). Wnt signaling is comprised of canonical (β-catenin dependent) and noncanonical pathways which are critical for normal development and physiology. Alterations are frequently associated with tumorigenesis and metastasis in many cancers including prostate cancer. Noncanonical Wnt5A signaling is mediated in part through ROR1, a fetal oncoprotein for which a therapeutic ROR1 inhibitory antibody, Cirmtuzumab, has been developed. Its safety has been clinically proven in trials for chronic lymphocytic leukemia (CLL) and metastatic breast cancer.Hypothesis: WNT5A may activate a stem-cell-like program via ROR1 that leads to castration resistance in bone metastatic prostate cancer. The anti-ROR1 biologic, Cirmtuzumab, may inhibit this mechanism of CRPC and re-sensitize bone metastatic prostate cancer to standard of care therapies. METHODS: We used patient-derived xenograft (PDX) bone metastatic prostate cancer models and PCa cell lines to test mechanism of action of a new therapeutic target, the WNT5A/ROR1 signaling pathway in prostate cancer for which a therapeutic ROR1 inhibitor antibody, Cirmtuzumab, has been developed and clinically tested in CLL and metastatic breast cancer patients. RESULTS: Preclinical studies using RNASeq, qRT-PCR, FACS and Westerns showed increased expression of ROR1 in the neuroendocrine prostate cancer cell lines, PC3 and DU145, and a patient derived xenograft (PDX) model of small cell bone metastatic prostate cancer, PCSD13. Pretreatment of the PCSD13 PDX with Cirmtuzumab increased the efficacy of the taxane docetaxel at inhibiting tumor growth. Intravenous infusion of anti-ROR1 CAR-T cells into mice bearing subcutaneous, ROR1-expressing, PC3 xenografts, showed marked reduction in tumor growth. ROR1 Knock out using CRISPR-Cas9 in PC3 and DU145 cells showed specificity of Cirmtuzumab-based immunotherapies. We have developed immunohistochemistry (IHC) assays to detect ROR1 in patient biopsy samples which will allow us to define the prostate cancer patient population that expressed ROR1 and to be able to evaluate the treatment in patients for a future clinical trial. CONCLUSIONS: ROR1 was expressed at high levels on castration resistant small cell PCa and neuroendocrine PCa models in PCa cell lines and PDX models. Cirmtuzumab has demonstrated efficacy in our patient derived xenograft organoid cultures. These studies have formed the rationale for development of a Phase 1b clinical trial of Cirmtuzumab in combination with docetaxel in metastatic CRPC patients. Source of Funding: Dept of Defense CDMRP PCRP Impact Award, JM Foundation © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e99 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Michelle Muldong More articles by this author Sanghee Lee More articles by this author Theresa Mendoza More articles by this author Danielle Burner More articles by this author Christina Wu More articles by this author Jamillah Murtadha More articles by this author Evodie Koutouan More articles by this author Naomi Pineda More articles by this author Gabriel Pineda More articles by this author Kathleen Lennon More articles by this author Hao Pham More articles by this author Karl Willert More articles by this author Nicholas Cacalano More articles by this author Catriona Jamieson More articles by this author Terry Gaasterland More articles by this author Christopher Kane More articles by this author Anna Kulidjian More articles by this author Christina Jamieson More articles by this author Expand All Advertisement PDF DownloadLoading ...

Gremlin1 is a therapeutically targetable FGFR1 ligand that regulates lineage plasticity and castration resistance in prostate cancer.

Among the greatest hurdles in clinical management of prostate cancer (PCa) are the progression to lethal castration-resistant prostate cancer (CRPC) and the lack of suitable targeted therapies for advanced disease. Here we identify Gremlin1 as a ligand for fibroblast growth factor receptor 1 (FGFR1), which promotes lineage plasticity and drives castration resistance. Importantly, we generate a specific anti-Gremlin1 therapeutic antibody and demonstrate synergistic effect with androgen deprivation therapy (ADT) in CRPC. GREM1 transcription is suppressed by androgen receptor (AR) and released following ADT. We show that Gremlin1 binds to FGFR1 and activates downstream MAPK signaling. Gremlin1 interacts with FGFR1 differently to its canonical ligand FGF1, as revealed through protein structure docking and mutagenesis experiments. Altogether, our data indicate Gremlin1 as a promising candidate therapeutic target for CRPC.

The cost impact of disease progression to metastatic castration-sensitive prostate cancer.

BACKGROUND: Metastatic prostate cancer (PC) is associated with declining survival rates and increased health care expenditure. However, there are few studies quantifying these increased costs. OBJECTIVE: To estimate overall health care resource utilization and costs associated with progression to metastatic disease in Medicare or commercially insured patients with nonmetastatic castration-sensitive PC (nmCSPC) or previously undiagnosed PC. METHODS: In this retrospective, observational cohort study, we used data from the IBM MarketScan Commercial and MarketScan Medicare Supplemental Databases. Included patients were aged 18 years or older, had 2 or more health care claims associated with a diagnosis of PC, and had a diagnosis of metastatic disease (index date) between January 1, 2014, and December 31, 2016. Patients with PC were identified at index as either progressing from a localized disease state (nmCSPC) without evidence of castration resistance (progressors) or de novo metastatic without a prior PC diagnosis. Unadjusted all-cause direct health care costs for the 2-year pre-index period and up to 2 years post-index were summarized. Metastasis-related incremental all-cause direct health care costs were estimated using regression modeling to adjust for patient baseline characteristics, follow-up duration, and possible selection bias. RESULTS: We identified 3,854 patients who met the criteria for CSPC at metastasis: 2,766 Medicare patients (mean age 78.8 ± 7.6 years) and 1,088 commercial patients (mean age 57.6 ± 4.3 years), with de novo patients accounting for 28.9% and 34.5% of the 2 analysis populations, respectively. Mean unadjusted total all-cause health care costs over the 24-month pre-index period among progressors were $52,661 (Medicare) and $43,111 (commercial); those among de novo patients were $39,756 (Medicare) and $22,090 (commercial). Mean unadjusted post-index costs for progressors were $100,331 (Medicare) and $127,374 (commercial) over a mean follow-up duration of 14.63 and 18.41 months, respectively, and $124,538 (Medicare) and $173,408 (commercial) over a mean follow-up duration of 14.14 and 17.29 months for patients with de novo disease. After multivariate adjustment, incremental cost increases due to metastasis in patients with CSPC pre-index were estimated at $104,051 (Medicare) and $93,334 (commercial), assuming data are available for 24 months post-index. Allowing for variation in the postindex observation period, estimates were $71,308 (Medicare) and $82,336 (commercial). Among de novo patients, cost increases due to metastasis were estimated at $180,932 (Medicare) and $215,397 (commercial), assuming all patients have data for 24 months postindex. Allowing for variable follow-up, estimates were $113,253 (Medicare) and $161,714 (commercial). CONCLUSIONS: Development of metastatic CSPC is associated with considerable costs over a 24-month follow-up period. Cost increases are greater for de novo patients than for those who progressed from localized disease. DISCLOSURES: Q.-D. Trinh received personal fees from Astellas, Bayer, and Janssen and grants from Intuitive Surgical. L. Passos Chaves, Q. Feng, J. Zhu, and T. Abbott are employees of Astellas Pharma Global Development, Inc. R. Sandin is an employee of, and holds stock in, Pfizer AB. This study was funded by Astellas Pharma Inc. (Northbrook, IL) and Pfizer Inc., the codevelopers of enzalutamide. Astellas Pharma Inc. was involved in the study design, data collection, analysis, interpretation of data, and decision to present these results.

MP51-09 THE UTILITY OF NOVEL QUANTIFICATION USING IMAGING SOFTWARE FOR ANALYZING WHOLE-BODY MAGNETIC RESONANCE IMAGING OF PATIENTS WITH METASTATIC PROSTATE CANCER

You have accessJournal of UrologyCME1 May 2022MP51-09 THE UTILITY OF NOVEL QUANTIFICATION USING IMAGING SOFTWARE FOR ANALYZING WHOLE-BODY MAGNETIC RESONANCE IMAGING OF PATIENTS WITH METASTATIC PROSTATE CANCER Yuki Kohada, Nozomi Satani, Yasuhiro Kaiho, Hiromichi Iwamura, Takashi Kukimoto, Masaaki Oikawa, Jun Ito, Tomonori Matsuura, Nobuyuki Hinata, Kaneki Koyama, and Makoto Sato Yuki KohadaYuki Kohada More articles by this author , Nozomi SataniNozomi Satani More articles by this author , Yasuhiro KaihoYasuhiro Kaiho More articles by this author , Hiromichi IwamuraHiromichi Iwamura More articles by this author , Takashi KukimotoTakashi Kukimoto More articles by this author , Masaaki OikawaMasaaki Oikawa More articles by this author , Jun ItoJun Ito More articles by this author , Tomonori MatsuuraTomonori Matsuura More articles by this author , Nobuyuki HinataNobuyuki Hinata More articles by this author , Kaneki KoyamaKaneki Koyama More articles by this author , and Makoto SatoMakoto Sato More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002626.09AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: We developed a novel quantification method that can automatically exclude the red bone marrow. This study assessed the utility of this novel method for accurately quantifying tumor volume (TV) and predicting the prognosis of patients with metastatic hormone sensitive prostate cancer (mHSPC) and metastatic castration resistance prostate cancer (mCRPC). METHODS: This was a prospective single-institution analysis of data acquired from patients diagnosed with mHSPC or mCRPC between 2017 and 2021. We developed a new function that automatically excluded the red bone marrow by analyzing whole-body diffusion-weighted imaging (DWI) and in-phase and opposed-phase T1-weighted imaging and integrated it into the original imaging software (Attractive BD_Score). The conventional quantification method estimates TV by analyzing whole-body DWI and does not exclude the red bone marrow. To assessed the prognostic value, prostate-specific antigen progression-free survival (PSA-PFS), time to pain progression (TPP), and overall survival were evaluated. RESULTS: Twenty-six patients with mHSPC and fourteen patients with mCRPC were included. A case that compares the novel and conventional quantification method is shown in Fig. 1. TV quantified using the novel quantification method was smaller than that by the conventional quantification in both mHSPC (median, 69.8 mL vs. 145.7 mL) and mCRPC (median, 38.7 mL vs. 56.9 mL). High TV, as measured using the new method, was significantly associated with poor PSA-PFS in patients with mHSPC (Fig. 2) and mCRPC and with poor TPP in patients with mHSPC (p<0.05). CONCLUSIONS: The novel quantification method could automatically exclude the red bone marrow, accurately quantify the TV, and help predict prognosis in patients with mHSPC and mCRPC. Source of Funding: None © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e878 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Yuki Kohada More articles by this author Nozomi Satani More articles by this author Yasuhiro Kaiho More articles by this author Hiromichi Iwamura More articles by this author Takashi Kukimoto More articles by this author Masaaki Oikawa More articles by this author Jun Ito More articles by this author Tomonori Matsuura More articles by this author Nobuyuki Hinata More articles by this author Kaneki Koyama More articles by this author Makoto Sato More articles by this author Expand All Advertisement PDF DownloadLoading ...

MP27-15 SABIZABULIN HAS BOTH CYTOTOXIC AND CYTOSTATIC ACTIVITY IN PHASE 1B/2 CLINICAL OF MEN WITH METASTATIC CASTRATION RESISTANT PROSTATE CANCER WHO PROGRESSED ON ANDROGEN RECEPTOR TARGETING AGENTS

You have accessJournal of UrologyCME1 May 2022MP27-15 SABIZABULIN HAS BOTH CYTOTOXIC AND CYTOSTATIC ACTIVITY IN PHASE 1B/2 CLINICAL OF MEN WITH METASTATIC CASTRATION RESISTANT PROSTATE CANCER WHO PROGRESSED ON ANDROGEN RECEPTOR TARGETING AGENTS Mark Markowski, Mario Eisenberger, Christopher Pieczonka, Robert Getzenberg, Domingo Rodriguez, K. Gary Barnette, MItchell Steiner, Daniel Saltzstein, Emmanuel Antonarakis, and Ronald Tutrone Mark MarkowskiMark Markowski More articles by this author , Mario EisenbergerMario Eisenberger More articles by this author , Christopher PieczonkaChristopher Pieczonka More articles by this author , Robert GetzenbergRobert Getzenberg More articles by this author , Domingo RodriguezDomingo Rodriguez More articles by this author , K. Gary BarnetteK. Gary Barnette More articles by this author , MItchell SteinerMItchell Steiner More articles by this author , Daniel SaltzsteinDaniel Saltzstein More articles by this author , Emmanuel AntonarakisEmmanuel Antonarakis More articles by this author , and Ronald TutroneRonald Tutrone More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002570.15AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Sabizabulin is a novel oral cytoskeleton disruptor being developed for use in metastatic castration resistant prostate cancer (mCRPC). A Phase 1b/2 clinical study was conducted to establish the maximum tolerated dose (MTD) and evaluate the preliminary efficacy in men with mCRPC resistant to androgen receptor targeting agents (ARTAs). METHODS: The Phase 1b portion of the study in 39 men utilized escalating and expanding dose and duration. The Phase 2 portion studied 41 men with mCRPC at the recommended Phase 2 dose (RP2D) of 63 mg daily. Based upon the Phase 1b/2 data, sabizabulin appears to have both cytotoxic and cytostatic activity. A analysis was conducted evaluating the best clinical response (BCR) defined as either an objective response assessed by PCWG3 criteria and/or stable disease defined as > 5 cycles ( > 15 weeks) of continuous treatment. RESULTS: Of the combined 80 patients in the Phase 1b/2 portions of the study, the BCR was 37.5% (30/80) and 5 of the responders remain on study with the longest being treated for more than 30 months. Of the patients with measurable disease at study entry, the BCR was 59% (17/29). Prior to study entry, 11/30 (37%) of those with a BCR had previously been treated with and subsequently progressed on a minimum of 2 ARTAs. The remaining 19/30 (63%) had progressed on a single ARTA agent. 11 (37%) were previously treated with enzalutamide or apalutamide and 8 (27%) with abiraterone as single agents. 8 (27%) received enzalutamide and abiraterone and 3 (10%) patients received more than two ARTAs. As described previously, the safety profile continues to be favorable with no clinically relevant neutropenia or neurotoxicity and the most commonly observed adverse events being gastrointestinal in nature. CONCLUSIONS: In this analysis, sabizabulin has demonstrated not only cytotoxic, but also significant cytostatic activity with similar responses in men that have progressed on a single or multiple ARTA agents. Sabizabulin is a novel agent with the potential provide men with mCRPC a well-tolerated chronic treatment cytostatic option after progressing on an ARTA and is being tested in the open Phase 3 VERACITY trial. Source of Funding: Veru Inc © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e456 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Mark Markowski More articles by this author Mario Eisenberger More articles by this author Christopher Pieczonka More articles by this author Robert Getzenberg More articles by this author Domingo Rodriguez More articles by this author K. Gary Barnette More articles by this author MItchell Steiner More articles by this author Daniel Saltzstein More articles by this author Emmanuel Antonarakis More articles by this author Ronald Tutrone More articles by this author Expand All Advertisement PDF DownloadLoading ...

Current Trends in Advanced Prostate Cancer Medical Setting

Abstract Treatment of advanced and metastatic prostate carcinoma (PCa) is still challenging and changing in the era of personalised medicine. Combination therapies with docetaxel and new anti-hormonal substances lead to improved OS (overall survival) in a broad group of patients with metastatic hormone sensitive prostate carcinoma (mHSPCa). Addition of docetaxel or an androgen receptor targeting agent (ARTA) with abiraterone plus prednisolone, with apalutamide or with enzalutamide leads to a significant improvement in OS and an increase in the time to transition to castration resistance. The choice of therapy sequence in advanced PCa should be based, among other things, on the side-effect profiles of the substances and patient’s preferences. Within metastatic castration resistant prostate carcinoma (mCRPCa) setting, the therapy with abiraterone, enzalutamide, docetaxel, cabazitaxel and radium-223 is approved and indicated in Europe. Respectively, five substances are available, each of which has led to a significant increase in survival time in phase III studies. The optimal therapy sequence in the mCRPCa stage is still unclear. The current trend in personalised medicine in the next decade in therapy, regarding prostate carcinoma, are poly(ADP)-ribose polymerase (PARP) inhibitors, which are and will be available as an effective therapy option for patients with mutations in DNA repair genes. The most important question is when and how patients should be tested for mutations in DNA repair genes and to which line of therapy will PARP inhibitors belong.

Comprehensive genomics in androgen receptor-dependent castration-resistant prostate cancer identifies an adaptation pathway mediated by opioid receptor kappa 1

Castration resistance is a lethal form of treatment failure of prostate cancer (PCa) and is associated with ligand-independent activation of the androgen receptor (AR). It is only partially understood how the AR mediates survival and castration-resistant growth of PCa upon androgen deprivation. We investigated integrative genomics using a patient-derived xenograft model recapitulating acquired, AR-dependent castration-resistant PCa (CRPC). Sequencing of chromatin immunoprecipitation using an anti-AR antibody (AR-ChIP seq) revealed distinct profiles of AR binding site (ARBS) in androgen-dependent and castration-resistant xenograft tumors compared with those previously reported based on human PCa cells or tumor tissues. An integrative genetic analysis identified several AR-target genes associated with CRPC progression including OPRK1, which harbors ARBS and was upregulated upon androgen deprivation. Loss of function of OPRK1 retarded the acquisition of castration resistance and inhibited castration-resistant growth of PCa both in vitro and in vivo. Immunohistochemical analysis showed that expression of OPRK1, a G protein-coupled receptor, was upregulated in human prostate cancer tissues after preoperative androgen derivation or CRPC progression. These data suggest that OPRK1 is involved in post-castration survival and cellular adaptation process toward castration-resistant progression of PCa, accelerating the clinical implementation of ORPK1-targeting therapy in the management of this lethal disease.