Publications by authors named "Martin Gleave"

483 Publications

Prognosis Associated With Luminal and Basal Subtypes of Metastatic Prostate Cancer.

JAMA Oncol 2021 Sep 23. Epub 2021 Sep 23.

Department of Human Oncology, University of Wisconsin, Madison.

Importance: Luminal and basal subtypes of primary prostate cancer have been shown to be molecularly distinct and clinically important in predicting response to therapy. These subtypes have not been described in metastatic prostate cancer.

Objectives: To identify clinical and molecular correlates of luminal and basal subtypes in metastatic castration-resistant prostate cancer (mCRPC) and investigate differences in survival, particularly after treatment with androgen-signaling inhibitors (ASIs).

Design, Setting, And Participants: In this cohort study, a retrospective analysis was conducted of 4 cohorts with mCRPC (N = 634) across multiple academic centers. Treatment was at the physicians' discretion. Details of the study cohorts have been published elsewhere between 2016 and 2019. Data were analyzed from March 2018 to February 2021.

Main Outcomes And Measures: The primary clinical end point was overall survival from the date of tissue biopsy/molecular profiling. Luminal and basal subtypes were also stratified by postbiopsy ASI treatment. The primary molecular analyses included associations with small cell/neuroendocrine prostate cancer (SCNC), molecular pathways, and DNA alterations.

Results: In the 634 patients, 288 (45%) had tumors classified as luminal, and 346 (55%) had tumors classified as basal. However, 53 of 59 (90%) SCNC tumors were basal (P < .001). Similar to primary prostate cancer, luminal tumors exhibited overexpression of AR pathway genes. In basal tumors, a significantly higher rate of RB1 loss (23% basal vs 4% luminal; P < .001), FOXA1 alterations (36% basal vs 27% luminal; P = .03) and MYC alterations (73% basal vs 56% luminal; P < .001) were identified. Patients with basal tumors had worse overall survival compared with those with luminal tumors only in patients treated with an ASI postbiopsy (East Coast Dream Team: hazard ratio [HR], 0.39; 95% CI, 0.20-0.74; P = .004; West Coast Dream Team: HR, 0.57; 95% CI, 0.33-0.97; P = .04). Among patients with luminal tumors, those treated with an ASI had significantly better survival (HR, 0.27; 95% CI, 0.14-0.53; P < .001), whereas patients with basal tumors did not (HR, 0.62; 95% CI, 0.36-1.04, P = .07). The interaction term between subtype and ASI treatment was statistically significant (HR, 0.42; 95% CI, 0.20-0.89; P = .02).

Conclusions And Relevance: These findings represent the largest integrated clinical, transcriptomic, and genomic analysis of mCRPC samples to date, and suggest that mCRPC can be classified as luminal and basal tumors. Analogous to primary prostate cancer, these data suggest that the benefit of ASI treatment is more pronounced in luminal tumors and support the use of ASIs in this population. In the basal tumors, a chemotherapeutic approach could be considered in some patients given the similarity to SCNC and the diminished benefit of ASI therapy. Further validation in prospective clinical trials is warranted.
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http://dx.doi.org/10.1001/jamaoncol.2021.3987DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8461554PMC
September 2021

Treatment in the absence of disease reclassification among men on active surveillance for prostate cancer.

Cancer 2021 Sep 13. Epub 2021 Sep 13.

Department of Urology, University of Washington, Seattle, Washington.

Background: Maintaining men on active surveillance for prostate cancer can be challenging. Although most men who eventually undergo treatment have experienced clinical progression, a smaller subset elects treatment in the absence of disease reclassification. This study sought to understand factors associated with treatment in a large, contemporary, prospective cohort.

Methods: This study identified 1789 men in the Canary Prostate Cancer Active Surveillance Study cohort enrolled as of 2020 with a median follow-up of 5.6 years. Clinical and demographic data as well as information on patient-reported quality of life and urinary symptoms were used in multivariable Cox proportional hazards regression models to identify factors associated with the time to treatment RESULTS: Within 4 years of their diagnosis, 33% of men (95% confidence interval [CI], 30%-35%) underwent treatment, and 10% (95% CI, 9%-12%) were treated in the absence of reclassification. The most significant factor associated with any treatment was an increasing Gleason grade group (adjusted hazard ratio [aHR], 14.5; 95% CI, 11.7-17.9). Urinary quality-of-life scores were associated with treatment without reclassification (aHR comparing "mostly dissatisfied/terrible" with "pleased/mixed," 2.65; 95% CI, 1.54-4.59). In a subset analysis (n = 692), married men, compared with single men, were more likely to undergo treatment in the absence of reclassification (aHR, 2.63; 95% CI, 1.04-6.66).

Conclusions: A substantial number of men with prostate cancer undergo treatment in the absence of clinical changes in their cancers, and quality-of-life changes and marital status may be important factors in these decisions.

Lay Summary: This analysis of men on active surveillance for prostate cancer shows that approximately 1 in 10 men will decide to be treated within 4 years of their diagnosis even if their cancer is stable. These choices may be related in part to quality-or-life or spousal concerns.
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http://dx.doi.org/10.1002/cncr.33911DOI Listing
September 2021

An androgen receptor switch underlies lineage infidelity in treatment-resistant prostate cancer.

Nat Cell Biol 2021 09 6;23(9):1023-1034. Epub 2021 Sep 6.

Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.

Cancers adapt to increasingly potent targeted therapies by reprogramming their phenotype. Here we investigated such a phenomenon in prostate cancer, in which tumours can escape epithelial lineage confinement and transition to a high-plasticity state as an adaptive response to potent androgen receptor (AR) antagonism. We found that AR activity can be maintained as tumours adopt alternative lineage identities, with changes in chromatin architecture guiding AR transcriptional rerouting. The epigenetic regulator enhancer of zeste homologue 2 (EZH2) co-occupies the reprogrammed AR cistrome to transcriptionally modulate stem cell and neuronal gene networks-granting privileges associated with both fates. This function of EZH2 was associated with T350 phosphorylation and establishment of a non-canonical polycomb subcomplex. Our study provides mechanistic insights into the plasticity of the lineage-infidelity state governed by AR reprogramming that enabled us to redirect cell fate by modulating EZH2 and AR, highlighting the clinical potential of reversing resistance phenotypes.
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http://dx.doi.org/10.1038/s41556-021-00743-5DOI Listing
September 2021

A phase 3 randomised study of enzalutamide plus leuprolide and enzalutamide monotherapy in high-risk non-metastatic hormone-sensitive prostate cancer with rising PSA after local therapy: EMBARK study design.

BMJ Open 2021 08 12;11(8):e046588. Epub 2021 Aug 12.

Carolina Urologic Research Center, Myrtle Beach, South Carolina, USA.

Introduction: Limited data from controlled clinical trials are available for men who experience biochemical recurrence after definitive therapy for prostate cancer. In the absence of overt metastases, patients with non-metastatic castration-sensitive prostate cancer (nmCSPC) often receive androgen deprivation therapy (ADT). There is no standard-of-care consensus on optimal ADT timing, although most men are treated prior to metastases, especially those with high-risk features (Gleason score 8-10 or prostate-specific antigen doubling time (PSADT) <9-12 months). Given data that ADT plus novel hormonal agents improve survival in men with metastatic CSPC, there is a desire to evaluate these agents earlier in the disease course. The main objective of EMBARK is the comparative assessment of enzalutamide plus leuprolide (luteinising hormone-releasing hormone agonist (LHRHa)) or enzalutamide monotherapy versus monotherapy LHRHa to improve metastasis-free survival (MFS) in patients with high-risk nmCSPC PSA recurrence after definitive therapy.

Methods And Analysis: EMBARK is a randomised, phase 3 study of high-risk patients with nmCSPC, a PSADT of ≤9 months and a screening PSA of ≥2 ng/mL above the nadir after radiotherapy (RT) or ≥1 ng/mL after radical prostatectomy (RP) with or without postoperative RT. Men (n=1050) are randomised 1:1:1 to enzalutamide 160 mg/day plus LHRHa or placebo plus LHRHa (double-blind arms) or enzalutamide monotherapy (open-label arm). Treatment is suspended at week 37 if PSA concentrations are <0.2 ng/mL and reinstated if levels rise to ≥2.0 ng/mL with RP or ≥5.0 ng/mL without RP. Patients with PSA ≥0.2 ng/mL at week 37 continue until treatment discontinuation criteria are met. The primary endpoint is MFS comparing enzalutamide plus LHRHa versus placebo plus LHRHa.

Ethics And Dissemination: The study is conducted under the guiding principles of the World Medical Association Declaration of Helsinki. The results will be disseminated at research conferences and in peer-reviewed journals.

Trial Registration Number: NCT02319837.
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http://dx.doi.org/10.1136/bmjopen-2020-046588DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8362713PMC
August 2021

Development of an Androgen Receptor Inhibitor Targeting the N-Terminal Domain of Androgen Receptor for Treatment of Castration Resistant Prostate Cancer.

Cancers (Basel) 2021 Jul 12;13(14). Epub 2021 Jul 12.

Vancouver Prostate Centre, University of British Columbia, 2660 Oak Street, Vancouver, BC V6H 3Z6, Canada.

Prostate cancer patients undergoing androgen deprivation therapy almost invariably develop castration-resistant prostate cancer. Resistance can occur when mutations in the androgen receptor (AR) render anti-androgen drugs ineffective or through the expression of constitutively active splice variants lacking the androgen binding domain entirely (e.g., ARV7). In this study, we are reporting the discovery of a novel AR-NTD covalent inhibitor 1-chloro-3-[(5-([(2S)-3-chloro-2-hydroxypropyl]amino)naphthalen-1-yl)amino]propan-2-ol (VPC-220010) targeting the AR-N-terminal Domain (AR-NTD). VPC-220010 inhibits AR-mediated transcription of full length and truncated variant ARV7, downregulates AR response genes, and selectively reduces the growth of both full-length AR- and truncated AR-dependent prostate cancer cell lines. We show that VPC-220010 disrupts interactions between AR and known coactivators and coregulatory proteins, such as CHD4, FOXA1, ZMIZ1, and several SWI/SNF complex proteins. Taken together, our data suggest that VPC-220010 is a promising small molecule that can be further optimized into effective AR-NTD inhibitor for the treatment of CRPC.
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http://dx.doi.org/10.3390/cancers13143488DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8304761PMC
July 2021

High fibroblast-activation-protein expression in castration-resistant prostate cancer supports the use of FAPI-molecular theranostics.

Eur J Nucl Med Mol Imaging 2021 Jul 5. Epub 2021 Jul 5.

Department of Urology, University of Duisburg-Essen, and German Cancer Consortium (DKTK), University Hospital Essen, Hufelandstrasse 55, 45147, Essen, Germany.

Purpose: To evaluate fibroblast-activation-protein (FAP) expression in different clinical stages of prostate cancer (PC) with regards to utility of [ Ga]Ga-FAPI-04 PET/CT imaging in patients with castration-resistant PC (CRPC).

Methods: Tissue microarrays (TMAs) were constructed from prostatic tissue from 94 patients at different stages of PC (primary PC, patients undergoing neoadjuvant androgen deprivation therapy, CRPC, and neuroendocrine PC (NEPC)) and were stained with anti-FAP monoclonal antibody. A positive pixel count algorithm (H-Index) was used to compare FAP expression between the groups. Additionally, three men with advanced CRPC or NEPC underwent [ Ga]Ga-FAPI-04 PET/CT, and PET positivity was analyzed.

Results: The mean H-index for benign tissue, primary PC, neoadjuvant androgen deprivation therapy before radical prostatectomy, CRPC, and NEPC was 0.018, 0.031, 0.042, 0.076, and 0.051, respectively, indicating a significant rise in FAP expression with advancement of disease. Corroborating these findings [ Ga]Ga-FAPI-04 PET/CT was highly positive in men with advanced CRPC.

Conclusion: Increased FAP tissue expression supports the use of FAP inhibitor (FAPI)-molecular theranostics in CRPC.
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http://dx.doi.org/10.1007/s00259-021-05423-yDOI Listing
July 2021

Evaluation of Darolutamide (ODM201) Efficiency on Androgen Receptor Mutants Reported to Date in Prostate Cancer Patients.

Cancers (Basel) 2021 Jun 11;13(12). Epub 2021 Jun 11.

Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, 2660 Oak St., Vancouver, BC V6H 3Z6, Canada.

Resistance to drug treatments is common in prostate cancer (PCa), and the gain-of-function mutations in human androgen receptor (AR) represent one of the most dominant drivers of progression to resistance to AR pathway inhibitors (ARPI). Previously, we evaluated the in vitro response of 24 AR mutations, identified in men with castration-resistant PCa, to five AR antagonists. In the current work, we evaluated 44 additional PCa-associated AR mutants, reported in the literature, and thus expanded the study of the effect of darolutamide to a total of 68 AR mutants. Unlike other AR antagonists, we demonstrate that darolutamide exhibits consistent efficiency against all characterized gain-of-function mutations in a full-length AR. Additionally, the response of the AR mutants to clinically used bicalutamide and enzalutamide, as well as to major endogenous steroids (DHT, estradiol, progesterone and hydrocortisone), was also investigated. As genomic profiling of PCa patients becomes increasingly feasible, the developed "AR functional encyclopedia" could provide decision-makers with a tool to guide the treatment choice for PCa patients based on their AR mutation status.
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http://dx.doi.org/10.3390/cancers13122939DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8230763PMC
June 2021

Evolution of Castration-Resistant Prostate Cancer in ctDNA during Sequential Androgen Receptor Pathway Inhibition.

Clin Cancer Res 2021 Aug 3;27(16):4610-4623. Epub 2021 Jun 3.

Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, British Columbia, Canada.

Purpose: Cross-resistance renders multiple lines of androgen receptor (AR) signaling inhibitors increasingly futile in metastatic castration-resistant prostate cancer (mCRPC). We sought to determine acquired genomic contributors to cross-resistance.

Experimental Design: We collected 458 serial plasma cell-free DNA samples at baseline and progression timepoints from 202 patients with mCRPC receiving sequential AR signaling inhibitors (abiraterone and enzalutamide) in a randomized phase II clinical trial (NCT02125357). We utilized deep targeted and whole-exome sequencing to compare baseline and posttreatment somatic genomic profiles in circulating tumor DNA (ctDNA).

Results: Patient ctDNA abundance was correlated across plasma collections and independently prognostic for sequential therapy response and overall survival. Most driver alterations in established prostate cancer genes were consistently detected in ctDNA over time. However, shifts in somatic populations after treatment were identified in 53% of patients, particularly after strong treatment responses. Treatment-associated changes converged upon the gene, with an average 50% increase in copy number, changes in mutation frequencies, and a 2.5-fold increase in the proportion of patients carrying AR ligand binding domain truncating rearrangements.

Conclusions: Our data show that the dominant genotype continues to evolve during sequential lines of AR inhibition and drives acquired resistance in patients with mCRPC.
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http://dx.doi.org/10.1158/1078-0432.CCR-21-1625DOI Listing
August 2021

Phase 3 Randomized Controlled Trial of Androgen Deprivation Therapy with or Without Docetaxel in High-risk Biochemically Recurrent Prostate Cancer After Surgery (TAX3503).

Eur Urol Oncol 2021 Aug 18;4(4):543-552. Epub 2021 May 18.

Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Medicine, Weill Cornell Medical College, New York, NY, USA.

Background: No standard of care exists for patients with high-risk biochemical recurrence (BCR) after prostatectomy.

Objective: To evaluate whether addition of docetaxel to androgen deprivation therapy (ADT) improved progression-free survival (PFS) in high-risk BCR patients.

Design, Setting, And Participants: TAX3503 was a multicenter phase 3 trial that randomized patients with high-risk BCR to ADT for 18 mo ± docetaxel (75 mg/m q3w for ten cycles). Eligibility included prostate-specific antigen (PSA) ≥1.0 ng/ml after prostatectomy alone or after postoperative radiation therapy, PSA doubling time ≤9 mo, and absence of metastases on computed tomography and bone scintigraphy.

Outcome Measurements And Statistical Analysis: The primary endpoint was PFS following testosterone recovery to noncastrate levels (testosterone >50 ng/dl). Secondary endpoints included time to testosterone recovery, overall survival (OS), quality of life, and safety.

Results And Limitations: Between September 2007 and May 2011, 413 patients were assigned to ADT ± docetaxel. In 2012, following completion of accrual and treatment, the sponsor withdrew support of the study, and in 2013, a registry was created to secure the primary endpoint. The final analysis included data from the original trial and registry. At a median follow-up of 33.6 mo, 260 patients demonstrated testosterone recovery, which occurred similarly between groups. ADT plus docetaxel trended toward a nonclinically meaningful improvement in PFS (median 26.2 vs 24.7 mo) for the testosterone-recovered population (218 events, hazard ratio [HR] 0.80, 95% confidence interval [CI] 0.61-1.04) and in OS for the intention-to-treat population (medians not reached, HR 0.51, 95% CI 0.23-1.10). Grade ≥3 adverse events occurred more frequently in the ADT plus docetaxel group (48.0% vs 10.8%).

Conclusions: TAX3503 did not demonstrate a meaningful benefit of adding docetaxel to ADT in patients with high-risk BCR. Testosterone recovery was unaffected by addition of docetaxel to ADT.

Patient Summary: Addition of docetaxel to androgen deprivation therapy did not meaningfully improve outcomes for men with high-risk biochemically recurrent prostate cancer.
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http://dx.doi.org/10.1016/j.euo.2021.04.008DOI Listing
August 2021

SLFN5 Regulates LAT1-Mediated mTOR Activation in Castration-Resistant Prostate Cancer.

Cancer Res 2021 Jul 13;81(13):3664-3678. Epub 2021 May 13.

CRUK Beatson Institute, Garscube Estate, Glasgow, United Kingdom.

Androgen deprivation therapy (ADT) is the standard of care for treatment of nonresectable prostate cancer. Despite high treatment efficiency, most patients ultimately develop lethal castration-resistant prostate cancer (CRPC). In this study, we performed a comparative proteomic analysis of three , androgen receptor (AR)-responsive orthograft models of matched hormone-naïve prostate cancer and CRPC. Differential proteomic analysis revealed that distinct molecular mechanisms, including amino acid (AA) and fatty acid metabolism, are involved in the response to ADT in the different models. Despite this heterogeneity, Schlafen family member 5 (SLFN5) was identified as an AR-regulated protein in CRPC. SLFN5 expression was high in CRPC tumors and correlated with poor patient outcome. depletion strongly impaired tumor growth in castrated conditions. Mechanistically, SLFN5 interacted with ATF4 and regulated the expression of LAT1, an essential AA transporter. Consequently, depletion in CRPC cells decreased intracellular levels of essential AA and impaired mTORC1 signaling in a LAT1-dependent manner. These results confirm that these orthograft models recapitulate the high degree of heterogeneity observed in patients with CRPC and further highlight SLFN5 as a clinically relevant target for CRPC. SIGNIFICANCE: This study identifies SLFN5 as a novel regulator of the LAT1 amino acid transporter and an essential contributor to mTORC1 activity in castration-resistant prostate cancer.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-3694DOI Listing
July 2021

Functional mapping of androgen receptor enhancer activity.

Genome Biol 2021 05 11;22(1):149. Epub 2021 May 11.

Vancouver Prostate Centre, Department of Urologic Science, University of British Columbia, Vancouver, Canada.

Background: Androgen receptor (AR) is critical to the initiation, growth, and progression of prostate cancer. Once activated, the AR binds to cis-regulatory enhancer elements on DNA that drive gene expression. Yet, there are 10-100× more binding sites than differentially expressed genes. It is unclear how or if these excess binding sites impact gene transcription.

Results: To characterize the regulatory logic of AR-mediated transcription, we generated a locus-specific map of enhancer activity by functionally testing all common clinical AR binding sites with Self-Transcribing Active Regulatory Regions sequencing (STARRseq). Only 7% of AR binding sites displayed androgen-dependent enhancer activity. Instead, the vast majority of AR binding sites were either inactive or constitutively active enhancers. These annotations strongly correlated with enhancer-associated features of both in vitro cell lines and clinical prostate cancer samples. Evaluating the effect of each enhancer class on transcription, we found that AR-regulated enhancers frequently interact with promoters and form central chromosomal loops that are required for transcription. Somatic mutations of these critical AR-regulated enhancers often impact enhancer activity.

Conclusions: Using a functional map of AR enhancer activity, we demonstrated that AR-regulated enhancers act as a regulatory hub that increases interactions with other AR binding sites and gene promoters.
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http://dx.doi.org/10.1186/s13059-021-02339-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8112059PMC
May 2021

Development of Novel Inhibitors Targeting the D-Box of the DNA Binding Domain of Androgen Receptor.

Int J Mol Sci 2021 Mar 2;22(5). Epub 2021 Mar 2.

Vancouver Prostate Centre, University of British Columbia, 2660 Oak Street, Vancouver, BC V6H 3Z6, Canada.

The inhibition of the androgen receptor (AR) is an established strategy in prostate cancer (PCa) treatment until drug resistance develops either through mutations in the ligand-binding domain (LBD) portion of the receptor or its deletion. We previously identified a druggable pocket on the DNA binding domain (DBD) dimerization surface of the AR and reported several potent inhibitors that effectively disrupted DBD-DBD interactions and consequently demonstrated certain antineoplastic activity. Here we describe further development of small molecule inhibitors of AR DBD dimerization and provide their broad biological characterization. The developed compounds demonstrate improved activity in the mammalian two-hybrid assay, enhanced inhibition of AR-V7 transcriptional activity, and improved microsomal stability. These findings position us for the development of AR inhibitors with entirely novel mechanisms of action that would bypass most forms of PCa treatment resistance, including the truncation of the LBD of the AR.
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http://dx.doi.org/10.3390/ijms22052493DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7958344PMC
March 2021

A noncanonical AR addiction drives enzalutamide resistance in prostate cancer.

Nat Commun 2021 03 9;12(1):1521. Epub 2021 Mar 9.

Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine and Science, Rochester, MN, USA.

Resistance to next-generation anti-androgen enzalutamide (ENZ) constitutes a major challenge for the treatment of castration-resistant prostate cancer (CRPC). By performing genome-wide ChIP-seq profiling in ENZ-resistant CRPC cells we identify a set of androgen receptor (AR) binding sites with increased AR binding intensity (ARBS-gained). While ARBS-gained loci lack the canonical androgen response elements (ARE) and pioneer factor FOXA1 binding motifs, they are highly enriched with CpG islands and the binding sites of unmethylated CpG dinucleotide-binding protein CXXC5 and the partner TET2. RNA-seq analysis reveals that both CXXC5 and its regulated genes including ID1 are upregulated in ENZ-resistant cell lines and these results are further confirmed in patient-derived xenografts (PDXs) and patient specimens. Consistent with the finding that ARBS-gained loci are highly enriched with H3K27ac modification, ENZ-resistant PCa cells, organoids, xenografts and PDXs are hyper-sensitive to NEO2734, a dual inhibitor of BET and CBP/p300 proteins. These results not only reveal a noncanonical AR function in acquisition of ENZ resistance, but also posit a treatment strategy to target this vulnerability in ENZ-resistant CRPC.
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http://dx.doi.org/10.1038/s41467-021-21860-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7943793PMC
March 2021

Androgen receptor (AR) antagonism triggers acute succinate-mediated adaptive responses to reactivate AR signaling.

EMBO Mol Med 2021 May 11;13(5):e13427. Epub 2021 Mar 11.

Vancouver Prostate Centre, Vancouver, BC, Canada.

Treatment-induced adaptive pathways converge to support androgen receptor (AR) reactivation and emergence of castration-resistant prostate cancer (PCa) after AR pathway inhibition (ARPI). We set out to explore poorly defined acute adaptive responses that orchestrate shifts in energy metabolism after ARPI and identified rapid changes in succinate dehydrogenase (SDH), a TCA cycle enzyme with well-known tumor suppressor activity. We show that AR directly regulates transcription of its catalytic subunits (SDHA, SDHB) via androgen response elements (AREs). ARPI acutely suppresses SDH activity, leading to accumulation of the oncometabolite, succinate. Succinate triggers calcium ions release from intracellular stores, which in turn phospho-activates the AR-cochaperone, Hsp27 via p-CaMKK2/p-AMPK/p-p38 axis to enhance AR protein stabilization and activity. Activation of this pathway was seen in tissue microarray analysis on prostatectomy tissues and patient-derived xenografts. This adaptive response is blocked by co-targeting AR with Hsp27 under both in vitro and in vivo studies, sensitizing PCa cells to ARPI treatments.
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http://dx.doi.org/10.15252/emmm.202013427DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8103094PMC
May 2021

Discovery of New Catalytic Topoisomerase II Inhibitors for Anticancer Therapeutics.

Front Oncol 2020 1;10:633142. Epub 2021 Feb 1.

The Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada.

Poison inhibitors of DNA topoisomerase II (TOP2) are clinically used drugs that cause cancer cell death by inducing DNA damage, which mechanism of action is also associated with serious side effects such as secondary malignancy and cardiotoxicity. In contrast, TOP2 catalytic inhibitors induce limited DNA damage, have low cytotoxicity, and are effective in suppressing cancer cell proliferation. They have been sought after to be prospective anticancer therapies. Herein the discovery of new TOP2 catalytic inhibitors is described. A new druggable pocket of TOP2 protein at its DNA binding domain was used as a docking site to virtually screen ~6 million molecules from the ZINC15 library. The lead compound, T60, was characterized to be a catalytic TOP2 inhibitor that binds TOP2 protein and disrupts TOP2 from interacting with DNA, resulting in no DNA cleavage. It has low cytotoxicity, but strongly inhibits cancer cell proliferation and xenograft growth. T60 also inhibits androgen receptor activity and prostate cancer cell growth. These results indicate that T60 is a promising candidate compound that can be further developed into new anticancer drugs.
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http://dx.doi.org/10.3389/fonc.2020.633142DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7883873PMC
February 2021

Emergence of Enzalutamide Resistance in Prostate Cancer is Associated with BCL-2 and IKKB Dependencies.

Clin Cancer Res 2021 Apr 4;27(8):2340-2351. Epub 2021 Feb 4.

Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.

Purpose: Although enzalutamide (ENZ) has been widely used to treat or castration-resistant metastatic prostate cancer, resistance develops and disease progression is ultimately inevitable. There are currently no approved targeted drugs to specifically delay or overcome ENZ resistance.

Experimental Design: We selected several ENZ-resistant cell lines that replicated clinical characteristics of the majority of patients with ENZ-resistant disease. A high-throughput pharmacologic screen was utilized to identify compounds with greater cytotoxic effect for ENZ-resistant cell lines, compared with parental ENZ-sensitive cells. We validated the potential hits and , and used knockdown and overexpression assays to study the dependencies in ENZ-resistant prostate cancer.

Results: ABT199 (BCL-2 inhibitor) and IMD0354 (IKKB inhibitor) were identified as potent and selective inhibitors of cell viability in ENZ-resistant cell lines and which were further validated using loss-of-function assays of BCL-2 and IKKB. Notably, we observed that overexpression of BCL-2 and IKKB in ENZ-sensitive cell lines was sufficient for the emergence of ENZ resistance. In addition, we confirmed that BCL-2 or IKKB inhibitors suppressed the development of ENZ resistance in xenografts. However, validation of both BCL-2 and IKKB in matched castration-sensitive/resistant clinical samples showed that, concurrent with the development of ENZ/abiraterone resistance in patients, only the protein levels of IKKB were increased.

Conclusions: Our findings identify BCL-2 and IKKB dependencies in clinically relevant ENZ-resistant prostate cancer cells and , but indicate that IKKB upregulation appears to have greater relevance to the progression of human castrate-resistant prostate cancer.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-3260DOI Listing
April 2021

Initial Management of Noncastrate Advanced, Recurrent, or Metastatic Prostate Cancer: ASCO Guideline Update.

J Clin Oncol 2021 04 26;39(11):1274-1305. Epub 2021 Jan 26.

Nanhealth, Inc, Culver City, CA.

Purpose: Update all preceding ASCO guidelines on initial hormonal management of noncastrate advanced, recurrent, or metastatic prostate cancer.

Methods: The Expert Panel based recommendations on a systematic literature review. Recommendations were approved by the Expert Panel and the ASCO Clinical Practice Guidelines Committee.

Results: Four clinical practice guidelines, one clinical practice guidelines endorsement, 19 systematic reviews with or without meta-analyses, 47 phase III randomized controlled trials, nine cohort studies, and two review papers informed the guideline update.

Recommendations: Docetaxel, abiraterone, enzalutamide, or apalutamide, each when administered with androgen deprivation therapy (ADT), represent four separate standards of care for noncastrate metastatic prostate cancer. Currently, the use of any of these agents in any particular combination or series cannot be recommended. ADT plus docetaxel, abiraterone, enzalutamide, or apalutamide should be offered to men with metastatic noncastrate prostate cancer, including those who received prior therapies, but have not yet progressed. The combination of ADT plus abiraterone and prednisolone should be considered for men with noncastrate locally advanced nonmetastatic prostate cancer who have undergone radiotherapy, rather than castration monotherapy. Immediate ADT may be offered to men who initially present with noncastrate locally advanced nonmetastatic disease who have not undergone previous local treatment and are unwilling or unable to undergo radiotherapy. Intermittent ADT may be offered to men with high-risk biochemically recurrent nonmetastatic prostate cancer. Active surveillance may be offered to men with low-risk biochemically recurrent nonmetastatic prostate cancer. The panel does not support use of either micronized abiraterone acetate or the 250 mg dose of abiraterone with a low-fat breakfast in the noncastrate setting at this time.Additional information is available at www.asco.org/genitourinary-cancer-guidelines.
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http://dx.doi.org/10.1200/JCO.20.03256DOI Listing
April 2021

Steroidogenesis in Peripheral and Transition Zones of Human Prostate Cancer Tissue.

Int J Mol Sci 2021 Jan 6;22(2). Epub 2021 Jan 6.

The Vancouver Prostate Centre, Vancouver General Hospital, 2660 Oak Street, Vancouver, BC V6H 3Z6, Canada.

The peripheral zone (PZ) and transition zone (TZ) represent about 70% of the human prostate gland with each zone having differential ability to develop prostate cancer. Androgens and their receptor are the primary driving cause of prostate cancer growth and eventually castration-resistant prostate cancer (CRPC). De novo steroidogenesis has been identified as a key mechanism that develops during CRPC. Currently, there is very limited information available on human prostate tissue steroidogenesis. The purpose of the present study was to investigate steroid metabolism in human prostate cancer tissues with comparison between PZ and TZ. Human prostate cancer tumors were procured from the patients who underwent radical prostatectomy without any neoadjuvant therapy. Human prostate homogenates were used to quantify steroid levels intrinsically present in the tissues as well as formed after incubation with 2 µg/mL of 17-hydroxypregnenolone (17-OH-pregnenolone) or progesterone. A Waters Acquity ultraperformance liquid chromatography coupled to a Quattro Premier XE tandem quadrupole mass spectrometer using a C column was used to measure thirteen steroids from the classical and backdoor steroidogenesis pathways. The intrinsic prostate tissue steroid levels were similar between PZ and TZ with dehydroepiandrosterone (DHEA), dihydrotestosterone (DHT), pregnenolone and 17-OH-pregnenolone levels higher than the other steroids measured. Interestingly, 5-pregnan-3,20-dione, 5-pregnan-3-ol-20-one, and 5-pregnan-17-ol-3,20-dione formation was significantly higher in both the zones of prostate tissues, whereas, androstenedione, testosterone, DHT, and progesterone levels were significantly lower after 60 min incubation compared to the 0 min control incubations. The incubations with progesterone had a similar outcome with 5-pregnan-3,20-dione and 5-pregnan-3-ol-20-one levels were elevated and the levels of DHT were lower in both PZ and TZ tissues. The net changes in steroid formation after the incubation were more observable with 17-OH-pregnenolone than with progesterone. In our knowledge, this is the first report of comprehensive analyses of intrinsic prostate tissue steroids and precursor-driven steroid metabolism using a sensitive liquid chromatography-mass spectrometry assay. In summary, the PZ and TZ of human prostate exhibited similar steroidogenic ability with distinction in the manner each zone utilizes the steroid precursors to divert the activity towards backdoor pathway through a complex matrix of steroidogenic mechanisms.
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http://dx.doi.org/10.3390/ijms22020487DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7825320PMC
January 2021

Clusterin Deficiency Predisposes C57BL/6j Mice to Cationic Bovine Serum Albumin-Induced Glomerular Inflammation.

J Inflamm Res 2020 24;13:969-983. Epub 2020 Nov 24.

Department of Urologic Sciences, University of British Columbia, Vancouver, BC V6H 3Z6, Canada.

Background: Membranous nephropathy (MN) is a specific entity of glomerulonephritis, and its glomerular inflammation is characterized by the deposition of immune complexes in the glomerular basement membrane and proteinuria. However, the molecular mechanisms underlying the glomerular inflammation of MN are not fully understood. This study was designed to investigate the role of clusterin (CLU) in the development of MN using a mouse model of cationic bovine serum albumin (cBSA)-induced MN.

Methods: Both wild-type C57BL/6j (WT) and CLU-knockout C57BL/6j (CLU-KO) mice were immunized with cBSA. The kidney function was determined by the levels of serum creatinine (SCr), blood urea nitrogen (BUN) and urinary protein. MN and glomerular deposits of CLU, complement C3 and immunoglobulins (Igs) were determined by histological analyses. Serum proteins were analyzed by the enzyme-linked immunosorbent assay, Western blot and liquid chromatography-mass spectrometry.

Results: Here, we showed that after cBSA immunization, SCr and proteinuria were increased in CLU-KO mice but not in WT mice. Similarly, severe glomerular atrophy and mesangial expansion along with C3 deposit were only found in the kidneys of CLU-KO mice but not in WT mice. However, there were no differences of serum IgG and complement 3 levels between CLU-KO and WT mice. In the serum of WT mice, CLU bound to anti-cBSA IgG, complements (eg, C8), proteinase/protease inhibitors and antioxidative proteins to form a complex, and incubation with WT serum reduced the complement-dependent lysis of podocytes in cultures.

Conclusion: Our data suggest that a CLU deficiency induces cBSA-initiated glomerular inflammation of MN in a disease-resistant strain of mice, suggesting an anti-glomerular inflammatory function of CLU in the resistance to MN development. This function may be at least in part due to the formation of CLU-anti-cBSA Igs complex that prevents glomerular inflammation or injury in the disease-resistant mice.
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http://dx.doi.org/10.2147/JIR.S285985DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7699998PMC
November 2020

A polymeric paste-drug formulation for local treatment of upper tract urothelial carcinoma.

Urol Oncol 2021 03 26;39(3):194.e1-194.e7. Epub 2020 Nov 26.

Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada. Electronic address:

Background: Intravesical instillation of chemo- or immunotherapy is commonly used in bladder cancer. Upper tract urothelial carcinoma (UTUC) shares similar pathological features, but current formulations are not suitable for direct instillation to the upper urinary tract.

Objective: To evaluate in vivo applicability, characteristics and toxicity of ST-UC, a mucoadhesive polymeric paste formulation of gemcitabine, for upper urinary tract instillation.

Material And Methods: Three pigs received 10 ml of ST-UC (100 mg/ml gemcitabine) retrogradely into 1 renal pelvis for pharmacokinetic studies. Four days later, a second injection into the contralateral renal pelvis was followed by serial euthanasia of the pigs and nephroureterectomy after 1, 3, and 6 hours. Adverse effects were monitored. Urine, serum, and tissue gemcitabine concentrations were measured, along with histologic examination of the upper urinary tract.

Results: Retrograde instillation of ST-UC was well tolerated with mild, completely receding hydronephrosis. Urine gemcitabine concentrations were highest in the first 3-hour collection interval. Hundred percent of gemcitabine was recovered in the urine within 24 hours. Serum peak concentrations (c) of gemcitabine were low at 5.5 µg/ml compared to the 10 to 30 µg/ml levels observed after a single intravenous dose of 1,000 mg/m gemcitabine. The formulation was still traceable after one hour and gemcitabine tissue concentrations are supportive of this extended drug exposure. No major histopathological changes were observed. The main limitation of this study is the lack of antitumor activity data.

Conclusion: This preclinical evaluation of ST-UC demonstrated feasible instillation in the renal pelvis, no significant safety concerns, and sustained release of gemcitabine.
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http://dx.doi.org/10.1016/j.urolonc.2020.07.028DOI Listing
March 2021

Integrated Expression of Circulating miR375 and miR371 to Identify Teratoma and Active Germ Cell Malignancy Components in Malignant Germ Cell Tumors.

Eur Urol 2021 01 4;79(1):16-19. Epub 2020 Nov 4.

Department of Medicine, Medical Oncology Division, BC Cancer, Vancouver Centre, University of British Columbia, Vancouver, BC, Canada. Electronic address:

Active germ cell malignancies express high levels of specific circulating micro-RNAs (miRNAs), including miR-371a-3p (miR371), which is undetectable in teratoma. Teratoma markers are urgently needed for theselection of patients and treatments because of the risk of malignant transformation and growing teratoma syndrome. To assess the accuracy of plasma miR375 alone or in combination with miR371 in detecting teratoma, 100 germ cell tumor patients, divided into two cohorts, were enrolled in a prospective multi-institutional study. In the discovery cohort, patients with pure teratoma and with no/low risk of harboring teratoma were compared; the validation cohort included patients with confirmed teratoma, active germ cell malignancy, or complete response after chemotherapy. The area under the receiver operating characteristic curve values for miR375, miR371, and miR371-miR375 were, respectively, 0.93 (95% confidence interval [CI]: 0.87-0.99), 0.59 (95% CI: 0.44-0.73), and 0.95 (95% CI: 0.90-0.99) in the discovery cohort and 0.55 (95% CI: 0.36-0.74), 0.74 (95% CI: 0.58-0.91), and 0.77 (95% CI: 0.62-0.93) in the validation cohort. Our study demonstrated that the plasma miR371-miR375 integrated evaluation is highly accurate to detect teratoma. PATIENT SUMMARY: The evaluation of two micro-RNAs (miR375-miR371) in the blood of patients with germ cell tumors is promising to predict teratoma. This test could be particularly relevant to the identification of teratoma in patients with postchemotherapy residual disease.
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http://dx.doi.org/10.1016/j.eururo.2020.10.024DOI Listing
January 2021

Improving prostate cancer classification in H&E tissue micro arrays using Ki67 and P63 histopathology.

Comput Biol Med 2020 12 14;127:104053. Epub 2020 Oct 14.

Electrical and Computer Engineering, University of British Columbia, Vancouver, BC, Canada. Electronic address:

Histopathology of Hematoxylin and Eosin (H&E)-stained tissue obtained from biopsy is commonly used in prostate cancer (PCa) diagnosis. Automatic PCa classification of digitized H&E slides has been developed before, but no attempts have been made to classify PCa using additional tissue stains registered to H&E. In this paper, we demonstrate that using H&E, Ki67 and p63-stained (3-stain) tissue improves PCa classification relative to H&E alone. We also show that we can infer PCa-relevant Ki67 and p63 information from the H&E slides alone, and use it to achieve H&E-based PCa classification that is comparable to the 3-stain classification. Reported improvements apply to classifying benign vs. malignant tissue, and low grade (Gleason group 2) vs. high grade (Gleason groups 3,4,5) cancer. Specifically, we conducted four classification tasks using 333 tissue samples extracted from 231 radical prostatectomy patients: regression tree-based classification using either (i) 3-stain features, with a benign vs malignant area under the curve (AUC = 92.9%), or (ii) real H&E features and H&E features learned from Ki67 and p63 stains (AUC = 92.4%), as well as deep learning classification using either (iii) real 3-stain tissue patches (AUC = 94.3%) and (iv) real H&E patches and generated Ki67 and p63 patches (AUC = 93.0%) using a deep convolutional generative adversarial network. Classification performance was assessed with Monte Carlo cross validation and quantified in terms of the Area Under the Curve, Brier score, sensitivity, and specificity. Our results are interpretable and indicate that the standard H&E classification could be improved by mimicking other stain types.
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http://dx.doi.org/10.1016/j.compbiomed.2020.104053DOI Listing
December 2020

Autoantibody Landscape in Patients with Advanced Prostate Cancer.

Clin Cancer Res 2020 12 23;26(23):6204-6214. Epub 2020 Sep 23.

Serimmune, Inc. Santa Barbara, California.

Purpose: Autoantibody responses in cancer are of great interest, as they may be concordant with T-cell responses to cancer antigens or predictive of response to cancer immunotherapies. Thus, we sought to characterize the antibody landscape of metastatic castration-resistant prostate cancer (mCRPC).

Experimental Design: Serum antibody epitope repertoire analysis (SERA) was performed on patient serum to identify tumor-specific neoepitopes. Somatic mutation-specific neoepitopes were investigated by associating serum epitope enrichment scores with whole-genome sequencing results from paired solid tumor metastasis biopsies and germline blood samples. A protein-based immunome-wide association study (PIWAS) was performed to identify significantly enriched epitopes, and candidate serum antibodies enriched in select patients were validated by ELISA profiling. A distinct cohort of patients with melanoma was evaluated to validate the top cancer-specific epitopes.

Results: SERA was performed on 1,229 serum samples obtained from 72 men with mCRPC and 1,157 healthy control patients. Twenty-nine of 6,636 somatic mutations (0.44%) were associated with an antibody response specific to the mutated peptide. PIWAS analyses identified motifs in 11 proteins, including NY-ESO-1 and HERVK-113, as immunogenic in mCRPC, and ELISA confirmed serum antibody enrichment in candidate patients. Confirmatory PIWAS, Identifying Motifs Using Next-generation sequencing Experiments (IMUNE), and ELISA analyses performed on serum samples from 106 patients with melanoma similarly revealed enriched cancer-specific antibody responses to NY-ESO-1.

Conclusions: We present the first large-scale profiling of autoantibodies in advanced prostate cancer, utilizing a new antibody profiling approach to reveal novel cancer-specific antigens and epitopes. Our study recovers antigens of known importance and identifies novel tumor-specific epitopes of translational interest.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-1966DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7710628PMC
December 2020

Clusterin regulates macrophage expansion, polarization and phagocytic activity in response to inflammation in the kidneys.

Immunol Cell Biol 2021 03 16;99(3):274-287. Epub 2020 Oct 16.

Department of Urologic Sciences, The University of British Columbia, Vancouver, BC, V5Z 1M9, Canada.

Clusterin (CLU) is a multifunctional protein localized extracellularly and intracellularly. Although CLU-knockout (KO) mice are more susceptible to renal ischemia-reperfusion injury (IRI), the mechanisms underlying the actions of CLU in IRI are not fully understood. Macrophages are key regulators of IRI severity and tissue repair. Therefore, we investigated the role of CLU in macrophage polarization and phagocytosis. Renal IRI was induced in wild-type (WT) or CLU-KO C57BL/6 mice by clamping the renal pedicles for 30 min at 32°C. Peritoneal macrophages were activated via an intraperitoneal injection of lipopolysaccharide (LPS). Renal tissue damage was examined using histology, whereas leukocyte phenotypes were assessed using flow cytometry and immunohistochemistry. We found that monocytes/macrophages expressed the CLU protein that was upregulated by hypoxia. The percentages of macrophages (F4/80 , CD11b or MAC3 ) infiltrating the kidneys of WT mice were significantly less than those in CLU-KO mice after IRI. The M1/M2 phenotype ratio of the macrophages in WT kidneys decreased at day 7 post-IRI when the injury was repaired, whereas that in KO kidneys increased consistently as tissue injury persisted. In response to LPS stimulation, WT mice produced fewer M1 macrophages, but not M2, than the control did. Phagocytosis was stimulated by CLU expression in macrophages compared with the CLU null controls and by the exogenous CLU protein. In conclusion, CLU suppresses macrophage infiltration and proinflammatory M1 polarization during the recovery period following IRI, and enhances phagocytic activity, which may be partly responsible for tissue repair in the kidneys of WT mice after injury.
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http://dx.doi.org/10.1111/imcb.12405DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7984284PMC
March 2021

Tailoring Intensity of Active Surveillance for Low-Risk Prostate Cancer Based on Individualized Prediction of Risk Stability.

JAMA Oncol 2020 10 8;6(10):e203187. Epub 2020 Oct 8.

Fred Hutchinson Cancer Research Center, Cancer Prevention Program, Public Health Sciences, Seattle, Washington.

Importance: Active surveillance is increasingly recognized as the preferred standard of care for men with low-risk prostate cancer. However, active surveillance requires repeated assessments, including prostate-specific antigen tests and biopsies that may increase anxiety, risk of complications, and cost.

Objective: To identify and validate clinical parameters that can identify men who can safely defer follow-up prostate cancer assessments.

Design, Setting, And Participants: The Canary Prostate Active Surveillance Study (PASS) is a multicenter, prospective active surveillance cohort study initiated in July 2008, with ongoing accrual and a median follow-up period of 4.1 years. Men with prostate cancer managed with active surveillance from 9 North American academic medical centers were enrolled. Blood tests and biopsies were conducted on a defined schedule for least 5 years after enrollment. Model validation was performed among men at the University of California, San Francisco (UCSF) who did not enroll in PASS. Men with Gleason grade group 1 prostate cancer diagnosed since 2003 and enrolled in PASS before 2017 with at least 1 confirmatory biopsy after diagnosis were included. A total of 850 men met these criteria and had adequate follow-up. For the UCSF validation study, 533 active surveillance patients meeting the same criteria were identified. Exclusion criteria were treatment within 6 months of diagnosis, diagnosis before 2003, Gleason grade score of at least 2 at diagnosis or first surveillance biopsy, no surveillance biopsy, or missing data.

Exposures: Active surveillance for prostate cancer.

Main Outcomes And Measures: Time from confirmatory biopsy to reclassification, defined as Gleason grade group 2 or higher on subsequent biopsy.

Results: A total of 850 men (median [interquartile range] age, 64 [58-68] years; 774 [91%] White) were included in the PASS cohort. A total of 533 men (median [interquartile range] age, 61 [57-65] years; 422 [79%] White) were included in the UCSF cohort. Parameters predictive of reclassification on multivariable analysis included maximum percent positive cores (hazard ratio [HR], 1.30 [95% CI, 1.09-1.56]; P = .004), history of any negative biopsy after diagnosis (1 vs 0: HR, 0.52 [95% CI, 0.38-0.71]; P < .001 and ≥2 vs 0: HR, 0.18 [95% CI, 0.08-0.4]; P < .001), time since diagnosis (HR, 1.62 [95% CI, 1.28-2.05]; P < .001), body mass index (HR, 1.08 [95% CI, 1.05-1.12]; P < .001), prostate size (HR, 0.40 [95% CI, 0.25-0.62]; P < .001), prostate-specific antigen at diagnosis (HR, 1.51 [95% CI, 1.15-1.98]; P = .003), and prostate-specific antigen kinetics (HR, 1.46 [95% CI, 1.23-1.73]; P < .001). For prediction of nonreclassification at 4 years, the area under the receiver operating curve was 0.70 for the PASS cohort and 0.70 for the UCSF validation cohort. This model achieved a negative predictive value of 0.88 (95% CI, 0.83-0.94) for those in the bottom 25th percentile of risk and of 0.95 (95% CI, 0.89-1.00) for those in the bottom 10th percentile.

Conclusions And Relevance: In this study, among men with low-risk prostate cancer, heterogeneity prevailed in risk of subsequent disease reclassification. These findings suggest that active surveillance intensity can be modulated based on an individual's risk parameters and that many men may be safely monitored with a substantially less intensive surveillance regimen.
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http://dx.doi.org/10.1001/jamaoncol.2020.3187DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7453344PMC
October 2020

Paternally Expressed Gene 10 (PEG10) Promotes Growth, Invasion, and Survival of Bladder Cancer.

Mol Cancer Ther 2020 10 26;19(10):2210-2220. Epub 2020 Aug 26.

The Vancouver Prostate Centre and Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada.

() has been associated with neuroendocrine muscle-invasive bladder cancer (MIBC), a subtype of the disease with the poorest survival. In this work, we further characterized the expression pattern of in The Cancer Genome Atlas database of 412 patients with MIBC, and found that, compared with other subtypes, mRNA level was enhanced in neuroendocrine-like MIBC and highly correlated with other neuroendocrine markers. PEG10 protein level also associated with neuroendocrine markers in a tissue microarray of 82 cases. In bladder cancer cell lines, PEG10 expression was induced in drug-resistant compared with parental cells, and knocking down of PEG10 resensitized cells to chemotherapy. Loss of PEG10 increased protein levels of cell-cycle regulators p21 and p27 and delayed G-S-phase transition, while overexpression of PEG10 enhanced cancer cell proliferation. PEG10 silencing also lowered levels of SLUG and SNAIL, leading to reduced invasion and migration. In an orthotopic bladder cancer model, systemic treatment with PEG10 antisense oligonucleotide delayed progression of T24 xenografts. In summary, elevated expression of in MIBC may contribute to the disease progression by promoting survival, proliferation, and metastasis. Targeting PEG10 is a novel potential therapeutic approach for a subset of bladder cancers.
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http://dx.doi.org/10.1158/1535-7163.MCT-19-1031DOI Listing
October 2020

Assessment of STAT5 as a potential therapy target in enzalutamide-resistant prostate cancer.

PLoS One 2020 13;15(8):e0237248. Epub 2020 Aug 13.

Department of Urology, Technische Universität Dresden, Dresden, Germany.

Despite enzalutamide's efficacy in delaying the progression of metastatic castration-resistant prostate cancer (CRPC), resistance to this anti-androgen inevitably occurs. Several studies have revealed that the signal transducer and activator of transcription (STAT) 5 plays a role in tumour progression and development of drug resistance such as enzalutamide. Data mining revealed heterogeneous expression of STAT5 in enzalutamide-treated mCRPC patients and enzalutamide-resistant prostate cancer (PCa). Isobologram analysis revealed that the STAT5 inhibitor pimozide combined with enzalutamide has? additive and synergistic inhibitory effects on cell viability in the used models. Functional analysis with siRNA-mediated STAT5 knockdown yielded divergent results. The LNCaP-derived cell line MR49F could be resensitised to enzalutamide by siRNA-mediated STAT5b-knock-down. In contrast, neither STAT5a nor STAT5b knockdown resensitised enzalutamide-resistant LAPC4-EnzaR cells to enzalutamide. In conclusion, our results indicate that STAT5 may be a possible target in a subgroup of enzalutamide-resistant PCa. However, based on the data presented here, a general role of STAT5 in enzalutamide-resistance and its potential as a therapeutic target could not be shown.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0237248PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7425943PMC
October 2020

Copy Number Loss of 17q22 Is Associated with Enzalutamide Resistance and Poor Prognosis in Metastatic Castration-Resistant Prostate Cancer.

Clin Cancer Res 2020 09 29;26(17):4616-4624. Epub 2020 Jul 29.

Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon.

Purpose: The purpose of this study was to measure genomic changes that emerge with enzalutamide treatment using analyses of whole-genome sequencing and RNA sequencing.

Experimental Design: One hundred and one tumors from men with metastatic castration-resistant prostate cancer (mCRPC) who had not been treated with enzalutamide ( = 64) or who had enzalutamide-resistant mCRPC ( = 37) underwent whole genome sequencing. Ninety-nine of these tumors also underwent RNA sequencing. We analyzed the genomes and transcriptomes of these mCRPC tumors.

Results: Copy number loss was more common than gain in enzalutamide-resistant tumors. Specially, we identified 124 protein-coding genes that were more commonly lost in enzalutamide-resistant samples. These 124 genes included eight putative tumor suppressors located at nine distinct genomic regions. We demonstrated that focal deletion of the 17q22 locus that includes and was not present in any patient with enzalutamide-naïve mCRPC but was present in 16% (6/37) of patients with enzalutamide-resistant mCRPC. 17q22 loss was associated with lower and expression and poor overall survival from time of biopsy [median overall survival of 19.3 months in 17q22 intact vs. 8.9 months in 17q22 loss, HR, 3.44 95% confidence interval (CI), 1.338-8.867, log-rank = 0.006]. Finally, 17q22 loss was linked with activation of several targetable factors, including CDK1/2, Akt, and PLK1, demonstrating the potential therapeutic relevance of 17q22 loss in mCRPC.

Conclusions: Copy number loss is common in enzalutamide-resistant tumors. Focal deletion of chromosome 17q22 defines a previously unappreciated molecular subset of enzalutamide-resistant mCRPC associated with poor clinical outcome.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-2303DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7484240PMC
September 2020

Cancer and Leukemia Group B 90203 (Alliance): Radical Prostatectomy With or Without Neoadjuvant Chemohormonal Therapy in Localized, High-Risk Prostate Cancer.

J Clin Oncol 2020 09 24;38(26):3042-3050. Epub 2020 Jul 24.

Memorial Sloan Kettering Cancer Center, New York, NY.

Purpose: Radical prostatectomy (RP) alone is often inadequate in curing men with clinically localized, high-risk prostate cancer (PC). We hypothesized that chemohormonal therapy (CHT) with androgen-deprivation therapy plus docetaxel before RP would improve biochemical progression-free survival (BPFS) over RP alone.

Patients And Methods: Men with clinically localized, high-risk PC were assigned to RP alone or neoadjuvant CHT with androgen deprivation plus docetaxel (75 mg/m body surface area every 3 weeks for 6 cycles) and RP. The primary end point was 3-year BPFS. Biochemical failure was defined as a serum prostate-specific antigen level > 0.2 ng/mL that increased on 2 consecutive occasions that were at least 3 months apart. Secondary end points included 5-year BPFS, overall BPFS, local recurrence, metastasis-free survival (MFS), PC-specific mortality, and overall survival (OS).

Results: In total, 788 men were randomly assigned. Median follow-up time was 6.1 years. The overall rates of grade 3 and 4 adverse events during chemotherapy were 26% and 19%, respectively. No difference was seen in 3-year BPFS between neoadjuvant CHT plus RP and RP alone (0.89 0.84, respectively; 95% CI for the difference, -0.01 to 0.11; = .11). Neoadjuvant CHT was associated with improved overall BPFS (hazard ratio [HR], 0.69; 95% CI, 0.48 to 0.99), improved MFS (HR, 0.70; 95% CI, 0.51 to 0.95), and improved OS (HR, 0.61; 95% CI, 0.40 to 0.94) compared with RP alone.

Conclusion: The primary study end point, 3-year BPFS, was not met. Although some improvement was seen in secondary end points, any potential benefit must be weighed against toxicity. Our data do not support the routine use of neoadjuvant CHT and RP in patients with clinically localized, high-risk PC at this time.
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http://dx.doi.org/10.1200/JCO.20.00315DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7479762PMC
September 2020
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