Agent-based modeling of the prostate tumor microenvironment uncovers spatial tumor growth constraints and immunomodulatory properties.

Inhibiting androgen receptor (AR) signaling through androgen deprivation therapy (ADT) reduces prostate cancer (PCa) growth in virtually all patients, but response may be temporary, in which case resistance develops, ultimately leading to lethal castration-resistant prostate cancer (CRPC). The tumor microenvironment (TME) plays an important role in the development and progression of PCa. In addition to tumor cells, TME-resident macrophages and fibroblasts express AR and are therefore also affected by ADT. However, the interplay of different TME cell types in the development of CRPC remains largely unexplored. To understand the complex stochastic nature of cell-cell interactions, we created a PCa-specific agent-based model (PCABM) based on in vitro cell proliferation data. PCa cells, fibroblasts, "pro-inflammatory" M1-like and "pro-tumor" M2-like polarized macrophages are modeled as agents from a simple set of validated base assumptions. PCABM allows us to simulate the effect of ADT on the interplay between various prostate TME cell types. The resulting in vitro growth patterns mimic human PCa. Our PCABM can effectively model hormonal perturbations by ADT, in which PCABM suggests that CRPC arises in clusters of resistant cells, as is observed in multifocal PCa. In addition, fibroblasts compete for cellular space in the TME while simultaneously creating niches for tumor cells to proliferate in. Finally, PCABM predicts that ADT has immunomodulatory effects on macrophages that may enhance tumor survival. Taken together, these results suggest that AR plays a critical role in the cellular interplay and stochastic interactions in the TME that influence tumor cell behavior and CRPC development.

It Takes Two to Tango: The Interplay between Prostate Cancer and Its Microenvironment from an Epigenetic Perspective.

Prostate cancer is the second most common cancer in men worldwide and is associated with high morbidity and mortality. Consequently, there is an urgent unmet need for novel treatment avenues. In addition to somatic genetic alterations, deviations in the epigenetic landscape of cancer cells and their tumor microenvironment (TME) are critical drivers of prostate cancer initiation and progression. Unlike genomic mutations, epigenetic modifications are potentially reversible. Therefore, the inhibition of aberrant epigenetic modifications represents an attractive and exciting novel treatment strategy for castration-resistant prostate cancer patients. Moreover, drugs targeting the epigenome also exhibit synergistic interactions with conventional therapeutics by directly enhancing their anti-tumorigenic properties by "priming" the tumor and tumor microenvironment to increase drug sensitivity. This review summarizes the major epigenetic alterations in prostate cancer and its TME, and their involvement in prostate tumorigenesis, and discusses the impact of epigenome-targeted therapies.

A common germline variant in CYP11B1 is associated with adverse clinical outcome of treatment with abiraterone or enzalutamide.

Extragonadal androgens play a pivotal role in prostate cancer disease progression on androgen receptor signaling inhibitors (ARSi), including abiraterone and enzalutamide. We aimed to investigate if germline variants in genes involved in extragonadal androgen synthesis contribute to resistance to ARSi and may predict clinical outcomes on ARSi. We included ARSi naive metastatic prostate cancer patients treated with abiraterone or enzalutamide and determined 18 germline variants in six genes involved in extragonadal androgen synthesis. Variants were tested in univariate and multivariable analysis for the relation with overall survival (OS) and time to progression (TTP) by Cox regression, and PSA response by logistic regression. A total of 275 patients were included. From the investigated genes CYP17A1, HSD3B1, CYP11B1, AKR1C3, SRD5A1 and SRD5A2, only rs4736349 in CYP11B1 in homozygous form (TT), present in 54 patients (20%), was related with a significantly worse OS (HR = 1.71, 95% CI 1.09 - 2.68, p = 0.019) and TTP (HR = 1.50, 95% CI 1.08 - 2.09, p = 0.016), and was related with a significantly less frequent PSA response (OR = 0.48, 95% CI 0.24 - 0.96, p = 0.038) on abiraterone or enzalutamide in a multivariable analysis. The frequent germline variant rs4736349 in CYP11B1 is, as homozygote, an independent negative prognostic factor for treatment with abiraterone or enzalutamide in ARSi naive metastatic prostate cancer patients. Our findings warrant prospective investigation of this potentially important predictive biomarker.

Cortisol as Biomarker for CYP17-Inhibition is Associated with Therapy Outcome of Abiraterone Acetate.

BACKGROUND: Abiraterone acetate is an irreversible 17α-hydroxylase/C17, 20-lyase (CYP17) inhibitor approved for the treatment of metastatic castration-resistant prostate cancer (mCRPC) patients. Inhibition of this enzyme leads to low testosterone and cortisol levels in blood. There is growing evidence that clinical efficacy of abiraterone is related to the rate of suppression of serum testosterone. However, quantification of very low levels of circulating testosterone is challenging. We therefore aimed to investigate whether circulating cortisol levels could be used as a surrogate biomarker for CYP17 inhibition in patients with mCRPC treated with abiraterone acetate. PATIENTS AND METHODS: mCRPC patients treated with abiraterone acetate were included. Abiraterone and cortisol levels were measured with a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS). On treatment cortisol and abiraterone concentrations were related to treatment response and progression free survival. RESULTS: In total 117 patients were included with a median cortisol concentration of 1.13 ng/ml (range: 0.03 - 82.2) and median abiraterone trough concentration (Cmin) of 10.2 ng/ml (range: 0.58 - 92.1). In the survival analyses, abiraterone Cmin ≥ 8.4 ng/mL and cortisol < 2.24 ng/mL were associated with a longer prostate-specific antigen (PSA) independent progression-free survival than patients with an abiraterone concentration ≥ 8.4 ng/mL and a cortisol concentration ≥ 2.24 ng/mL (13.8 months vs. 3.7 months). CONCLUSION: Our study shows that cortisol is not an independent predictor of abiraterone response in patients with mCRPC, but it is of added value in combination with abiraterone levels, to predict a response on abiraterone.

Exploring the Onset and Progression of Prostate Cancer through a Multicellular Agent-based Model.

Over 10% of men will be diagnosed with prostate cancer during their lifetime. Arising from luminal cells of the prostatic acinus, prostate cancer is influenced by multiple cells in its microenvironment. To expand our knowledge and explore means to prevent and treat the disease, it is important to understand what drives the onset and early stages of prostate cancer. In this study, we developed an agent-based model of a prostatic acinus including its microenvironment, to allow for in silico studying of prostate cancer development. The model was based on prior reports and in-house data of tumor cells cocultured with cancer-associated fibroblasts (CAF) and protumor and/or antitumor macrophages. Growth patterns depicted by the model were pathologically validated on hematoxylin and eosin slide images of human prostate cancer specimens. We identified that stochasticity of interactions between macrophages and tumor cells at early stages strongly affect tumor development. In addition, we discovered that more systematic deviations in tumor development result from a combinatorial effect of the probability of acquiring mutations and the tumor-promoting abilities of CAFs and macrophages. In silico modeled tumors were then compared with 494 patients with cancer with matching characteristics, showing strong association between predicted tumor load and patients' clinical outcome. Our findings suggest that the likelihood of tumor formation depends on a combination of stochastic events and systematic characteristics. While stochasticity cannot be controlled, information on systematic effects may aid the development of prevention strategies tailored to the molecular characteristics of an individual patient. Significance: We developed a computational model to study which factors of the tumor microenvironment drive prostate cancer development, with potential to aid the development of new prevention strategies.

Radiogenomics Analysis Linking Multiparametric MRI and Transcriptomics in Prostate Cancer.

Prostate cancer (PCa) is a highly prevalent cancer type with a heterogeneous prognosis. An accurate assessment of tumor aggressiveness can pave the way for tailored treatment strategies, potentially leading to better outcomes. While tumor aggressiveness is typically assessed based on invasive methods (e.g., biopsy), radiogenomics, combining diagnostic imaging with genomic information can help uncover aggressive (imaging) phenotypes, which in turn can provide non-invasive advice on individualized treatment regimens. In this study, we carried out a parallel analysis on both imaging and transcriptomics data in order to identify features associated with clinically significant PCa (defined as an ISUP grade ≥ 3), subsequently evaluating the correlation between them. Textural imaging features were extracted from multi-parametric MRI sequences (T2W, DWI, and DCE) and combined with DCE-derived parametric pharmacokinetic maps obtained using magnetic resonance dispersion imaging (MRDI). A transcriptomic analysis was performed to derive functional features on transcription factors (TFs), and pathway activity from RNA sequencing data, here referred to as transcriptomic features. For both the imaging and transcriptomic features, different machine learning models were separately trained and optimized to classify tumors in either clinically insignificant or significant PCa. These models were validated in an independent cohort and model performance was used to isolate a subset of relevant imaging and transcriptomic features to be further investigated. A final set of 31 imaging features was correlated to 33 transcriptomic features obtained on the same tumors. Five significant correlations (p < 0.05) were found, of which, three had moderate strength (|r| ≥ 0.5). The strongest significant correlations were seen between a perfusion-based imaging feature-MRDI A median-and the activities of the TFs STAT6 (-0.64) and TFAP2A (-0.50). A higher-order T2W textural feature was also significantly correlated to the activity of the TF STAT6 (-0.58). STAT6 plays an important role in controlling cell proliferation and migration. Loss of the AP2alpha protein expression, quantified by TFAP2A, has been strongly associated with aggressiveness and progression in PCa. According to our findings, a combination of texture features extracted from T2W and DCE, as well as perfusion-based pharmacokinetic features, can be considered for the prediction of clinically significant PCa, with the pharmacokinetic MRDI A feature being the most correlated with the underlying transcriptomic information. These results highlight a link between quantitative imaging features and the underlying transcriptomic landscape of prostate tumors.

Treating Primary Node-Positive Prostate Cancer: A Scoping Review of Available Treatment Options.

There is currently no consensus on the optimal treatment for patients with a primary diagnosis of clinically and pathologically node-positive (cN1M0 and pN1M0) hormone-sensitive prostate cancer (PCa). The treatment paradigm has shifted as research has shown that these patients could benefit from intensified treatment and are potentially curable. This scoping review provides an overview of available treatments for men with primary-diagnosed cN1M0 and pN1M0 PCa. A search was conducted on Medline for studies published between 2002 and 2022 that reported on treatment and outcomes among patients with cN1M0 and pN1M0 PCa. In total, twenty-seven eligible articles were included in this analysis: six randomised controlled trials, one systematic review, and twenty retrospective/observational studies. For cN1M0 PCa patients, the best-established treatment option is a combination of androgen deprivation therapy (ADT) and external beam radiotherapy (EBRT) applied to both the prostate and lymph nodes. Based on most recent studies, treatment intensification can be beneficial, but more randomised studies are needed. For pN1M0 PCa patients, adjuvant or early salvage treatments based on risk stratification determined by factors such as Gleason score, tumour stage, number of positive lymph nodes, and surgical margins appear to be the best-established treatment options. These treatments include close monitoring and adjuvant treatment with ADT and/or EBRT.

Grade Group 1 Prostate Cancers Exhibit Tumor-defining Androgen Receptor-driven Programs.

Grade group 1 (GG1) primary prostate cancers with a pathologic Gleason score of 6 are considered indolent and generally not associated with fatal outcomes, so treatment is not indicated for most cases. These low-grade cancers have an overall negligible risk of locoregional progression and metastasis to distant organs, which is why there is an ongoing debate about whether these lesions should be reclassified as "noncancerous". However, the underlying molecular activity of key disease drivers, such as the androgen receptor (AR), have thus far not been thoroughly characterized in low-grade tumors. Therefore, we set out to delineate the AR chromatin-binding landscape in low-grade GG1 prostate cancers to gain insights into whether these AR-driven programs are actually tumor-specific or are normal prostate epithelium-like. These analyses showed that GG1 tumors do not harbor a distinct AR cistrome and, similar to higher-grade cancers, AR preferentially binds to tumor-defining cis-regulatory elements. Furthermore, the enhancer activity of these regions and the expression of their respective target genes were not significantly different in GG1 tumors. From an epigenetic perspective, this finding supports the cancer designation currently given to these low-grade tumors and clearly distinguishes them from noncancerous benign tissue. PATIENT SUMMARY: We characterized the molecular activity of the androgen receptor protein, which drives prostate cancer disease, in low-grade tumors. Our results show that these tumors are true cancers and are clearly separate from benign prostate tissue despite their low clinical aggressiveness.

Genetic Aspects and Molecular Testing in Prostate Cancer: A Report from a Dutch Multidisciplinary Consensus Meeting.

Background: Germline and tumour genetic testing in prostate cancer (PCa) is becoming more broadly accepted, but testing indications and clinical consequences for carriers in each disease stage are not yet well defined. Objective: To determine the consensus of a Dutch multidisciplinary expert panel on the indication and application of germline and tumour genetic testing in PCa. Design setting and participants: The panel consisted of 39 specialists involved in PCa management. We used a modified Delphi method consisting of two voting rounds and a virtual consensus meeting. Outcome measurements and statistical analysis: Consensus was reached if ≥75% of the panellists chose the same option. Appropriateness was assessed by the RAND/UCLA appropriateness method. Results and limitations: Of the multiple-choice questions, 44% reached consensus. For men without PCa having a relevant family history (familial PCa/BRCA-related hereditary cancer), follow-up by prostate-specific antigen was considered appropriate. For patients with low-risk localised PCa and a family history of PCa, active surveillance was considered appropriate, except in case of the patient being a BRCA2 germline pathogenic variant carrier. Germline and tumour genetic testing should not be done for nonmetastatic hormone-sensitive PCa in the absence of a relevant family history of cancer. Tumour genetic testing was deemed most appropriate for the identification of actionable variants, with uncertainty for germline testing. For tumour genetic testing in metastatic castration-resistant PCa, consensus was not reached for the timing and panel composition. The principal limitations are as follows: (1) a number of topics discussed lack scientific evidence, and therefore the recommendations are partly opinion based, and (2) there was a small number of experts per discipline. Conclusions: The outcomes of this Dutch consensus meeting may provide further guidance on genetic counselling and molecular testing related to PCa. Patient summary: A group of Dutch specialists discussed the use of germline and tumour genetic testing in prostate cancer (PCa) patients, indication of these tests (which patients and when), and impact of these tests on the management and treatment of PCa.

Enhancer profiling identifies epigenetic markers of endocrine resistance and reveals therapeutic options for metastatic castration-resistant prostate cancer patients.

Androgen Receptor (AR) signaling inhibitors, including enzalutamide, are treatment options for patients with metastatic castration-resistant prostate cancer (mCRPC), but resistance inevitably develops. Using metastatic samples from a prospective phase II clinical trial, we epigenetically profiled enhancer/promoter activities with H3K27ac chromatin immunoprecipitation followed by sequencing, before and after AR-targeted therapy. We identified a distinct subset of H3K27ac-differentially marked regions that associated with treatment responsiveness. These data were successfully validated in mCRPC patient-derived xenograft models (PDX). In silico analyses revealed HDAC3 as a critical factor that can drive resistance to hormonal interventions, which we validated in vitro . Using cell lines and mCRPC PDX tumors in vitro , we identified drug-drug synergy between enzalutamide and the pan-HDAC inhibitor vorinostat, providing therapeutic proof-of-concept. These findings demonstrate rationale for new therapeutic strategies using a combination of AR and HDAC inhibitors to improve patient outcome in advanced stages of mCRPC.

Current Routine Testosterone Immunoassays Are Unsuitable for Lowering the General Castration Cutoff Recommendation to <0.7 nmol/l (20 ng/dl).

Testosterone measurements are essential in the management of patients with prostate cancer undergoing castration and androgen deprivation therapy. There has been an ongoing discussion on the testosterone castration cutoff (TCC), with the primary focus on large cohort studies in which the testosterone measurement system was not specified or studies that used individual testosterone measurement systems. Here we present a post hoc analysis of a study comparing testosterone measurement systems in a cohort of 120 castrated patients with prostate cancer. We investigated the suitability of general, measurement system-independent, TCC values recommended in all clinical guidelines. We show that the four testosterone immunoassays commonly used are unsuitable to support lowering of TCC to 0.7 nmol/l (20 ng/dl) testosterone, since testosterone levels are falsely quantified as higher than this cutoff in 4.2-29.2% of the castrated cohort, depending on the testosterone immunoassay used. When using 1.0 nmol/l (30 ng/dl) as the TCC for the Beckman immunoassay, 13.3% of the results were falsely quantified as being higher than this value. The results suggest that the measurement systems used in current practice do not support lowering the TCC to 0.7 nmol/l. Furthermore, a more local, immunoassay-dependent TCC should be considered. Patient summary: Patients with advanced prostate cancer who are treated to reduce their testosterone to a castration level are monitored using testosterone measurements. The testing systems currently used for measurement do not support lowering of the testosterone cutoff value to 0.7 nmol/l. Testosterone cutoff values to define castration status should preferably be based on the measurement system in local use.

Serum testosterone measured by liquid chromatography-tandem mass spectrometry is an independent predictor of response to castration in metastatic hormone-sensitive prostate cancer.

BACKGROUND: Although testosterone levels have been associated with progression-free survival (PFS) in metastatic hormone-sensitive prostate cancer (mHSPC) patients, this has primarily been investigated using inaccurate immunoassays (IA). Here, we investigated whether castrate testosterone levels determined by a liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay is an independent risk factor for treatment response in mHSPC. METHODS: In total, 106 mHSPC patients treated with luteinizing-hormone releasing-hormone (LHRH) agonists were retrospectively analyzed between March 2018 and August 2021. Testosterone levels in serum samples were quantitated using an LC-MS/MS assay. In a subset of patients, IA (Roche Cobas Pro) values were compared with LC-MS/MS results. Survival analysis was performed using Kaplan-Meier curves and Cox proportional hazard models. RESULTS: Median PFS was shorter for high testosterone levels (>0.231 nmol/L, 18.4 v. 42.6 months, HR 1.7, p = 0.018). Low testosterone levels and a PSA response below 4 ng/mL was associated with longer median PFS (46.2 months) than the remaining combinations (13.8-19.3 months, 3.4-5.8, overall p < 0.01). In 67 patients, testosterone levels below the median remained associated with longer PFS, whereas IA measurements did not show a similar difference. CONCLUSION: Our results suggest that high castration testosterone levels measured by LC-MS/MS is an independent response predictor for mHSPC patients.

Predictive value of low testosterone concentrations during and prior to enzalutamide treatment in metastatic castration-resistant prostate cancer.

BACKGROUND: Enzalutamide is an effective treatment for metastatic castration-resistant prostate cancer (mCRPC) patients. However, variances in responses are observed and there is a need for biomarkers predicting treatment outcome and selection. In this study, we aimed to explore the predictive value of testosterone for first-line enzalutamide treatment of mCRPC. METHODS: A retrospective analysis of 72 mCRPC patients with no prior abiraterone or docetaxel treatment was performed. Serum testosterone was measured using a liquid chromatography tandem-mass spectrometry method. Association of pre- and during-enzalutimide treatment testosterone levels with progression-free survival (PFS) and failure-free survival (FFS) was investigated using univariate and multivariate Cox models. Testosterone levels were dichotomized into a low (Q1) and high (interquartile range-Q4) group. RESULTS: Median PFS (7.4 v. 20.8 months, P<0.0001) and FFS (6.6 v. 17.7 months, P<0.0001) were shorter for patients with low testosterone levels (<0.217 nmol/L) during enzalutamide treatment. Furthermore, univariate Cox proportional hazards models revealed that low testosterone levels were associated with shorter PFS (HR 3.5, 95%CI 1.9-6.3; P<0.001) and FFS (HR 3.1, 95%CI 1.7-5.5; P<0.001). Pre-treatment testosterone levels were lower than during-treatment levels (P<0.0001) and low pre-treatment testosterone levels (<0.143 nmol/L) were associated with shorter median PFS (12.6 v. 20.5 months, P<0.01) and FFS (12.6 v. 22.5 months, P<0.01). CONCLUSION: The results of this study suggest that low serum testosterone levels during and prior to enzalutamide treatment can predict progression in mCRPC patients and identifies tumors resistant to next-in-line enzalutamide treatment. Validation in a prospective cohort is warranted.

Role of Local and/or Metastasis-directed Therapy in Patients with Hormone-sensitive M1a Prostate Cancer-A Systematic Review.

CONTEXT: It remains unclear whether men with hormone-sensitive prostate cancer (PCa) metastasized to nonregional lymph nodes (M1a) benefit from prostate-directed therapy (PDT) and/or metastasis-directed therapy (MDT). OBJECTIVE: To systematically summarize the literature regarding oncological outcomes of de novo and recurrent M1a PCa patients treated with PDT and/or MDT. EVIDENCE ACQUISITION: We searched Medline (Ovid), Embase, and Scopus according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines for reports on oncological outcomes of de novo or recurrent hormone-sensitive M1a PCa patients treated with PDT (radical prostatectomy or radiotherapy) and/or MDT (nodal radiotherapy or salvage lymph node dissection) with or without androgen deprivation therapy. A descriptive data synthesis and a methodological quality assessment were performed to evaluate the impact of PDT and/or MDT on survival in M1a PCa patients. EVIDENCE SYNTHESIS: A total of 6136 articles were screened and 24 studies were included in this systematic review. In de novo M1a PCa patients, PDT was associated with improved oncological outcomes compared with no PDT. In recurrent M1a PCa, MDT could delay the need for systemic treatment in a selection of patients, but high-level evidence from prospective phase III randomized controlled trials is still awaited. CONCLUSIONS: This systematic review summarized the limited literature data on the management of M1a PCa. Subgroup analyses suggest a role for PDT plus systemic therapy in de novo M1a PCa. MDT to distant nodal metastases delayed the need for systemic therapy in recurrent disease, but robust data are lacking. The predominantly retrospective nature of the included studies and significant heterogeneity in study designs limit the strength of evidence. PATIENT SUMMARY: We reviewed the treatment of patients with prostate cancer that has spread to lymph nodes outside the pelvis without metastases in other organ systems. There is evidence that treatment of the primary prostate tumor improves outcomes in well-selected patients and that treatment targeting distant lymph node metastases can delay the start of systemic treatment.

Extensive androgen receptor enhancer heterogeneity in primary prostate cancers underlies transcriptional diversity and metastatic potential.

Androgen receptor (AR) drives prostate cancer (PCa) development and progression. AR chromatin binding profiles are highly plastic and form recurrent programmatic changes that differentiate disease stages, subtypes and patient outcomes. While prior studies focused on concordance between patient subgroups, inter-tumor heterogeneity of AR enhancer selectivity remains unexplored. Here we report high levels of AR chromatin binding heterogeneity in human primary prostate tumors, that overlap with heterogeneity observed in healthy prostate epithelium. Such heterogeneity has functional consequences, as somatic mutations converge on commonly-shared AR sites in primary over metastatic tissues. In contrast, less-frequently shared AR sites associate strongly with AR-driven gene expression, while such heterogeneous AR enhancer usage also distinguishes patients' outcome. These findings indicate that epigenetic heterogeneity in primary disease is directly informative for risk of biochemical relapse. Cumulatively, our results illustrate a high level of AR enhancer heterogeneity in primary PCa driving differential expression and clinical impact.

Homing in on a Moving Target: Androgen Receptor Cistromic Plasticity in Prostate Cancer.

The androgen receptor (AR) is the critical driver in prostate cancer and exerts its function mainly through transcriptional control. Recent advances in clinical studies and cell line models have illustrated that AR chromatin binding features are not static; rather they are highly variable yet reproducibly altered between clinical stages. Extensive genomic analyses of AR chromatin binding features in different disease stages have revealed a high degree of plasticity of AR chromatin interactions in clinical samples. Mechanistically, AR chromatin binding patterns are associated with specific somatic mutations on AR and other permutations, including mutations of AR-interacting proteins. Here we summarize the most recent studies on how the AR cistrome is dynamically altered in prostate cancer models and patient samples, and what implications this has for the identification of therapeutic targets to avoid the emergence of treatment resistance.

Prostate Cancer Epigenetic Plasticity and Enhancer Heterogeneity: Molecular Causes, Consequences and Clinical Implications.

Prostate cancer (PCa) proliferation is dictated by androgen receptor (AR) signaling, which regulates gene expression through cis-regulatory regions including proximal and distal enhancers. The repertoire of AR interactions at enhancers is dependent on tissue and cellular contexts and thus shape a spectrum of phenotypes through such epigenetic heterogeneity. Moreover, PCa is a multifocal disease and displays a high degree of intra- and inter-tumor heterogeneity, adding to the phenotypic complexity. It is increasingly becoming clear that PCa may be considered an epigenetic disease caused by various molecular causes with profound consequences and clinical implications which are underpinned by enhancer interaction heterogeneity.In this review, we provide a detailed overview of molecular interactors that affect prostate cancer epigenetic heterogeneity, such as coding and non-coding somatic variants, large scale structural variations, pioneer factor binding at enhancers and various contexts that influence enhancer engagement heterogeneity in PCa development and progression. Finally, we explore how the vast heterogeneity in epigenetic profiles identified in recent omics studies results in distinct genomic subtypes which predict disease progression and thus offer opportunities in biomarker discovery and further personalizing cancer treatment. As such, heterogeneous enhancer interactions take center stage in elucidating mechanisms of prostate cancer progression, patient prognostication, therapy discovery and overcoming acquired treatment resistance.

Drug-Induced Epigenomic Plasticity Reprograms Circadian Rhythm Regulation to Drive Prostate Cancer toward Androgen Independence.

In prostate cancer, androgen receptor (AR)-targeting agents are very effective in various disease stages. However, therapy resistance inevitably occurs, and little is known about how tumor cells adapt to bypass AR suppression. Here, we performed integrative multiomics analyses on tissues isolated before and after 3 months of AR-targeting enzalutamide monotherapy from patients with high-risk prostate cancer enrolled in a neoadjuvant clinical trial. Transcriptomic analyses demonstrated that AR inhibition drove tumors toward a neuroendocrine-like disease state. Additionally, epigenomic profiling revealed massive enzalutamide-induced reprogramming of pioneer factor FOXA1 from inactive chromatin sites toward active cis-regulatory elements that dictate prosurvival signals. Notably, treatment-induced FOXA1 sites were enriched for the circadian clock component ARNTL. Posttreatment ARNTL levels were associated with patients' clinical outcomes, and ARNTL knockout strongly decreased prostate cancer cell growth. Our data highlight a remarkable cistromic plasticity of FOXA1 following AR-targeted therapy and revealed an acquired dependency on the circadian regulator ARNTL, a novel candidate therapeutic target. SIGNIFICANCE: Understanding how prostate cancers adapt to AR-targeted interventions is critical for identifying novel drug targets to improve the clinical management of treatment-resistant disease. Our study revealed an enzalutamide-induced epigenomic plasticity toward prosurvival signaling and uncovered the circadian regulator ARNTL as an acquired vulnerability after AR inhibition, presenting a novel lead for therapeutic development. See related commentary by Zhang et al., p. 2017. This article is highlighted in the In This Issue feature, p. 2007.

Comparison of docetaxel pharmacokinetics between castration-resistant and hormone-sensitive metastatic prostate cancer patients.

PURPOSE: Recently, docetaxel treatment of metastatic prostate cancer patients shifted towards the hormone-sensitive stage of the disease. There are contradictive reports on differences in toxicity of docetaxel in metastatic hormone-sensitive prostate cancer (mHSPC) and metastatic castration-resistant prostate cancer (mCRPC) patients. Possible differences in toxicity might be attributed to different pharmacokinetics (PK) in the two patient populations. METHODS: Patients with mCRPC or mHSPC and a standard indication for docetaxel treatment were included in the study. All patients had suppressed serum testosterone levels (≤ 0.5 ng/mL or 1.73 nmol/L). Venous blood samples were obtained at the first docetaxel treatment, until 48 h after infusion. Plasma concentrations of docetaxel, unbound docetaxel and docetaxel metabolites were measured using validated liquid chromatography coupled tandem mass spectrometry (LC-MS/MS) assays and compared between the two groups. Moreover, serum levels of docetaxel transporting α1-acid glycoprotein were measured and docetaxel toxicity recorded. RESULTS: A total of ten mCRPC and nine mHSPC patients were included in the study. The two cohorts differed in the number of prior treatments and opiate use, which were higher for mCRPC patients. The docetaxel PK was not different between mCRPC and mHSPC patients, with areas under the plasma concentration versus time curve (AUC0-48) 1710 [coefficient of variation (CV) 28.4%] and 1486 (CV 25.2%) ng/mL*h (p = 0.27), respectively. Also, the PK profile of unbound docetaxel, M1/M3, M2 and M4 metabolites were similar in both groups. Docetaxel doses were reduced in 50% of the mCRPC patients and 11% of the mHSPC patients. CONCLUSION: The PK profile of docetaxel was similar in mCPRC and mHSPC patients. Therefore, possible differences in toxicity between mCRPC and mHSPC patients cannot be explained by differences in docetaxel PK in our study population. These results suggest that treatment adaptations are not recommended in the new population of patients with mHSPC.

Being Transparent About Brilliant Failures: An Attempt to Use Real-World Data in a Disease Model for Patients with Castration-Resistant Prostate Cancer.

BACKGROUND: Real-world disease models spanning multiple treatment lines can provide insight into the (cost) effectiveness of treatment sequences in clinical practice. OBJECTIVE: Our objective was to explore whether a disease model based solely on real-world data (RWD) could be used to estimate the effectiveness of treatments for patients with castration-resistant prostate cancer (CRPC) that could then be suitably used in a cost-effectiveness analysis. METHODS: We developed a patient-level simulation model using patient-level data from the Dutch CAPRI registry as input parameters. Time to event (TTE) and overall survival (OS) were estimated with multivariate regression models, and type of event (i.e., next treatment or death) was estimated with multivariate logistic regression models. To test internal validity, TTE and OS from the simulation model were compared with the observed outcomes in the registry. RESULTS: Although patient characteristics and survival outcomes of the simulated data were comparable to those in the observed data (median OS 20.6 vs. 19.8 months, respectively), the disease model was less accurate in estimating differences between treatments (median OS simulated vs. observed population: 18.6 vs. 17.9 [abiraterone acetate plus prednisone], 24.0 vs. 25.0 [enzalutamide], 20.2 vs. 18.7 [docetaxel], and 20.0 vs. 23.8 months [radium-223]). CONCLUSIONS: Overall, the disease model accurately approximated the observed data in the total CRPC population. However, the disease model was unable to predict differences in survival between treatments due to unobserved differences. Therefore, the model is not suitable for cost-effectiveness analysis of CRPC treatment. Using a combination of RWD and data from randomised controlled trials to estimate treatment effectiveness may improve the model.