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1.
J Pathol ; 262(1): 105-120, 2024 01.
Article in English | MEDLINE | ID: mdl-37850574

ABSTRACT

HOXB13 is a key lineage homeobox transcription factor that plays a critical role in the differentiation of the prostate gland. Several studies have suggested that HOXB13 alterations may be involved in prostate cancer development and progression. Despite its potential biological relevance, little is known about the expression of HOXB13 across the disease spectrum of prostate cancer. To this end, we validated a HOXB13 antibody using genetic controls and investigated HOXB13 protein expression in murine and human developing prostates, localized prostate cancers, and metastatic castration-resistant prostate cancers. We observed that HOXB13 expression increases during later stages of murine prostate development. All localized prostate cancers showed HOXB13 protein expression. Interestingly, lower HOXB13 expression levels were observed in higher-grade tumors, although no significant association between HOXB13 expression and recurrence or disease-specific survival was found. In advanced metastatic prostate cancers, HOXB13 expression was retained in the majority of tumors. While we observed lower levels of HOXB13 protein and mRNA levels in tumors with evidence of lineage plasticity, 84% of androgen receptor-negative castration-resistant prostate cancers and neuroendocrine prostate cancers (NEPCs) retained detectable levels of HOXB13. Notably, the reduced expression observed in NEPCs was associated with a gain of HOXB13 gene body CpG methylation. In comparison to the commonly used prostate lineage marker NKX3.1, HOXB13 showed greater sensitivity in detecting advanced metastatic prostate cancers. Additionally, in a cohort of 837 patients, 383 with prostatic and 454 with non-prostatic tumors, we found that HOXB13 immunohistochemistry had a 97% sensitivity and 99% specificity for prostatic origin. Taken together, our studies provide valuable insight into the expression pattern of HOXB13 during prostate development and cancer progression. Furthermore, our findings support the utility of HOXB13 as a diagnostic biomarker for prostate cancer, particularly to confirm the prostatic origin of advanced metastatic castration-resistant tumors. © 2023 The Pathological Society of Great Britain and Ireland.


Subject(s)
Prostatic Neoplasms, Castration-Resistant , Prostatic Neoplasms , Animals , Humans , Male , Mice , Genes, Homeobox , Homeodomain Proteins/genetics , Homeodomain Proteins/metabolism , Prostate/pathology , Prostatic Neoplasms/pathology , Prostatic Neoplasms, Castration-Resistant/metabolism , Transcription Factors/genetics , Transcription Factors/metabolism , United Kingdom
2.
Cancer Res Commun ; 3(11): 2358-2374, 2023 11 20.
Article in English | MEDLINE | ID: mdl-37823778

ABSTRACT

Castration-resistant prostate cancer (CRPC) consists of multiple phenotypic subtypes including androgen receptor (AR)-active prostate cancer (ARPC) and neuroendocrine prostate cancer (NEPC). Tumor cells with these phenotypes can coexist between metastases within a patient and within an individual tumor. Treatments that are effective across CRPC subtypes are currently lacking. Histone deacetylation is crucial for the regulation of chromatin structure and maintenance of cancer cell state and activation of the PI3K/AKT/mTOR signaling cascade is a tumor growth-promoting pathway. We therefore investigated combined targeting of histone deacetylase (HDAC) and PI3K using a rationally designed dual inhibitor, fimepinostat, in CRPC subtypes in vitro and in vivo. Dual HDAC1/2 and PI3K/AKT pathway inhibition by fimepinostat led to robust tumor growth inhibition in both ARPC and NEPC models including cell line- and patient-derived xenografts. HDAC1/2 inhibition combined with PI3K/AKT inhibition was more effective than targeting each pathway alone, producing growth inhibitory effects through cell-cycle inhibition and apoptosis. Molecular profiling revealed on-target effects of combined HDAC1/2 and PI3K/AKT inhibition independent of tumor phenotype. Fimepinostat therapy was also associated with the suppression of lineage transcription factors including AR in ARPC and Achaete-scute homolog 1 (ASCL1) in NEPC. Together, these results indicate that fimepinostat represents a novel therapeutic that may be effective against both ARPC and NEPC through CRPC subtype-dependent and -independent mechanisms. SIGNIFICANCE: CRPC is a heterogeneous disease constituting multiple phenotypic subtypes that often co-occur within tumors or across metastases in patients. Existing targeted therapies for CRPC do not take this into account. Here we show that fimepinostat, a dual HDAC1/2 and PI3K/AKT inhibitor investigated clinically in other cancer types but not prostate cancer, may overcome this heterogeneity by effectively inhibiting both ARPC and NEPC subtypes of CRPC.


Subject(s)
Prostatic Neoplasms, Castration-Resistant , Male , Humans , Prostatic Neoplasms, Castration-Resistant/drug therapy , Phosphatidylinositol 3-Kinases/genetics , Proto-Oncogene Proteins c-akt/genetics , Histone Deacetylases/genetics , Phenotype , Castration
3.
J Clin Invest ; 133(22)2023 11 15.
Article in English | MEDLINE | ID: mdl-37725435

ABSTRACT

Antibody-drug conjugates (ADCs) are a promising targeted cancer therapy; however, patient selection based solely on target antigen expression without consideration for cytotoxic payload vulnerabilities has plateaued clinical benefits. Biomarkers to capture patients who might benefit from specific ADCs have not been systematically determined for any cancer. We present a comprehensive therapeutic and biomarker analysis of a B7H3-ADC with pyrrolobenzodiazepine(PBD) payload in 26 treatment-resistant, metastatic prostate cancer (mPC) models. B7H3 is a tumor-specific surface protein widely expressed in mPC, and PBD is a DNA cross-linking agent. B7H3 expression was necessary but not sufficient for B7H3-PBD-ADC responsiveness. RB1 deficiency and/or replication stress, characteristics of poor prognosis, and conferred sensitivity were associated with complete tumor regression in both neuroendocrine (NEPC) and androgen receptor positive (ARPC) prostate cancer models, even with low B7H3 levels. Non-ARPC models, which are currently lacking efficacious treatment, demonstrated the highest replication stress and were most sensitive to treatment. In RB1 WT ARPC tumors, SLFN11 expression or select DNA repair mutations in SLFN11 nonexpressors governed response. Importantly, WT TP53 predicted nonresponsiveness (7 of 8 models). Overall, biomarker-focused selection of models led to high efficacy of in vivo treatment. These data enable a paradigm shift to biomarker-driven trial designs for maximizing clinical benefit of ADC therapies.


Subject(s)
Antineoplastic Agents , Immunoconjugates , Prostatic Neoplasms , Male , Humans , Immunoconjugates/pharmacology , Immunoconjugates/therapeutic use , Biomarkers, Tumor/genetics , Cell Line, Tumor , Xenograft Model Antitumor Assays , Prostatic Neoplasms/drug therapy , Prostatic Neoplasms/genetics , Antineoplastic Agents/therapeutic use , Nuclear Proteins
4.
Cancer Discov ; 13(3): 632-653, 2023 03 01.
Article in English | MEDLINE | ID: mdl-36399432

ABSTRACT

Advanced prostate cancers comprise distinct phenotypes, but tumor classification remains clinically challenging. Here, we harnessed circulating tumor DNA (ctDNA) to study tumor phenotypes by ascertaining nucleosome positioning patterns associated with transcription regulation. We sequenced plasma ctDNA whole genomes from patient-derived xenografts representing a spectrum of androgen receptor active (ARPC) and neuroendocrine (NEPC) prostate cancers. Nucleosome patterns associated with transcriptional activity were reflected in ctDNA at regions of genes, promoters, histone modifications, transcription factor binding, and accessible chromatin. We identified the activity of key phenotype-defining transcriptional regulators from ctDNA, including AR, ASCL1, HOXB13, HNF4G, and GATA2. To distinguish NEPC and ARPC in patient plasma samples, we developed prediction models that achieved accuracies of 97% for dominant phenotypes and 87% for mixed clinical phenotypes. Although phenotype classification is typically assessed by IHC or transcriptome profiling from tumor biopsies, we demonstrate that ctDNA provides comparable results with diagnostic advantages for precision oncology. SIGNIFICANCE: This study provides insights into the dynamics of nucleosome positioning and gene regulation associated with cancer phenotypes that can be ascertained from ctDNA. New methods for classification in phenotype mixtures extend the utility of ctDNA beyond assessments of somatic DNA alterations with important implications for molecular classification and precision oncology. This article is highlighted in the In This Issue feature, p. 517.


Subject(s)
Circulating Tumor DNA , Prostatic Neoplasms , Male , Humans , Circulating Tumor DNA/genetics , Nucleosomes/genetics , Precision Medicine , Prostatic Neoplasms/pathology , Gene Expression Regulation, Neoplastic , Phenotype
5.
Prostate Cancer Prostatic Dis ; 26(1): 194-200, 2023 03.
Article in English | MEDLINE | ID: mdl-36564459

ABSTRACT

BACKGROUND: Bipolar androgen therapy (BAT) results in rapid fluctuation of testosterone (T) between near-castrate and supraphysiological levels and has shown promise in metastatic castration-resistant prostate cancer (mCRPC). Its clinical effects may be mediated through induction of DNA damage, and preclinical studies suggest synergy with PARP inhibitors. PATIENTS AND METHODS: This was a single-center, Phase II trial testing olaparib plus BAT (T cypionate/enanthate 400 mg every 28 days) with ongoing androgen deprivation. Planned recruitment was 30 subjects (equal proportions with/without homologous recombination repair [HRR] gene mutations) with mCRPC post abiraterone and/or enzalutamide. The primary objective was to determine PSA50 response (PSA decline ≥50% from baseline) rate at 12-weeks. The primary analysis utilized the entire (intent-to-treat [ITT]) cohort, with those dropping out early counted as non-responders. Secondary/exploratory analyses were in those treated beyond 12-weeks (response-evaluable cohort). RESULTS: Thirty-six patients enrolled and 6 discontinued prior to response assessment. In the ITT cohort, PSA50 response rate at 12-weeks was 11/36 (31%; 95% CI 17-48%), and 16/36 (44%, 95% CI 28-62%) had a PSA50 response at any time on-study. After a median follow-up of 19 months, the median clinical/radiographic progression-free survival in the ITT cohort was 13.0 months (95% CI 7-17). Clinical outcomes were similar regardless of HRR gene mutational status. CONCLUSIONS: BAT plus olaparib is associated with high response rates and long PFS. Clinical benefit was observed regardless of HRR gene mutational status.


Subject(s)
Prostatic Neoplasms, Castration-Resistant , Male , Humans , Prostatic Neoplasms, Castration-Resistant/drug therapy , Prostatic Neoplasms, Castration-Resistant/genetics , Prostatic Neoplasms, Castration-Resistant/pathology , Androgens/therapeutic use , Treatment Outcome , Prostate-Specific Antigen/therapeutic use , Androgen Antagonists/therapeutic use , Nitriles/therapeutic use
6.
Cancer Res Commun ; 2(5): 277-285, 2022 05.
Article in English | MEDLINE | ID: mdl-36337169

ABSTRACT

Anaplastic lymphoma kinase (ALK) is a tyrosine kinase with genomic and expression changes in many solid tumors. ALK inhibition is first line therapy for lung cancers with ALK alterations, and an effective therapy in other tumor types, but has not been well-studied in prostate cancer. Here, we aim to delineate the role of ALK genomic and expression changes in primary and metastatic prostate cancer. We determined ALK expression by immunohistochemistry and RNA-Seq, and genomic alterations by NGS. We assessed functional consequences of ALK overexpression and pharmacological ALK inhibition by cell proliferation and cell viability assays. Among 372 primary prostate cancer cases we identified one case with uniformly high ALK protein expression. Genomic analysis revealed a SLC45A3-ALK fusion which promoted oncogenesis in in vitro assays. We observed ALK protein expression in 5/52 (9%) of metastatic prostate cancer cases, of which 4 of 5 had neuroendocrine features. ALK-expressing neuroendocrine prostate cancer had a distinct transcriptional program, and earlier disease progression. An ALK-expressing neuroendocrine prostate cancer model was sensitive to pharmacological ALK inhibition. In summary, we found that ALK overexpression is rare in primary prostate cancer, but more frequent in metastatic prostate cancers with neuroendocrine differentiation. Further, ALK fusions similar to lung cancer are an occasional driver in prostate cancer. Our data suggest that ALK-directed therapies could be an option in selected patients with advanced prostate cancer.


Subject(s)
Lung Neoplasms , Prostatic Neoplasms , Male , Humans , Anaplastic Lymphoma Kinase/genetics , Protein Kinase Inhibitors/pharmacology , Lung Neoplasms/drug therapy , Protein-Tyrosine Kinases/genetics , Prostatic Neoplasms/drug therapy
7.
Nat Commun ; 13(1): 6828, 2022 11 11.
Article in English | MEDLINE | ID: mdl-36369237

ABSTRACT

Cancer-associated fibroblasts (CAFs) mediate an immunosuppressive effect, but the underlying mechanism remains incompletely defined. Here we show that increasing prostatic stromal Foxf2 suppresses the growth and progression of both syngeneic and autochthonous mouse prostate cancer models in an immunocompetent context. Mechanistically, Foxf2 moderately attenuates the CAF phenotype and transcriptionally downregulates Cxcl5, which diminish the immunosuppressive myeloid cells and enhance T cell cytotoxicity. Increasing prostatic stromal Foxf2 sensitizes prostate cancer to the immune checkpoint blockade therapies. Augmenting lung stromal Foxf2 also mediates an immunosuppressive milieu and inhibits lung colonization of prostate cancer. FOXF2 is expressed higher in the stroma of human transition zone (TZ) than peripheral zone (PZ) prostate. The stromal FOXF2 expression level in primary prostate cancers inversely correlates with the Gleason grade. Our study establishes Foxf2 as a stromal transcription factor modulating the tumor immune microenvironment and potentially explains why cancers are relatively rare and indolent in the TZ prostate.


Subject(s)
Forkhead Transcription Factors , Prostate , Prostatic Neoplasms , Animals , Humans , Male , Mice , Forkhead Transcription Factors/genetics , Forkhead Transcription Factors/metabolism , Gene Expression Regulation , Prostate/pathology , Prostatic Neoplasms/pathology , Tumor Microenvironment/genetics
9.
Nat Cell Biol ; 24(4): 538-553, 2022 04.
Article in English | MEDLINE | ID: mdl-35411081

ABSTRACT

Skeletal muscle has long been recognized as an inhospitable site for disseminated tumour cells (DTCs). Yet its antimetastatic nature has eluded a thorough mechanistic examination. Here, we show that DTCs traffic to and persist within skeletal muscle in mice and in humans, which raises the question of how this tissue suppresses colonization. Results from mouse and organotypic culture models along with metabolomic profiling suggested that skeletal muscle imposes a sustained oxidative stress on DTCs that impairs their proliferation. Functional studies demonstrated that disrupting reduction-oxidation homeostasis via chemogenetic induction of reactive oxygen species slowed proliferation in a more fertile organ: the lung. Conversely, enhancement of the antioxidant potential of tumour cells through ectopic expression of catalase in the tumour or host mitochondria allowed robust colonization of skeletal muscle. These findings reveal a profound metabolic bottleneck imposed on DTCs and sustained by skeletal muscle. A thorough understanding of this biology could reveal previously undocumented DTC vulnerabilities that can be exploited to prevent metastasis in other more susceptible tissues.


Subject(s)
Neoplasms , Oxidative Stress , Animals , Mice , Muscle, Skeletal/metabolism , Neoplasms/metabolism , Oxidation-Reduction , Oxidative Stress/physiology , Reactive Oxygen Species/metabolism
10.
Prostate ; 82(5): 517-530, 2022 04.
Article in English | MEDLINE | ID: mdl-35014711

ABSTRACT

INTRODUCTION: The Wnt proteins play key roles in the development, homeostasis, and disease progression of many organs including the prostate. However, the spatiotemporal expression patterns of Wnt proteins in prostate cell lineages at different developmental stages and in prostate cancer remain inadequately characterized. METHODS: We isolated the epithelial and stromal cells in the developing and mature mouse prostate by flow cytometry and determined the expression levels of Wnt ligands. We used Visium spatial gene expression analysis to determine the spatial distribution of Wnt ligands in the mouse prostatic glands. Using laser-capture microscopy in combination with gene expression analysis, we also determined the expression patterns of Wnt signaling components in stromal and cancer cells in advanced human prostate cancer specimens. To investigate how the stroma-derived Wnt ligands affect prostate development and homeostasis, we used a Col1a2-CreERT2 mouse model to disrupt the Wnt transporter Wntless specifically in prostate stromal cells. RESULTS: We showed that the prostate stromal cells are a major source of several Wnt ligands. Visium spatial gene expression analysis revealed a distinct spatial distribution of Wnt ligands in the prostatic glands. We also showed that Wnt signaling components are highly expressed in the stromal compartment of primary and advanced human prostate cancer. Blocking stromal Wnt secretion attenuated prostate epithelial proliferation and regeneration but did not affect cell survival and lineage maintenance. DISCUSSION: Our study demonstrates a critical role of stroma-derived Wnt ligands in prostate development and homeostasis.


Subject(s)
Prostate , Prostatic Neoplasms , Animals , Cell Proliferation , Humans , Ligands , Male , Mice , Prostate/metabolism , Prostatic Neoplasms/genetics , Prostatic Neoplasms/metabolism , Stromal Cells/metabolism , Wnt Proteins/genetics , Wnt Signaling Pathway
11.
JCI Insight ; 6(23)2021 12 08.
Article in English | MEDLINE | ID: mdl-34877933

ABSTRACT

Cancers with homology-directed DNA repair (HRR) deficiency exhibit high response rates to poly(ADP-ribose) polymerase inhibitors (PARPi) and platinum chemotherapy. Though mutations disrupting BRCA1 and BRCA2 associate with HRR deficiency (HRRd), patterns of genomic aberrations and mutation signatures may be more sensitive and specific indicators of compromised repair. Here, we evaluated whole-exome sequences from 418 metastatic prostate cancers (mPCs) and determined that one-fifth exhibited genomic characteristics of HRRd that included Catalogue Of Somatic Mutations In Cancer mutation signature 3. Notably, a substantial fraction of tumors with genomic features of HRRd lacked biallelic loss of a core HRR-associated gene, such as BRCA2. In this subset, HRRd associated with loss of chromodomain helicase DNA binding protein 1 but not with mutations in serine-protein kinase ATM, cyclin dependent kinase 12, or checkpoint kinase 2. HRRd genomic status was strongly correlated with responses to PARPi and platinum chemotherapy, a finding that supports evaluating biomarkers reflecting functional HRRd for treatment allocation.


Subject(s)
DNA Repair-Deficiency Disorders/genetics , Genomics/methods , Prostatic Neoplasms/genetics , Animals , Disease Models, Animal , Humans , Male , Mice , Neoplasm Metastasis
13.
J Clin Invest ; 131(10)2021 05 17.
Article in English | MEDLINE | ID: mdl-33998604

ABSTRACT

Prostate cancer (PC) is driven by androgen receptor (AR) activity, a master regulator of prostate development and homeostasis. Frontline therapies for metastatic PC deprive the AR of the activating ligands testosterone (T) and dihydrotestosterone (DHT) by limiting their biosynthesis or blocking AR binding. Notably, AR signaling is dichotomous, inducing growth at lower activity levels, while suppressing growth at higher levels. Recent clinical studies have exploited this effect by administration of supraphysiological concentrations of T, resulting in clinical responses and improvements in quality of life. However, the use of T as a therapeutic agent in oncology is limited by poor drug-like properties as well as rapid and variable metabolism. Here, we investigated the antitumor effects of selective AR modulators (SARMs), which are small-molecule nonsteroidal AR agonists developed to treat muscle wasting and cachexia. Several orally administered SARMs activated the AR program in PC models. AR cistromes regulated by steroidal androgens and SARMs were superimposable. Coregulatory proteins including HOXB13 and GRHL2 comprised AR complexes assembled by both androgens and SARMs. At bioavailable concentrations, SARMs repressed MYC oncoprotein expression and inhibited the growth of castration-sensitive and castration-resistant PC in vitro and in vivo. These results support further clinical investigation of SARMs for treating advanced PC.


Subject(s)
Androgens/pharmacology , Neoplasm Proteins/agonists , Neoplasm Proteins/metabolism , Prostatic Neoplasms/metabolism , Receptors, Androgen/metabolism , Signal Transduction/drug effects , Animals , Cell Line, Tumor , Dihydrotestosterone/metabolism , Humans , Male , Mice , Mice, Inbred NOD , Mice, SCID , Neoplasm Proteins/genetics , Prostatic Neoplasms/genetics , Prostatic Neoplasms/pathology , Receptors, Androgen/genetics , Signal Transduction/genetics
14.
Cell Stem Cell ; 24(5): 753-768.e6, 2019 05 02.
Article in English | MEDLINE | ID: mdl-30982770

ABSTRACT

Cell-autonomous Wnt signaling has well-characterized functions in controlling stem cell activity, including in the prostate. While niche cells secrete Wnt ligands, the effects of Wnt signaling in niche cells per se are less understood. Here, we show that stromal cells in the proximal prostatic duct near the urethra, a mouse prostate stem cell niche, not only produce multiple Wnt ligands but also exhibit strong Wnt/ß-catenin activity. The non-canonical Wnt ligand Wnt5a, secreted by proximal stromal cells, directly inhibits proliefration of prostate epithelial stem or progenitor cells whereas stromal cell-autonomous canonical Wnt/ß-catenin signaling indirectly suppresses prostate stem or progenitor activity via the transforming growth factor ß (TGFß) pathway. Collectively, these pathways restrain the proliferative potential of epithelial cells in the proximal prostatic ducts. Human prostate likewise exhibits spatially restricted distribution of stromal Wnt/ß-catenin activity, suggesting a conserved mechanism for tissue patterning. Thus, this study shows how distinct stromal signaling mechanisms within the prostate cooperate to regulate tissue homeostasis.


Subject(s)
Epithelial Cells/physiology , Prostate/cytology , Stem Cells/physiology , Stromal Cells/physiology , Wnt-5a Protein/metabolism , Animals , Cell Proliferation , Cells, Cultured , Humans , Male , Mice , Mice, Inbred C57BL , Mice, SCID , Receptor Cross-Talk , Stem Cell Niche , Transforming Growth Factor beta/metabolism , Wnt Signaling Pathway , beta Catenin/metabolism
15.
Clin Cancer Res ; 25(1): 426-439, 2019 01 01.
Article in English | MEDLINE | ID: mdl-30181386

ABSTRACT

PURPOSE: Tumor androgens in castration-resistant prostate cancer (CRPC) reflect de novo intratumoral synthesis or adrenal androgens. We used C.B.-17 SCID mice in which we observed adrenal CYP17A activity to isolate the impact of adrenal steroids on CRPC tumors in vivo. EXPERIMENTAL DESIGN: We evaluated tumor growth and androgens in LuCaP35CR and LuCaP96CR xenografts in response to adrenalectomy (ADX). We assessed protein expression of key steroidogenic enzymes in 185 CRPC metastases from 42 patients. RESULTS: Adrenal glands of intact and castrated mice expressed CYP17A. Serum DHEA, androstenedione (AED), and testosterone (T) in castrated mice became undetectable after ADX (all P < 0.05). ADX prolonged median survival (days) in both CRPC models (33 vs. 179; 25 vs. 301) and suppressed tumor steroids versus castration alone (T 0.64 pg/mg vs. 0.03 pg/mg; DHT 2.3 pg/mg vs. 0.23 pg/mg; and T 0.81 pg/mg vs. 0.03 pg/mg, DHT 1.3 pg/mg vs. 0.04 pg/mg; all P ≤ 0.001). A subset of tumors recurred with increased steroid levels, and/or induction of androgen receptor (AR), truncated AR variants, and glucocorticoid receptor (GR). Metastases from 19 of 35 patients with AR positive tumors concurrently expressed enzymes for adrenal androgen utilization and nine expressed enzymes for de novo steroidogenesis (HSD3B1, CYP17A, AKR1C3, and HSD17B3). CONCLUSIONS: Mice are appropriate for evaluating adrenal impact of steroidogenesis inhibitors. A subset of ADX-resistant CRPC tumors demonstrate de novo androgen synthesis. Tumor growth and androgens were suppressed more strongly by surgical ADX than prior studies using abiraterone, suggesting reduction in adrenally-derived androgens beyond that achieved by abiraterone may have clinical benefit. Proof-of-concept studies with agents capable of achieving true "nonsurgical ADX" are warranted.


Subject(s)
Androgens/genetics , Cell Proliferation/genetics , Prostatic Neoplasms, Castration-Resistant/genetics , Receptors, Androgen/genetics , 17-Hydroxysteroid Dehydrogenases/genetics , Adrenal Glands/pathology , Adrenal Glands/surgery , Adrenalectomy , Aldo-Keto Reductase Family 1 Member C3/genetics , Androgens/biosynthesis , Animals , Cell Line, Tumor , Gene Expression Regulation, Neoplastic , Heterografts , Humans , Male , Mice , Multienzyme Complexes/genetics , Neoplasm Recurrence, Local , Progesterone Reductase/genetics , Prostatic Neoplasms, Castration-Resistant/pathology , Prostatic Neoplasms, Castration-Resistant/surgery , Steroid 17-alpha-Hydroxylase/genetics , Steroid Isomerases/genetics , Testosterone/genetics , Testosterone/metabolism
17.
PLoS One ; 13(6): e0198389, 2018.
Article in English | MEDLINE | ID: mdl-29856824

ABSTRACT

BACKGROUND: Niclosamide, an FDA-approved anti-helminthic drug, has activity in preclinical models of castration-resistant prostate cancer (CRPC). Potential mechanisms of action include degrading constitutively active androgen receptor splice variants (AR-Vs) or inhibiting other drug-resistance pathways (e.g., Wnt-signaling). Published pharmacokinetics data suggests that niclosamide has poor oral bioavailability, potentially limiting its use as a cancer drug. Therefore, we launched a Phase I study testing oral niclosamide in combination with enzalutamide, for longer and at higher doses than those used to treat helminthic infections. METHODS: We conducted a Phase I dose-escalation study testing oral niclosamide plus standard-dose enzalutamide in men with metastatic CRPC previously treated with abiraterone. Niclosamide was given three-times-daily (TID) at the following dose-levels: 500, 1000 or 1500mg. The primary objective was to assess safety. Secondary objectives, included measuring AR-V expression from circulating tumor cells (CTCs) using the AdnaTest assay, evaluating PSA changes and determining niclosamide's pharmacokinetic profile. RESULTS: 20 patients screened and 5 enrolled after passing all screening procedures. 13(65%) patients had detectable CTCs, but only one was AR-V+. There were no dose-limiting toxicities (DLTs) in 3 patients on the 500mg TID cohort; however, both (N = 2) subjects on the 1000mg TID cohort experienced DLTs (prolonged grade 3 nausea, vomiting, diarrhea; and colitis). The maximum plasma concentration ranged from 35.7 to 182 ng/mL and was not consistently above the minimum effective concentration in preclinical studies. There were no PSA declines in any enrolled subject. Because plasma concentrations at the maximum tolerated dose (500mg TID) were not consistently above the expected therapeutic threshold, the Data Safety Monitoring Board closed the study for futility. CONCLUSIONS: Oral niclosamide could not be escalated above 500mg TID, and plasma concentrations were not consistently above the threshold shown to inhibit growth in CRPC models. Oral niclosamide is not a viable compound for repurposing as a CRPC treatment. CLINICAL TRIAL REGISTRY: Clinicaltrials.gov: NCT02532114.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Niclosamide/administration & dosage , Phenylthiohydantoin/analogs & derivatives , Prostatic Neoplasms, Castration-Resistant/drug therapy , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/pharmacokinetics , Benzamides , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Resistance, Neoplasm/drug effects , Humans , Male , Maximum Tolerated Dose , Middle Aged , Neoplasm Metastasis , Niclosamide/adverse effects , Niclosamide/pharmacokinetics , Nitriles , Phenylthiohydantoin/administration & dosage , Phenylthiohydantoin/adverse effects , Phenylthiohydantoin/pharmacokinetics , Prostatic Neoplasms, Castration-Resistant/metabolism , Prostatic Neoplasms, Castration-Resistant/pathology
18.
J Urol ; 199(6): 1494-1501, 2018 06.
Article in English | MEDLINE | ID: mdl-29339080

ABSTRACT

PURPOSE: Prostate circulating tumor cells escape into peripheral blood and enter bone marrow as disseminated tumor cells, representing an early step before conventionally detectable metastasis. It is unclear how frequently this occurs in localized disease and existing detection methods rely on epithelial markers with low specificity and sensitivity. We used multiple methodologies of disseminated tumor cell detection in bone marrow harvested at radical prostatectomy. MATERIALS AND METHODS: Bone marrow was harvested from 208 clinically localized cases, 16 controls and 5 metastatic cases with peripheral blood obtained from 37 metastatic cases. Samples were evaluated at 4 centers with 4 distinct platforms using antibody enrichment with the AdnaTest (Qiagen®) or VERSA (versatile exclusion based rare sample analysis), or whole sample interrogation with the RareCyte platform (Seattle, Washington) or HD-SCA (high definition single cell assay) using traditional epithelial markers and prostate specific markers. We investigated the sensitivity and specificity of these markers by evaluating expression levels in control and metastatic cases. RESULTS: EpCAM, NKX3.1 and AR were nonspecifically expressed in controls and in most samples using AdnaTest with no relation to perioperative variables. Only 1 patient with localized disease showed positive results for the prostate specific marker PSA. With the VERSA platform no localized case demonstrated disseminated tumor cells. With the RareCyte and HD-SCA platforms only a single patient had 1 disseminated tumor cell. CONCLUSIONS: Evaluation across multiple platforms revealed that epithelial markers are nonspecific in bone marrow and, thus, not suitable for disseminated tumor cell detection. Using prostate specific markers disseminated tumor cells were typically not detected in patients with localized prostate cancer.


Subject(s)
Bone Marrow/pathology , Neoplastic Cells, Circulating/pathology , Prostatectomy/methods , Prostatic Neoplasms/pathology , Adult , Aged , Biopsy , Cohort Studies , Epithelial Cell Adhesion Molecule/analysis , Homeodomain Proteins/analysis , Humans , Kallikreins/analysis , Male , Middle Aged , Prostate/pathology , Prostate/surgery , Prostate-Specific Antigen/analysis , Prostatic Neoplasms/surgery , Receptors, Androgen/analysis , Transcription Factors/analysis
19.
Cancer Cell ; 32(4): 474-489.e6, 2017 10 09.
Article in English | MEDLINE | ID: mdl-29017058

ABSTRACT

Androgen receptor (AR) signaling is a distinctive feature of prostate carcinoma (PC) and represents the major therapeutic target for treating metastatic prostate cancer (mPC). Though highly effective, AR antagonism can produce tumors that bypass a functional requirement for AR, often through neuroendocrine (NE) transdifferentiation. Through the molecular assessment of mPCs over two decades, we find a phenotypic shift has occurred in mPC with the emergence of an AR-null NE-null phenotype. These "double-negative" PCs are notable for elevated FGF and MAPK pathway activity, which can bypass AR dependence. Pharmacological inhibitors of MAPK or FGFR repressed the growth of double-negative PCs in vitro and in vivo. Our results indicate that FGF/MAPK blockade may be particularly efficacious against mPCs with an AR-null phenotype.


Subject(s)
Fibroblast Growth Factors/physiology , Prostatic Neoplasms/pathology , Receptors, Androgen/physiology , Signal Transduction/physiology , Androgen Antagonists/therapeutic use , Animals , Cell Differentiation , Cell Line, Tumor , Fibroblast Growth Factors/antagonists & inhibitors , Humans , Inhibitor of Differentiation Protein 1/physiology , MAP Kinase Signaling System/drug effects , Male , Mice , Neoplasm Metastasis , Prostatic Neoplasms/drug therapy , Receptors, Fibroblast Growth Factor/antagonists & inhibitors , Receptors, Fibroblast Growth Factor/physiology
20.
Nat Med ; 22(4): 369-78, 2016 Apr.
Article in English | MEDLINE | ID: mdl-26928463

ABSTRACT

Tumor heterogeneity may reduce the efficacy of molecularly guided systemic therapy for cancers that have metastasized. To determine whether the genomic alterations in a single metastasis provide a reasonable assessment of the major oncogenic drivers of other dispersed metastases in an individual, we analyzed multiple tumors from men with disseminated prostate cancer through whole-exome sequencing, array comparative genomic hybridization (CGH) and RNA transcript profiling, and we compared the genomic diversity within and between individuals. In contrast to the substantial heterogeneity between men, there was limited diversity among metastases within an individual. The number of somatic mutations, the burden of genomic copy number alterations and aberrations in known oncogenic drivers were all highly concordant, as were metrics of androgen receptor (AR) activity and cell cycle activity. AR activity was inversely associated with cell proliferation, whereas the expression of Fanconi anemia (FA)-complex genes was correlated with elevated cell cycle progression, expression of the E2F transcription factor 1 (E2F1) and loss of retinoblastoma 1 (RB1). Men with somatic aberrations in FA-complex genes or in ATM serine/threonine kinase (ATM) exhibited significantly longer treatment-response durations to carboplatin than did men without defects in genes encoding DNA-repair proteins. Collectively, these data indicate that although exceptions exist, evaluating a single metastasis provides a reasonable assessment of the major oncogenic driver alterations that are present in disseminated tumors within an individual, and thus may be useful for selecting treatments on the basis of predicted molecular vulnerabilities.


Subject(s)
Ataxia Telangiectasia Mutated Proteins/genetics , E2F1 Transcription Factor/biosynthesis , Prostatic Neoplasms/genetics , Receptors, Androgen/biosynthesis , Retinoblastoma Protein/genetics , Adult , Aged , Carboplatin/administration & dosage , Cell Proliferation/drug effects , Comparative Genomic Hybridization , DNA Copy Number Variations/genetics , E2F1 Transcription Factor/genetics , Gene Expression Regulation, Neoplastic/drug effects , Genetic Variation , Genome, Human , Humans , Male , Middle Aged , Neoplasm Metastasis , Prostatic Neoplasms/drug therapy , Prostatic Neoplasms/pathology , Receptors, Androgen/genetics
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