Targeting adenocarcinoma and enzalutamide-resistant prostate cancer using the novel anti-androgen inhibitor ADA-308
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE267309 | GEO | 2024/07/08
REPOSITORIES: GEO
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Project description:Prostate cancer is the most commonly diagnosed and second-most lethal cancer among men in the United States. The vast majority of prostate cancer deaths are due to castration-resistant prostate cancer (CRPC) â?? the lethal form of the disease that has progressed despite therapies that interfere with activation of androgen receptor (AR) signaling. One emergent resistance mechanism to medical castration is synthesis of intratumoral androgens that activate the AR. This insight led to the development of the AR antagonist enzalutamide. However, resistance to enzalutamide invariably develops, and disease progression is nearly universal. One mechanism of resistance to enzalutamide is an F877L mutation in the AR ligand-binding domain that can convert enzalutamide to an agonist of AR activity. However, mechanisms that contribute to the agonist switch had not been fully clarified, and there were no therapies to block AR F877L. Using cell line models of castration-resistant prostate cancer (CRPC), we determined that cellular androgen content influences enzalutamide agonism of mutant F877L AR. Further, enzalutamide treatment of AR F877L-expressing cell lines recapitulated the effects of androgen activation of F877L AR or wild-type AR. Because the BET bromodomain inhibitor JQ-1 was previously shown to block androgen activation of wild-type AR, we tested JQ-1 in AR F877L-expressing CRPC models. We determined that JQ-1 suppressed androgen or enzalutamide activation of mutant F877L AR and suppressed growth of mutant F877L AR CRPC tumors in vivo, demonstrating a new strategy to treat tumors harboring this mutation. RNA-seq profiles of prostate cancer cell lines to understand gene expression associated with enzalutamide treatment
2016-06-10 | E-GEOD-69896 | biostudies-arrayexpress
Project description:Prostate cancer is the most commonly diagnosed and second-most lethal cancer among men in the United States. The vast majority of prostate cancer deaths are due to castration-resistant prostate cancer (CRPC) – the lethal form of the disease that has progressed despite therapies that interfere with activation of androgen receptor (AR) signaling. One emergent resistance mechanism to medical castration is synthesis of intratumoral androgens that activate the AR. This insight led to the development of the AR antagonist enzalutamide. However, resistance to enzalutamide invariably develops, and disease progression is nearly universal. One mechanism of resistance to enzalutamide is an F877L mutation in the AR ligand-binding domain that can convert enzalutamide to an agonist of AR activity. However, mechanisms that contribute to the agonist switch had not been fully clarified, and there were no therapies to block AR F877L. Using cell line models of castration-resistant prostate cancer (CRPC), we determined that cellular androgen content influences enzalutamide agonism of mutant F877L AR. Further, enzalutamide treatment of AR F877L-expressing cell lines recapitulated the effects of androgen activation of F877L AR or wild-type AR. Because the BET bromodomain inhibitor JQ-1 was previously shown to block androgen activation of wild-type AR, we tested JQ-1 in AR F877L-expressing CRPC models. We determined that JQ-1 suppressed androgen or enzalutamide activation of mutant F877L AR and suppressed growth of mutant F877L AR CRPC tumors in vivo, demonstrating a new strategy to treat tumors harboring this mutation.
2016-06-10 | GSE69896 | GEO
Project description:Targeting adenocarcinoma and enzalutamide-resistant prostate cancer using the novel anti-androgen inhibitor ADA-308
| PRJNA1111024 | ENA
Project description:In prostate cancer, androgen receptor (AR)-targeting agents are very effective in various stages of the disease. However, therapy resistance inevitably occurs and little is known about how tumor cells adapt to bypass AR suppression. Here, we performed integrative multi-omics analyses on tissues isolated before and after 3 months of AR-targeting enzalutamide monotherapy from high-risk prostate cancer patients enrolled in a neoadjuvant clinical trial. Transcriptomic analyses demonstrated that AR inhibition drove tumors towards a neuroendocrine-like disease state. In addition, epigenomic profiling revealed massive enzalutamide-induced reprogramming of pioneer factor FOXA1 – from inactive chromatin binding sites towards active cis-regulatory elements that dictate pro-survival signals. Notably, treatment-induced FOXA1 sites were enriched for the circadian rhythm core component ARNTL. Post-treatment ARNTL levels associated with poor outcome, and ARNTL suppression decreased cell growth in vitro. Our data highlight a remarkable cistromic plasticity of FOXA1 following AR-targeted therapy, and revealed an acquired dependency on circadian regulator ARNTL, a novel candidate therapeutic target.
2022-10-14 | PXD032041 | Pride
Project description:Background. Androgen receptor splice variant-7 (AR-V7) is a truncated form of the androgen receptor protein which lacks the ligand-binding domain, the target of enzalutamide and abiraterone, but remains constitutively active as a transcription factor. We hypothesized that detection of AR-V7 in circulating tumor cells (CTCs) from men with advanced prostate cancer would be associated with resistance to enzalutamide and abiraterone. Methods. We used quantitative reverse-transcription polymerase-chain-reaction (qRT-PCR) to interrogate CTCs for the presence or absence of AR-V7 from prospectively enrolled patients with metastatic castration-resistant prostate cancer initiating treatment with either enzalutamide or abiraterone. We examined associations between AR-V7 status and PSA response rates, PSA-progression-free-survival (PSA-PFS), clinical/radiographic-progression-free-survival (PFS), and overall survival (OS). Multivariable Cox regression analyses were performed to determine the independent effect of AR-V7 status on clinical outcomes. Results. Thirty-one enzalutamide-treated patients and thirty-one abiraterone-treated patients were enrolled, of which 38.7% and 19.4% had detectable AR-V7 from CTCs, respectively. Among men receiving enzalutamide, AR-V7–positive patients had inferior PSA response rates (0% vs 52.6%, P=0.004), PSA-PFS (median: 1.4 vs 6.0 months, P<0.001), PFS (median: 2.1 vs 6.1 months, P<0.001), and OS (median: 5.5 months vs not reached, P=0.002) compared to AR-V7–negative patients. Similarly, among men receiving abiraterone, AR-V7–positive patients had inferior PSA response rates (0% vs 68.0%, P=0.004), PSA-PFS (median: 1.3 months vs not reached, P<0.001), PFS (median: 2.3 months vs not reached, P<0.001), and OS (median: 10.6 months vs not reached, P=0.006). The negative prognostic impact of AR-V7 was maintained after adjusting for full-length-AR expression. Conclusions. Detection of AR-V7 in CTCs from patients with castration-resistant prostate cancer is associated with resistance to enzalutamide and abiraterone. A total of four metastatic castration-resistant prostate tumor samples from four patients were subjected to RNA-seq. Two samples were positive for androgen receptor splice variant 7 and the other two were negative for this variant.
2014-09-03 | E-GEOD-56701 | biostudies-arrayexpress
Project description:Inhibition of androgen-receptor (AR)signaling is the foundation of therapeutic regimens for advanced prostate cancers. However, nearly all patientsdevelop resistance and some never respond. To identify genes that mediate resistance to androgen ablation therapy, we performed an open reading frame (ORF) expression screen of17,255 ORFs and found that the transcription factorCREB5robustly conferred resistance to androgen deprivation and AR inhibition by enzalutamide. CREB5 overexpressionincreased enzalutamide-resistance 45-fold, enhanced resistance of tumor xenografts. CREB5 expression was also essential for enzalutamide-resistance patient-derived organoids. In clinical mCRPC, CREB5is frequently amplified and itsoverexpression positively correlated with castration resistance gene signatures including those of MYC and cell cycle. Mechanistically, CREB5 directly interacted at AR binding sites andenhanced site-specific AR bindingin enzalutamide. This dysregulated expression of 393 AR target genes including MYC and CDK1.These observations identifyCREB5asadriver of enzalutamide-resistance in a subset of advancedprostate cancer.
2019-09-21 | GSE137775 | GEO
Project description:Enzalutamide, a second-generation androgen receptor (AR) antagonist, has demonstrated clinical benefit in men with prostate cancer. However, it only provides a temporary response and modest increase in survival, indicating a rapid evolution of resistance. Previous studies suggest that enzalutamide may function as a partial transcriptional agonist, but the underlying mechanisms for enzalutamide-induced transcription remain poorly understood. Here, we show that enzalutamide stimulates expression of a novel subset of genes distinct from androgen-responsive genes. Treatment of prostate cancer cells with enzalutamide enhances recruitment of pioneer factor GATA2, AR, Mediator subunits MED1 and MED14, and RNA Pol II to regulatory elements of enzalutamide-responsive genes. Mechanistically, GATA2 functions in directing AR, Mediator and Pol II loading to enzalutamide-responsive gene loci. Importantly, the GATA2 inhibitor K7174 inhibits enzalutamide-induced transcription by decreasing binding of the GATA2/AR/Mediator/Pol II transcriptional complex, contributing to sensitization of prostate cancer cells to enzalutamide treatment. Our findings provide mechanistic insight into the future combination of GATA2 inhibitors and enzalutamide for improved AR-targeted therapy.
2019-09-03 | GSE125014 | GEO
Project description:Prostate cancer patients benefit from treatment with androgen receptor signaling inhibitors such as AR antagonists. The emergence of resistance to the clinically applied AR antagonists opens up the need for development of alternative AR antagonists. We show here the development of a novel AR antagonists that is structurally different from enzalutamide. Moreover, MEL-6 remains active in the presence of several AR mutations (T877A, W741C and F876L) that are found in patients resistant to hydroxyflutamide, bicalutamide and enzalutamide. To validate the androgen receptor (AR) as the target of our experimental AR antagonist, MEL-6, we investigated the effect of MEL-6 treatment on the prostate cancer cell line, LNCaP.
2024-02-05 | GSE243329 | GEO
Project description:The treatment of advanced prostate cancer has been transformed by novel antiandrogen therapies such as enzalutamide. Using the LnCaP/AR xenograft model, we identified induction of glucocorticoid receptor (GR) expression as a common feature of drug resistant tumors. From a resistant xenograft tumor, we derived a GR expressing resistant subline called LREX' which maintains the resistant phenotype. mRNA expression was used to characterize resistant tissues. LnCaP/AR cells were injected into castrate mice and tumors were established. Mice were then treated with vehicle (Con), 4 days of anti-androgen (ARN-509 10mgkg), or were maintained on anti-androgen (10mg/kg ARN-509 or enzalutamide) until emergence of resistance. Resistant tissues continued to be exposed to anti-androgen through time of harvest. LREX' (LnCaP/AR Resistant to Enzalutamide Xenograft Derived) was derived from an enzalutamide resistant xenograft and was re-injected into castrate mice undergoing continual treatment with enzalutamide. The GR probe on the Illumina array failed to detect GR expression. Therefore, GR expression as determined by qPCR is annotated separately. Of the 10 control tissues, 8 were analyzed twice (technical duplicates annotated as A and B).
2013-12-27 | E-GEOD-51873 | biostudies-arrayexpress
Project description:Androgen-deprivation therapy is a standard treatment for advanced prostate cancer. However, most patients eventually acquire resistance and progress to castration-resistant prostate cancer (CRPC). In this study, we established new CRPC cell lines, AILNCaP14 and AILNCaP15, from LNCaP cells under androgen-deprived conditions. Unlike most pre-existing CRPC cell lines, both cell lines expressed higher levels of androgen receptor (AR) and prostate-specific antigen (PSA) than parental LNCaP cells. Moreover, these cells exhibited primary resistance to enzalutamide. Since AR signaling plays a significant role in the development of CRPC, PSA promoter sequences fused with GFP were introduced into AILNCaP14 cells to conduct GFP fluorescence-based chemical screening. We identified flavopiridol, a broad spectrum CDK inhibitor, as a candidate drug that could repress AR transactivation of CRPC cells, presumably through the inhibition of phosphorylation of AR on the serine 81 residue (pARSer81). Importantly, this broad spectrum CDK inhibitor inhibited the proliferation of AILNCaP14 cells both in vitro and in vivo. Moreover, a newly developed liver metastatic model using AILNCaP15 cells revealed that the compound attenuated tumor growth of CRPC harboring highly metastatic properties. Finally, we developed a patient-derived xenograft (PDX) model of CRPC and DCaP CR from a patient presenting therapeutic resistance to enzalutamide, abiraterone, and docetaxel. Flavopiridol successfully suppressed the tumor growth of CRPC in this PDX model. Since ARSer81 was found to be phosphorylated in clinical CRPC samples, our data suggested that broad spectrum CDK inhibitors, might be a potent candidate drug for the treatment of CRPC, including those exhibiting primary resistance to enzalutamide.
2024-02-28 | GSE258991 | GEO