AR amplification

This study revealed valuable findings for the clinical care of metastatic prostate cancer. Especially, predictive factors such as HRR defect in mCSPC should be validated in the future.

(Trial registration: ClinicalTrials.gov NCT04159896. Registration date: November 12, 2019.).

Our findings provide evidence that IDH1 hotspot mutations serve as driver alterations in this rare yet distinct molecular subset of PCa. Further studies are warranted to correlate response to androgen deprivation and IDH inhibitors.

The androgen receptor AR antagonists, such as enzalutamide and apalutamide, are efficient therapeutics for the treatment of prostate cancer (PCa). It potently inhibits cell growth with IC50 values of 4.87 ± 0.52 and 2.07 ± 0.34 μM in the LNCaP and 22RV1 cell lines, respectively, and exhibited effective tumor growth inhibition (TGI = 50.9 %) in the 22RV1 xenograft study. These data suggest that 20i has the potential for development as an AR/AR-V7 inhibitor with degradation ability to treat advanced prostate cancer.

Among 23 patients with castration-resistant prostate cancer (CRPC), 6 patients (26.1%) had one or a combination of several AR alterations, while only 2 out of 54 patients (3.7%) in the hormone-sensitive stage showed AR alterations. These findings were consistent with other studies and suggest that implementation of a comprehensive AR status detection in clinical practice is feasible and can support the treatment decision-making process.

The patient received docetaxel chemotherapy and pelvic radiotherapy. In a literature review, this case demonstrated the longest duration of effectiveness with olaparib alone without platinum-based chemotherapy. Additionally, the occurrence of relatively rare, fatal brain metastases in prostate cancer after a long period of CR suggests the necessity of regular brain imaging examinations.

In this real-world clinicogenomics database-driven study we explored the development of AR alterations and their association with ARTA treatment outcomes. Our study showed that AR amplifications are associated with longer time to progression on first ARTA treatment. Further prospective studies are needed to optimize therapeutic strategies for patients with AR alterations.

AR-amp was associated with high nadir PSA and low iPSA/PSA ratio. AR-amp was significantly associated with poor prognosis in Japanese patients with CRPC.

Our study revealed dynamic shifts in genetic mutations in pts with mCRPC following ARSi, PARPi and taxanes. Additionally, we highlight the prognostic significant of ctDNA burden in mCRPC. These data can help inform personalized sequential tx strategies for pts with mCRPC.

Although FGFRi treatments suppressed tumor growth across CRPC phenotypes, our analyses did not identify a single pathway or biomarker that would identify tumor response to FGFRi. This is very likely due to the array of FGFR1-4 expression and tumor phenotypes present in CRPC. Nevertheless, our data nominate the FGFR pathway as a clinically actionable target that promotes tumor growth in diverse phenotypes of treatment-refractory metastatic CRPC.

We identified genomic alterations (TP53 mutations, FOXA1 and AR amplification, RB1 and BRCA2 deletions) from primary prostate tumors that are predictive of wide-spread metastases and poor outcomes.

We identified genomic alterations (TP53 mutations, FOXA1 and AR amplification, RB1 and BRCA2 deletions) from primary prostate tumors that are predictive of wide-spread metastases and poor outcomes.

Analysis of PDX models by optical genome mapping and fluorescence in situ hybridization showed that AR residing on extrachromosomal DNA (ecDNA) was an underlying mechanism, and was associated with elevated levels and diversity of AR expression. This study identifies co-evolution of AR gene copy number and structural complexity via ecDNA as a mechanism associated with endocrine therapy resistance.

Using a ML approach that incorporates multiple omic features improves the prediction accuracy for metastatic prostate cancer outcomes significantly. Validation of these models will be needed in independent data sets in future.

Importantly, in castration resistant prostate cancer, ARVs lacking the LBD become constitutively active and promote hormone-independent development, underlining the need to concentrate on the other domain or the AR-DNA interface for the identification of novel actionable targets. In this review, we highlight the plasticity of AR-DNA binding and explain how fine-tuning AR's cooperative interactions with DNA translate into developing an alternative strategy to antagonize AR activity.

Second generation hormonal therapies such as abiraterone acetate and enzalutamide are typically given to men with CRPC. Lastly, we also found that the saracatinib-enzalutamide combination reduced DNA replication compared to the saracatinib-docetaxel combination, resulting in marked increased apoptosis. By elucidating this combination strategy, we provide pre-clinical data that suggests combining SRC kinase inhibitors with enzalutamide in select patients that express both AR-FL and AR-Vs.

Our data indicated that six tricyclic diterpenoids possess greater potency than enzalutamide (FDA-approved AR antagonist) towards LNCaP and 22Rv1 AR-positive cells, and four diterpenoids are more potent than enzalutamide against 22Rv1 AR-positive cells. The optimal derivative possesses greater potency (IC = 0.27 µM) and selectivity than QW07 towards AR-positive 22Rv1 cells.

As per the results obtained, the MM-PBSA binding energies of inhibitors 2,2'-((4-methoxyphenyl)methylene)bis(3,4-hydroxy-5,5-dimethylcyclohex-2-en-1-one is -132.456 kJ mol and 2,2'-(phenylmethylene)bis(3-hydroxy-5,5-dimethylcyclohex-2-en-1-one is -81.017 kJ mol . These results create a promising approach to drug design based on its fit to the structures of the receptor site rather than basing it on analogies to other active structures.

BAT responders are distinct from nonresponders in several ways however each of these distinctions are imperfect. Patterns of metastatic disease, prior therapies, duration of prior therapies, and genomics each contribute to an understanding of patients that will or will not respond. Additional studies are needed to refine the parameters that clinicians can utilize before choosing among the numerous treatment alternatives available for CRPC patients.

To date, the AR ligand-binding domain (LBD) is the only targeted region for all clinically available AR signaling antagonists, such as enzalutamide (ENZ)...SC428 inhibited in vitro proliferation and in vivo tumor growth of cells that expressed a high level of AR-V7 and were unresponsive to ENZ treatment. Together, these results indicated the potential therapeutic benefits of AR-NTD targeting for overcoming drug resistance in CRPC.

AR protein can be measured in CTCs with IF staining and is supported by the agreement with data from lpWGS. ARhigh CTC subpopulations can be detected at baseline for 1L-ARSI, but these cells were all cleared from circulation after 4-12 weeks of therapy. In a subset of patients at progression, resistance appears at least partially attributable to selection for ARhigh CTC subclones.

We identified genomic alterations (TP53 mutations, FOXA1 and AR amplification, RB1 and BRCA2 deletions) from primary prostate tumors that are predictive of wide-spread metastases and poor outcomes.

Uterine angioleiomyoma was identified as the cause of the coagulation abnormality. CCND2 and AR gene amplification was detected in the tumor. Uterine tumors that present with coagulopathy despite a clinical course suggestive of benign disease should undergo differential diagnosis for uterine angioleiomyoma.

We identified genomic alterations (TP53 mutations, FOXA1/AR amplification, RB1/BRCA2 deletion) from primary prostate carcinomas that are predictive of wide-spread metastases and poor outcome.

This study utilizes samples from a recently performed clinical trial for patients with CRPC that included sequential biopsies of soft tissue metastases before BAT and after 3 cycles of BAT and before patients were treated with nivolumab.Tumor cells were present in FFPE blocks for both the pretreatment and C4D1 time points for 24 of the patients...These results indicate that men who are likely to respond to high dose testosterone treatment harbor tumors that are immunologically distinct prior to treatment than those men unlikely to respond. Additional spatial analysis and comparisons with RNAseq data will be presented.

RIPTACs were optimized for oral bioavailability, and tumor ternary complex formation in prostate cancer cell line-derived xenograft models. RIPTAC therapeutics display nanomolar in vitro potency in AR:RIPTAC:EP ternary complex formation, which results in abrogation of the EP function and antiproliferative activity in prostate cancer cell lines, but not in AR-knockout control cells. Taken together, our in vitro mechanistic data and in vivo PD/efficacy observations in multiple prostate cancer models support further investigation of prostate cancer RIPTAC therapeutics as a novel heterobifunctional therapeutic modality in mCRPC.

We identify CIN as one of the strongest genetic predictors of poor patient outcomes in metastatic PCa. Future research is needed to identify therapeutic vulnerabilities in this newly-described genetic subset of aggressive prostate cancers.

As expected, only CRPC patients were positive for AR amplification, while interestingly the T877A mutation was identified in two patients still considered HSPC at the time. The ddPCR based analysis of AR alterations in cfDNA is highly economic, feasible, and informative to provide biomarker detection that may help to decide on the best follow-up therapy for CRPC patients.

Background: IMbassador250 was a prospective phase III international trial which showed no overall survival (OS) benefit for adding atezolizumab to enzalutamide for men with mCRPC who had prior progression on abiraterone. In this cohort TF < 2% at baseline is strongly associated with favorable OS on enzalutamide after progression on abiraterone compared to TF ≥ 2%. TF alone has comparable discriminatory ability to anticipate overall survival compared to all available clinical features combined, and adds significant prognostic power when combined with clinical features in this setting. AR amplifications, but not mutations, further improve strengths of association.

The AR inhibitor targeting NTD could potentially block the activation of both full-length AR and AR-Vs, thus overcoming major resistance mechanisms to current treatments. This review discusses the progress of research in various NTD inhibitors and provides new insight into the development of AR-NTD inhibitors.

Collectively, these PDX-PDXO pairs constitute a reliable new resource for in-depth studies of treatment-induced, AR-driven resistance mechanisms. Moreover, PDXOs can be leveraged for large-scale tumor-specific drug response profiling critical for accelerating therapeutic advances in CRPC.

SPOP mutation occurs in a moderate number of CAPC cases and is associated with lower TMPRSS2:ERG fusions, AR amplifications, cell cycle GA and MTOR pathway GA and higher frequencies of IO drug efficacy biomarkers including MSI, TMB and PD-L1 status. Further consideration of SPOP status in CAPC especially for planning hormonal and IO drug treatments appears warranted.

This special issue also highlights the therapeutic strategies to combat against resistant subtype. This issue comprehensively reviews the mCRPC and delivers the update in the forum of mCRPC resistance development.

Genomic alteration and survival analysis revealed that TP53 and SPOP mutations represented distinct molecular subtypes. Our data suggest that molecular stratification on the basis of TP53 and SPOP mutation status should be implemented for metastatic PCa to optimize and modify clinical decision-making.

Hormonal therapies including androgen deprivation therapy and androgen receptor (AR) pathway inhibitors such as abiraterone and enzalutamide have been widely used to treat advanced prostate cancer. Currently, precision medicine utilizing genetic and genomic data to choose suitable treatment for the patient is becoming to play an increasingly important role in clinical practice for prostate cancer management. Therefore, monitoring the AR mutation status is a promising approach for providing precision medicine in prostate cancer, which would be implemented through the development of clinically available testing modalities for AR mutations using liquid biopsy.

Protein phosphorylation, on the other hand, might be an important regulatory mechanism of PP1c isoforms' activity. Altogether, our results suggest differential expression, localization, and regulation of PP1c isoforms in PCa and support the need for investigating isoform-specific roles in prostate carcinogenesis in future studies.

Background AR gene alterations, detected by ctDNA sequencing, in the first line mCRPC setting were associated with worse outcomes on ARATs (abiraterone and enzalutamide) in a phase 2 trial (PMID: 29367197)...Receipt of docetaxel in the castration-sensitive setting was allowed...Table: 1399P Conclusions In this hypothesis-generating study, pts with mCRPC harboring AR alterations in ctDNA had worse outcomes on first-line ARAT compared to AR wt . These data may aid in patient counseling, prognostication, and treatment decision.

Conclusions SPOP mutation occurs in a moderate number of CAPC cases and is associated with fewer TMPRSS2:ERG fusions, AR amplifications, cell cycle GA and MTOR pathway GA and higher frequencies of IO drug efficacy biomarkers including MSI, TMB and PD-L1 status. Further consideration of SPOP status in CAPC especially for planning hormonal and IO drug treatments appears warranted.

Finally, we present evidence that this plastic dimer interface may have been adopted for transactivation at the expense of DNA binding. Our work highlights how fine-tuning AR's cooperative interactions translate to consequences in development and disease.

Finally, we present evidence this plastic dimer interface was adopted for transactivation at the expense of DNA binding. Our work highlights how fine-tuning AR's cooperative interactions translate to consequences in development and disease.

Prior treatment with enzalutamide, apalutamide, darolutamide, or experimental AR-directed therapies is not permitted. Bavdegalutamide, abiraterone, and a corticosteroid will be administered daily in 28-day cycles. Primary objectives are to evaluate the safety and tolerability of bavdegalutamide plus abiraterone and determine the recommended phase 2 dose and schedule of this combination (based on the incidence of first-cycle dose-limiting toxicities and the frequency and severity of adverse events and laboratory abnormalities).