AR splice variant 7 expression

Notably, in this model, we found that vaccination in combination with enzalutamide, an AR antagonist, suppressed these aggressive immune suppressive cancers and resulted in enhanced survival in comparison to control vaccinated and enzalutamide-treated mice. While anti-PD-1 immune checkpoint inhibition (ICI) alone slowed tumor growth, the majority of vaccinated mice that received anti-PD-1 therapy showed complete tumor elimination. Collectively, these results validate the importance of AR signaling in prostate cancer immune suppression and suggest the potential of AR-V7-specific vaccines as therapeutic strategies against prostate cancer, offering significant protective and therapeutic anti-tumor responses, even in the presence of androgen signaling inhibitors.

Our study unravels AR-V7 as a marker for poor clinical outcomes, predicting breast cancer aggressiveness, and encourages consideration of AR-V7 as a probable target for therapeutic intervention.

The combination of high multiplex capacity and microscopy-based single-cell analysis is a unique and powerful feature of the CoDuCo in situ assay. This synergy enables the simultaneous identification and characterization of CTCs with epithelial, epithelial-mesenchymal, and neuroendocrine phenotypes, the detection of CTC clusters, the visualization of CTC heterogeneity, as well as the spatial investigation of tumor tissue. This assay holds significant potential as a tool for monitoring dynamic molecular changes associated with drug response and resistance in prostate cancer.

Moreover, ATC-324 remains potent in enzalutamide-resistant PCa cells. These results demonstrate the potential of the AUTOTAC platform to target previously considered undruggable proteins and overcome certain drug resistance mechanisms.

CDK8/19 inhibition significantly decreased PSA secretion in LNCaP and 22Rv1 cells and, when combined with enzalutamide, additively reduced proliferation in 22Rv1 cells. Our study revealed that MED12 and CDK8/19 regulate AR activity and that their inhibition may modulate response to enzalutamide in prostate cancer.

Liquid biopsy gives an early indication of docetaxel futility, could guide patient selection for continuing enzalutamide, and identifies cell cycle gene alterations as a potential cause of docetaxel resistance in mCRPC.

Genetically diverse PDM models provide a clinically relevant system for biomarker identification and personalized medicine in metastatic castration-resistant prostate cancer.

VTX-1 enables isolation of CTCs and plasma exosomes from a single blood draw and can be used for detecting AR-V7 and PSMA mRNA in both CTCs and cfRNA in patients with mCRPC and resistance to ARIs. This technology facilitates combining RNA measurements in CTCs and exosomal cfRNA for future studies to develop potentially clinically relevant cancer biomarker detection in blood.

Furthermore, overexpression of kinase-deficient CLK1 mutant leads to diminished AR-V7 levels during G2/M, underlining the essential contribution of CLK1's kinase activity in modulating AR-V7 expression. Collectively, our findings, for the first time, show periodic regulation of AR-V7 expression, its effect on cell cycle progression and the critical role of CLK1-pSRSF1 axis in modulating AR-V7 expression throughout the cell cycle.

Docetaxel has been recently shown to be an effective chemotherapeutic agent for high-volume metastatic hormone-sensitive PCa and metastatic castration-resistant PCa, and these increased efficacy create the impetus to assess the potential role of preoperative docetaxel in high-risk localized PCa...Therefore, suitable patient selection is crucial and pathological response might be a surrogate endpoint. Furthermore, we also found that molecular imaging prostate-specific membrane antigen (PSMA) PET/CT was a promising tool to evaluation the effectiveness of NCHT, and the expression status of AR, AR-V7, Ki-67, PTEN and TP53 might be helpful for urologists to identify more suitable candidates for NCHT.

Intraperitoneal injection of 10 mg/kg CAPE retarded the growth of 22Rv1 xenografts in nude mice and suppressed the protein levels of AR-V7, CDK1 and AKT in 22Rv1 xenografts. Our study provided the rationale of applying CAPE for inhibition of AR-V7 in prostate tumors.

Quantitative bone scan assessment with aBSI and CTC analyses are prognostic markers in patients treated with radium-223. AR-V7 expression in CTCs is a particularly promising prognostic biomarker and warrants validation in larger cohorts.

Next-generation androgen receptor signaling inhibitors (ARSIs), such as enzalutamide (Enza) and darolutamide (Daro), are initially effective for the treatment of advanced prostate cancer (PCa) and castration-resistant prostate cancer (CRPC). Our findings indicate that PAK1 represents a promising therapeutic target gene for the treatment of ARSI cross-resistant PCa patients in the clinic. STATEMENT OF SIGNIFICANCE: PAK1 drives ARSI cross-resistance in prostate cancer progression.

Bicalutamide inhibited PCa cell viability but not in the adapted cell lines...In vivo, high AR-expressing LNCaP cells proliferated under castrate conditions, while BAT-treated xenografts exhibited significant growth inhibition with low Ki-67 and mitotic indexes and a high cell death index. This study provides preliminary evidence that BAT is effective for the treatment of CRPC through rapid cycling between supraphysiologic and near-castrate serum testosterone levels, inducing an anti-tumor effect.

This confers ligand-independent transcriptional activity to AR-V7 and makes it susceptible to nonsteroidal antiandrogens such as Bicalutamide or Enzalutamide which target the LBD of AR. It can serve as a screening marker of poor clinical outcomes and aid in appropriate therapeutic intervention. These outcomes, however, seek extensive prospective validation.

TA1 also blocked the migration and malignant transformation of prostate cancer cells. Our data clearly demonstrate that using peptides to target the important interaction AR has with TM4SF3 provides a novel method to kill enzalutamide-resistant prostate cancer cells that can potentially lead to new more effective therapy for CRPC.

Consistent with a role of AR variants in taxane resistance, ectopically expressed AR-V7 increased BUB1 levels and reduced sensitivity to taxanes. This work shows that disruption of BUB1 kinase activity reverted resistance to taxanes, which is essential to advancing BUB1 as a potential therapeutic target for intractable chemotherapy resistant CRPC including AR variant driven CRPC, which lacks durable treatment options.

In only LNCaP cells, the NKX3-1 mRNA expression was significantly increased by transfection of an miR-3121-3p mimic but not that of the miR-449c-3p mimic. Thus, fibroblast-derived exosomal miR-3121-3p may be involved in preventing the oncogenic dedifferentiation of PCa cells by targeting NKX3-1 in androgen-sensitive, AR-dependent PCa cells.

P2, N=36, Active, not recruiting, OHSU Knight Cancer Institute | Trial completion date: Jun 2023 --> Jun 2024

Detection of AR-V7 in intact live CTC isolated by CytoGen's Smart BiopsyTM CTC isolator might overcome limitations of tissue biopsy. In this study, we developed a novel method of detection of AR-V7 in CTC with high sensitivity and specificity by in vitro assay and clinical test will be conducted for validation.

These results support further studies on Trop-2 as a therapeutic and diagnostic target for mCRPC.

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.

P1, N=6, Completed, Mamta Parikh | Active, not recruiting --> Completed | N=12 --> 6

Interestingly, nuclear TM4SF3 was co-recruited to the promoters of AR- and AR-V7-regulated genes and required for their expression, showing that TM4SF3 interaction is critical for their transcriptional functions. The results collectively show the multiple critical regulatory functions of TM4SF3 on AR or AR-V7 in prostate cancer cells.

Whilst the trial did not complete to target, we have ascertained that men with advanced cancer are willing to take part in trials utilising biomarker guided treatment. A number of issues were identified that serve as important learning points in future clinical trials.

Furthermore, oxLDL/LOX1 increases AR and AR-V7 expression and decreases enzalutamide cytotoxicity in CRPC. Thus, our investigation suggests that new factors associated with cardiovascular pathologies, such as LOX-1/oxLDL, may also promote important signaling axes for the progression of CRPC and its resistance to drugs used for its treatment.

Owing to its flexibility, we also confirmed that the developed approach can be used to detection of other AR-Vs, including AR-v3 and ARv567es. We expect that the further in-depth analyses including larger samples and clinical outcomes can discover clinical applicability of AR-Vs.

These data demonstrate the potential of AR and AR splice variants as immunologic targets of prostate cancer vaccines, which elicit AR specific T cell immunity and produce anti-tumor responses in prostate cancers.

More investigations are still warranted to clarify the association between CRPC and AR-V7 testing. https://www.crd.york.ac.uk/prospero/, identifier CRD42022297014.

pcPrF from PCa specimens increase the expression of aberrant AR-V7 in PCa cells. IL-8 may be a target for preventing the expression of aberrant AR-Vs in PCa.

The androgen receptor activity was assessed by reporter assay when the expression of signalling proteins was evaluated by immunoblotting. (20S,22R)-22-Acetoxy-21,22-cyclo-5α-cholest-5-ene with the moderate antiandrogenic potency revealed IC values of 18.4 ± 1.2 and 14.6 ± 1.4 µM against MCF-7 and 22Rv1 cells, respectively, and its effects on the expression of AR-V7, cyclin D1 and BCL2 were explored.

AR-V7 positivity predicted poor overall survival (OS). However, cabazitaxel-treated AR-V7 positive patients and those lacking AR-V7 positivity, who received cabazitaxel as standard of care, appeared to have similar OS. Therefore, despite the low response rate, cabazitaxel may still be an effective treatment in this poor prognosis, AR-V7 positive patient population.

Androgen receptor splice variant-7 (AR-V7) expression in circulating tumor cells (CTCs) in metastatic castration-resistant prostate cancer (mCRPC) is associated with abiraterone and enzalutamide resistance...This is the first prospective, open-label, Asian validation study of CBZ in Japanese patients with mCRPC after docetaxel (n = 48; four CBZ cycles; 2017-2020, Juntendo University Hospitals)...AR-V7 was not associated with CBZ resistance in CTCs. Reductions in BSI and PSA in early stages of CBZ treatment may predict OS.

The expression of AR splice variants such as AR-V7 in PCA patients following ADT might be a reason for reduced or absent therapy effects in patients on additional PARP inhibition due to the modulation of DNA repair gene expression. Consequently, AR-Vs should be further studied as predictive biomarkers for therapy response in this setting.

The combination of carotuximab and ARSI (i.e. enzalutamide or abiraterone) provided disease stabilization in four of nine assessable ARSI-refractory patients. Circulating tumor cell evaluation showed AR-V7 downregulation in the responsive subjects on combination treatment and revealed a three-gene panel that was predictive of response. The systemic antagonism of BMP/CD105 signaling can support ARSI re-sensitization in pre-clinical models and subjects that have otherwise developed resistance due to AR-V7 expression.

Ra seems to be a reasonable treatment for patients with metastatic castration-resistant prostate cancer and asymptomatic bone metastases progressing on novel hormonal therapy and had an acceptable safety profile.

This study demonstrates that further analytical validation and clinical qualification is required before AR-V7 can be considered for clinical use in CSPC as a predictive biomarker.

Overall, the findings reveal that prostate cancer cell interactions with the cellular and ECM components in the osteogenic microenvironment plays critical role in regulating AR-V7 associated with metastatic CRPC. Video Abstract.