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.
4 days ago
Journal • Metastases
|
AR (Androgen receptor)
|
AR expression • AR splice variant 7 • AR-V7 expression • AR-V7 positive • FOLH1 positive • AR splice variant 7 expression
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.
13 days ago
Journal
|
AR (Androgen receptor) • CDK1 (Cyclin-dependent kinase 1)
|
AR splice variant 7 • AR-V7 expression • AR-V7 overexpression • AR splice variant 7 expression
We showed that AR-FL and AR-V7 form heterodimers that localize to the nucleus, whereas AR-V7/AR-V7 dimers were found to localize in the absence of androgens in the nucleus.
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.
2 months ago
Journal • Metastases
|
AR (Androgen receptor)
|
AR splice variant 7 • AR-V7 expression • AR splice variant 7 expression
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.
2 months ago
Journal
|
RELA (RELA Proto-Oncogene)
|
AR splice variant 7 • AR-V7 expression • AR splice variant 7 expression
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.
3 months ago
Preclinical • Journal
|
AR (Androgen receptor)
|
AR overexpression • AR expression • AR splice variant 7 • AR-V7 expression • AR splice variant 7 expression
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.
7 months ago
Journal
|
AR (Androgen receptor)
|
AR expression • AR splice variant 7 • AR-V7 expression • AR splice variant 7 expression
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.
7 months ago
Journal
|
AR (Androgen receptor) • BUB1 (BUB1 Mitotic Checkpoint Serine/Threonine Kinase)
|
AR expression • AR splice variant 7 • AR-V7 expression • AR splice variant 7 expression
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.
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.
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.
1 year ago
Journal
|
AR (Androgen receptor)
|
AR expression • AR splice variant 7 • AR-V7 expression • AR splice variant 7 expression
Ectopic ARv7 overexpression not only enhanced 22Rv1 or PC-3 cell growth and invasion in vitro but also the tumor growth of PC-3 cells in vivo. These results indicate that an androgen receptor induces MALT1 expression androgen-dependently and -independently in ARFL- or ARv7-overexpressed prostate cancer cells, suggesting a novel ARv7/MALT1/NF-κB-signaling pathway may exist in the cells of prostate cancer.
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.
1 year ago
Review • Journal • Metastases
|
AR (Androgen receptor)
|
AR splice variant 7 • AR-V7 expression • AR splice variant 7 expression
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.
1 year ago
Journal
|
AR (Androgen receptor) • IL6 (Interleukin 6) • STAT3 (Signal Transducer And Activator Of Transcription 3)
|
AR expression • AR splice variant 7 • AR-V7 expression • AR splice variant 7 expression • IL6 expression • OLR1 overexpression
These results indicate that AR-SVs are not restricted to CRPC, but also are expressed in primary PCa at higher rate than previously reported. Future investigation of the relative expression of NTD vs. LBD AR-SVs could guide the use of newly developed treatments targeting the NTD earlier in the treatment paradigm.
1 year ago
Journal
|
AR (Androgen receptor)
|
AR expression • AR splice variant 7 • AR-V7 expression • AR-V7 positive • AR negative
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.
1 year ago
Clinical
|
AR (Androgen receptor)
|
AR splice variant 7 • AR-V7 expression • AR-V7 positive • AR splice variant 7 expression
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.
1 year ago
PD(L)-1 Biomarker • IO biomarker
|
AR (Androgen receptor)
|
AR overexpression • AR expression • AR splice variant 7 • AR-V7 expression • AR splice variant 7 expression
More investigations are still warranted to clarify the association between CRPC and AR-V7 testing. https://www.crd.york.ac.uk/prospero/, identifier CRD42022297014.
1 year ago
Review
|
AR (Androgen receptor)
|
AR expression • AR splice variant 7 • AR-V7 expression • AR-V7 positive • AR splice variant 7 expression
Our results suggest that the AR-V7 exacerbates the c-MYC-driven hepatocarcinogenesis by potentiating the oncogenic roles and minimizing the anti-oncogenic functions of c-MYC. Since AR-V7 is expressed in a subpopulation of HCC cases, it could contribute to the inter- and intra-heterogeneity of HCC.
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.
over 1 year ago
Journal • IO biomarker
|
BCL2 (B-cell CLL/lymphoma 2) • CCND1 (Cyclin D1)
|
BCL2 expression • AR expression • AR splice variant 7 • AR-V7 expression • CCND1 expression • AR splice variant 7 expression
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.
over 1 year ago
Journal
|
AR (Androgen receptor)
|
AR splice variant 7 • AR-V7 expression • AR-V7 positive • AR splice variant 7 expression
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.
over 1 year ago
Journal • Circulating Tumor Cells
|
AR (Androgen receptor)
|
AR expression • AR splice variant 7 • AR-V7 expression • AR-V7 positive • AR splice variant 7 expression
ARV7 expression was independently associated with shorter CRPC-FS (HR 1.5, 95% CI 1.1-2.1, p = 0.008) and OS (HR 1.8, 95% CI 1.2-2.6, p = 0.004), high ESR2 was associated with longer OS (HR 0.5, 95% CI 0.2-1, p = 0.048) and low expression of RB1 was independently associated with shorter OS (HR 1.9, 95% CI 1.1-3.2, p = 0.014). (4) AR, ESR, and TSG expression signatures, as well as ARV7, RB1, and ESR2 expression, have a prognostic value in mHSPC patients treated with ADT+DX.
over 1 year ago
Clinical data • Journal
|
ER (Estrogen receptor) • TP53 (Tumor protein P53) • PTEN (Phosphatase and tensin homolog) • AR (Androgen receptor) • RB1 (RB Transcriptional Corepressor 1)
|
AR expression • AR splice variant 7 • AR-V7 expression • ER expression • ER overexpression
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.
over 1 year ago
Journal • PARP Biomarker
|
AR (Androgen receptor)
|
AR expression • AR splice variant 7 • AR-V7 expression • AR splice variant 7 expression
Besides, ZIC5 inhibition reduced AR and AR-V7 protein expression and enhanced the sensitivity of PCa to enzalutamide (Enz) treatment, both in vitro and in vivo. These findings indicate that the reciprocal activation between AR and ZIC5 promotes metastasis and Enz resistance of PCa and suggest the therapeutic value of cotargeting ZIC5 and AR for the treatment of advanced PCa.
over 1 year ago
Journal
|
AR (Androgen receptor) • TWIST1 (Twist Family BHLH Transcription Factor 1) • MIR27B (MicroRNA 27b) • NCOA3 (Nuclear Receptor Coactivator 3) • ZIC5 (Zic Family Member 5)
|
AR expression • AR splice variant 7 • AR-V7 expression
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.
over 1 year ago
Journal
|
AR (Androgen receptor) • IL6 (Interleukin 6) • ARSI (Arylsulfatase Family Member I) • ENG (Endoglin) • RBM38 (RNA Binding Motif Protein 38)
|
AR expression • AR splice variant 7 • AR-V7 expression • AR splice variant 7 expression • IL6 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.
over 1 year ago
P2 data • Clinical Trial,Phase II • Journal
|
AR (Androgen receptor)
|
AR expression • AR splice variant 7 • AR-V7 expression • AR splice variant 7 expression