Kate Liodaki
A5115819712- Molecular Biology Techniques and Applications
- Cancer Research and Treatments
- Endoplasmic Reticulum Stress and Disease
- Heat shock proteins research
- Mass Spectrometry Techniques and Applications
- Metabolomics and Mass Spectrometry Studies
- Machine Learning in Bioinformatics
Institute of Cancer Research
2025
Abstract Purpose: Advanced prostate cancer (PCa) is invariably fatal with the androgen receptor (AR) being a major therapeutic target. AR signaling inhibitors have improved overall survival for men advanced PCa, but treatment resistance inevitable and includes reactivation of signaling. Novel approaches targeting these mechanisms to block tumor growth an urgent unmet clinical need. One attractive strategy target heat shock proteins critical functional activity. Experimental Design: We first...
<p>NXP800-resistant 22Rv1 prostate cancer cell sublines demonstrate the reversal of NXP800-mediated phenotype. <b>A,</b> Long-term treatment cells with increasing concentrations (up to 2.5 μmol/L) DMSO (vehicle-C, white), CCT365248 (inactive-C, blue), and NXP800 (NXP800-R, red) led generation cell–derived sublines. Mean growth was determined after 5 days by CellTiter-Glo Luminescent Cell Viability Assay compared day 0 vehicle-C SD for each subline developed is shown....
<p>Supplementary figure 6: Inhibition of the unfolded protein response with ISRIB rescues NXP800-mediated suppression AR signaling and PCa model growth</p>
<p>GO cellular response to heat gene expression signature associates with AR signaling and poorer prognosis in men suffering from CRPC. <b>A</b> <b>G,</b> Two independent (PCF-SU2C ICR-RMH) transcriptome cohorts of patients Quantification GO each cohort CRPC the PCF-SU2C (<b>A</b>) ICR-RMH (<b>G</b>) cohorts. Biopsies (red dots) >80th percentile (dotted line) are shown. <b>B</b> <b>H,</b> Kaplan–Meier curves for...
<p>Supplementary figure 2: AR and AR-V7 bind members of the 70KDa heat shock protein family mediated cellular stress increases HSP72 expression, associates with GO Cellular Response to Heat gene expression signature, in PCa cells</p>
<p>NXP800 inhibits the growth of AR-dependent and AR-independent prostate cancer models with activation UPR inhibition key signaling pathways. <b>A</b> <b>B,</b> PDX-O [CP50, CP89, CP129, CP142 (<b>A</b>)], AR-positive (VCaP, LNCaP, LNCaP95, 22Rv1), AR-negative (PC3 DU145) cell lines (<b>B</b>) were treated vehicle (DMSO 0.1%) or various concentrations (5, 10, 50, 100, 250 nmol/L) NXP800 (active, red line), CCT365248 (inactive, blue in...
<p>Supplementary figure 1: Chemical structures of NXP800 and CCT365248</p>
<p>Supplementary figure 3: GO Cellular Response to Heat gene expression signature associates with AR signaling in CRPC transcriptomes</p>
<p>NXP800 activates the UPR and inhibits key signaling pathways identifying a novel mechanism of action in prostate cancer models. <b>A,</b> VCaP, LNCaP95, 22Rv1 cells were treated with 250 nmol/L CCT365248 (inactive) or NXP800 (active) for 24 hours prior to addition puromycin 30 minutes. PERK, phospho-eIF2α, ATF4 (PERK arm); ATF6 (ATF6 IRE1 (IRE1 arm) protein; E2F1; (incorporation surrogate protein synthesis); GAPDH (housekeeping) expression was determined by Western blot...
<p>Supplementary figure 4: NXP800 decreases basal HSP72 protein levels and blocks induction in response to HSP90 inhibition PCa cell lines</p>
<div>AbstractPurpose:<p>Advanced prostate cancer is invariably fatal, with the androgen receptor (AR) being a major therapeutic target. AR signaling inhibitors have improved overall survival for men advanced cancer, but treatment resistance inevitable and includes reactivation of signaling. Novel approaches targeting these mechanisms to block tumor growth an urgent unmet clinical need. One attractive strategy target heat shock proteins (HSP) critical functional...
<p>Supplementary figure 9: NXP800 demonstrates tolerability in a castration-resistant VCaP PCa cell line-derived mouse xenograft</p>
<p>Supplementary figure 7: NXP800 does not decrease basal HSP72 protein levels and HSP90 inhibitor-induced induction in NXP800-resistant 22Rv1 PCa cell sub-lines</p>
<p>NXP800 inhibits AR transactivation and signaling to inhibit the growth of aberrant prostate cancer models. <b>A–C,</b> VCaP (<b>A</b>), LNCaP95 (<b>B</b>), 22Rv1 (<b>C</b>) cells were treated with vehicle (DMSO 0.1%) or various concentrations (5, 10, 50, 100, 250 nmol/L) NXP800 (active, red line) CCT365248 (inactive, blue line), was determined after 5 days by CellTiter-Glo Luminescent Cell Viability Assay. Mean (compared vehicle;...
<p>Supplementary figure 10: NXP800 demonstrates limited impact on AR and AR-V7 protein levels associated signaling in-vivo but does induce apoptosis reduce cellular proliferation</p>
<p>NXP800 activates the UPR and inhibits E2F-mediated transcription to drive antitumor activity against castration-resistant VCaP prostate cancer cell line–derived mouse xenograft. <b>A</b> <b>B,</b> Castration-resistant emergent xenografts were treated with vehicle (<i>n</i> = 7, gray) or 35 mg/kg NXP800 (active, <i>n</i> 8, red) after tumors had established growth a defined dosing schedule for 38 days. Mean tumor volume (normalized...
<p>Supplementary figure 5: Enzalutamide inhibits AR signaling in enzalutamide responsive VCaP PCa cells but not resistant LNCaP95 and 22Rv1 cells.</p>
<p>Supplementary figure 8: NXP800 does not further impact AR transactivation or signaling in NXP800-resistant 22Rv1 PCa cell sub-lines.</p>