NXP800 Activates the Unfolded Protein Response, Altering AR and E2F Function to Impact Castration-Resistant Prostate Cancer Growth.
Loading...
Embargo End Date
ICR Authors
Authors
Welti, J
Bogdan, D
Figueiredo, I
Coleman, I
Jiménez Vacas, J
Liodaki, K
Weigl, F
Buroni, L
Zeng, W
Bernett, I
Bertan, C
Roumeliotis, TI
Bhamra, A
Rekowski, J
Gurel, B
Neeb, AJ
Ning, J
Li, D
Gil, VS
Riisnaes, R
Miranda, S
Crespo, M
Ferreira, A
Tunariu, N
Pasqua, E
Chessum, N
Cheeseman, M
Te Poele, R
Powers, M
Carreira, S
Choudhary, J
Clarke, P
Banerji, U
Swain, A
Jones, K
Yuan, W
Workman, P
Nelson, PS
de Bono, JS
Sharp, A
Bogdan, D
Figueiredo, I
Coleman, I
Jiménez Vacas, J
Liodaki, K
Weigl, F
Buroni, L
Zeng, W
Bernett, I
Bertan, C
Roumeliotis, TI
Bhamra, A
Rekowski, J
Gurel, B
Neeb, AJ
Ning, J
Li, D
Gil, VS
Riisnaes, R
Miranda, S
Crespo, M
Ferreira, A
Tunariu, N
Pasqua, E
Chessum, N
Cheeseman, M
Te Poele, R
Powers, M
Carreira, S
Choudhary, J
Clarke, P
Banerji, U
Swain, A
Jones, K
Yuan, W
Workman, P
Nelson, PS
de Bono, JS
Sharp, A
Document Type
Journal Article
Date
2025-03-17
Date Accepted
2024-12-19
Abstract
PURPOSE: 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 with advanced prostate cancer, but treatment resistance is inevitable and includes reactivation of AR signaling. Novel therapeutic approaches targeting these mechanisms to block tumor growth is an urgent unmet clinical need. One attractive strategy is to target heat shock proteins (HSP) critical to AR functional activity. EXPERIMENTAL DESIGN: We first did transcriptome analysis on multiple castration-resistant prostate cancer (CRPC) cohorts to correlate the association between the Gene Ontology cellular response to heat gene expression signature and overall survival. Next, we analyzed the impact of targeting the heat shock factor 1 (HSF1) pathway, with an inhibitor in clinical development, namely, NXP800 (formerly CCT361814), in models of treatment-resistant prostate cancer. Finally, we confirmed our mechanistic and phenotypic findings using an NXP800-resistant model and an in vivo model of CRPC. RESULTS: We report that in multiple CRPC transcriptome cohorts, the Gene Ontology cellular response to heat gene expression signature associates with AR signaling and worse clinical outcome. We demonstrate the effects of targeting the HSF1 pathway, central to cellular stress, with an inhibitor in clinical development, namely, NXP800, in prostate cancer. Targeting the HSF1 pathway with the inhibitor NXP800 decreases HSP72 expression, activates the unfolded protein response, and inhibits AR- and E2F-mediated activity, inhibiting the growth of treatment-resistant prostate cancer models. CONCLUSIONS: Overall, NXP800 has antitumor activity against treatment-resistant prostate cancer models, including molecular subtypes with limited treatment options, supporting its consideration for prostate cancer-specific clinical development.
Citation
Clinical Cancer Research, 2025,
Source Title
Clinical Cancer Research
Publisher
AMER ASSOC CANCER RESEARCH
ISSN
1078-0432
eISSN
1557-3265
Collections
Research Team
Cancer Biomarkers
Paediatric Tumour Biology
Translational Therapeutic
Functional Proteomics
Adult DDU ICR & RM
Prote & Metabolomics Fac
RNA Bio & Mol Therap
Clinical Pharmacology
Development & Cancer
Signal Trans & Mol Pharma
PrCa Targeted Therapy
Paediatric Tumour Biology
Translational Therapeutic
Functional Proteomics
Adult DDU ICR & RM
Prote & Metabolomics Fac
RNA Bio & Mol Therap
Clinical Pharmacology
Development & Cancer
Signal Trans & Mol Pharma
PrCa Targeted Therapy