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posted on 2025-03-17, 07:21 authored by Jonathan Welti, Denisa Bogdan, Ines Figueiredo, Ilsa Coleman, Juan Jiménez Vacas, Kate Liodaki, Franziska Weigl, Lorenzo Buroni, Wanting Zeng, Ilona Bernett, Claudia Bertan, Theodoros I. Roumeliotis, Amandeep Bhamra, Jan Rekowski, Bora Gurel, Antje J. Neeb, Jian Ning, Dapei Li, Veronica S. Gil, Ruth Riisnaes, Susana Miranda, Mateus Crespo, Ana Ferreira, Nina Tunariu, Elisa Pasqua, Nicola Chessum, Matthew Cheeseman, Robert te Poele, Marissa Powers, Suzanne Carreira, Jyoti Choudhary, Paul Clarke, Udai Banerji, Amanda Swain, Keith Jones, Wei Yuan, Paul Workman, Peter S. Nelson, Johann S. de Bono, Adam Sharp Supplementary figure 4: NXP800 decreases basal HSP72 protein levels and blocks HSP72 protein induction in response to HSP90 inhibition in PCa cell lines
Funding
Prostate Cancer UK (ProstateUK)
Prostate Cancer Foundation (PCF)
Medical Research Council (MRC)
Academy of Medical Sciences (The Academy of Medical Sciences)
Wellcome Trust (WT)
NIHR Biomedical Research Centre, Royal Marsden NHS Foundation Trust/Institute of Cancer Research (BRC)
National Institute of Health Sciences (NIHS)
Cancer Research UK (CRUK)
Chordoma Foundation (CF)
Mark Foundation For Cancer Research (The Mark Foundation for Cancer Research)
Bone Cancer Research Trust (BCRT)
CRIS Cancer Foundation (CRIS Foundation)
History
ARTICLE ABSTRACT
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.
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.
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.
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.
