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 with advanced PCa, 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 critical to AR functional activity.
We first did transcriptome analysis on multiple castration-resistant PCa (CRPC) cohorts to correlate the association between the GO 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, in models of treatment-resistant PCa. 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 GO 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 (formerly CCT361814), in PCa. 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 PCa models.
Overall, NXP800 has anti-tumor activity against treatment-resistant PCa models, including molecular subtypes with limited treatment options, supporting its consideration for PCa-specific clinical development.
Clinical cancer research : an official journal of the American Association for Cancer Research. 2025 Jan 09 [Epub ahead of print]
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
Institute of Cancer Research, London, United Kingdom., Institute of Cancer Research, Sutton, Surrey, United Kingdom., Fred Hutchinson Cancer Center, Seattle, WA, United States., Institute of Cancer Research, Sutton, United Kingdom., Institute of Cancer Research, London, Surrey, United Kingdom., Institute of Cancer Research, Surrey, United Kingdom., University of Washington, Seattle, United States., The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, London, United Kingdom., Royal Marsden Hospital, Surrey, United Kingdom., Boehringer Ingelheim., Institute of Cancer Research, London, London, United Kingdom.