Method development for identification of targetable genes in ADT-induced prostate cancer dormancy : the case of Interleukin-33

Background: Prostate cancer is the most common cancer in Canadian men. Androgen receptor drives PCa, and androgen deprivation therapy is the standard of care for advanced PCa, initially ADT elicits a response but often leads to ADT-induced dormancy that precedes relapse to castration-resistant PCa, which is incurable. This underscores the need to better understand tumor dormancy, identify critical genes for dormant cell survival, and develop therapies to target cancer in the earlier disease state when it is more easily treated. We hypothesize that dormancy PDX models provide accurate tumor recapitulation for study of actionable disease targets through wet lab and computational methodology. We will use IL33 as an example for this study. Materials and Methods: A panel of hormone-naïve PCa PDX models were used to establish ADT-induced dormancy. Bulk RNA sequencing of PDX models were analysed to assess IL33 RNA expression. IL33 protein was examined by IHC on sections taken pre-castration and during dormancy. The same methods were applied to FVB Myc-CaP models to recapitulate the immunocompetent TME at chronological timepoints following ADT. We carried out sequencing analysis on clinical cohorts and IHC staining on ADT-treated tissue microarrays. Functional analysis was carried out using single cell sequencing of the LTL331 model in the dormant stage and clinical cohorts for correlation analysis. Results: We confirmed a significant upregulation of IL33 in PDX models at both RNA and protein levels in the dormant stage. Importantly we also found upregulation of IL33 in Myc-CaP immunocompetent mouse models after host-castration. This was also observed in several cohorts of ADT-treated clinical PCa samples, suggesting IL33 is clinically relevant. Using a single cell sequencing dataset of LTL331 model, we also discovered the enrichment of IL33 in a dormant cluster and predicted function roles of IL33 in PCa dormancy. Conclusion: Our results establish a enrichment of IL33 in ADT-induced dormancy in PCa. We confirmed IL33 upregulation across multiple PDX and immunocompetent mouse models, and established clinical relevance of IL33 upregulation following ADT. We also predicted functional roles for IL33 in dormancy by computational methods. This study has successfully established a reproducible methodology for analysis of target genes in ADT-induced dormancy.

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