Abstract 5316: Risk of cognitive impairment associated with androgen deprivation therapy in prostate cancer

Abstract

Abstract Androgen deprivation therapy (ADT) is a commonly used clinical treatment for non-metastatic and metastatic hormone-sensitive prostate cancer. Long-term ADT treatment results in adverse side-effects in patients including depression, frailty, cognitive impairment and dementia. Studies have reported increased levels of pro-inflammatory cytokines and inflammatory markers in older cancer patients, however, the relationship between inflammatory biomarkers and the severity of cognition in prostate cancer patients under ADT has not been investigated. We sought to identify peripheral biomarkers that could provide links between the mental changes and major pathological mechanisms responsible for the development of cognition in these patients. For these studies, gene expression data (GSE69223) of 30 matched malignant and non-malignant prostate tissue samples from 15 prostate cancer patients receiving neoadjuvant antiandrogen therapy before prostatectomy, were compared in parallel with postmortem brain tissue samples of Parkinson's and Alzheimer patients as additional neurological diagnosis. IPA analysis was performed in the context of known biological response and regulatory networks. Fisher’s exact test for each network was converted to a score of −log10 (p-value). Further validation was performed in BT142-neural cells and M059K-glial cells by qRT-PCR with and without antiandrogen (enzalutamide) treatment. A total of 1952 DEGs were identified in postmortem brain tissue specimens, and 101 DEGs were identified in prostate cancer patients receiving ADT before surgery. IPA analysis revealed 33 commonly expressed genes with changes in cytokine-cytokine signaling network overlapped in both patient cohorts. Pathway analysis showed that IL17 signaling pathway, regulation of cytokine production and changes in T-cell subsets by IL-17A and IL-17F were overrepresented. Furthermore, lipopolysaccharide, tumor necrosis factor and toll-like receptors were identified as upstream transcriptional regulators of these signaling pathways. Gene expression of pro-inflammatory cytokines viz. LIFR, IL1RN, IL6, IL10 and LIF were increased in both neural and glial cells treated with enzalutamide, compared to non-enzalutamide treated cells. Our results suggest that changes in cytokine signaling under the influence of ADT in prostate cancer patients may linked with cognitive impairment presenting new areas for diagnostic and therapeutic development in combating brain deficits. Citation Format: Shiv Verma, Eswar Shankar, Viabhav Singh, Sanjay Gupta. Risk of cognitive impairment associated with androgen deprivation therapy in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5316.