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Prostate adenocarcinoma is the second most commonly diagnosed cancer in men worldwide, and the initiating factors are unknown. Oncogenic TMPRSS2:ERG (ERG+) gene fusions are facilitated by DNA breaks and occur in up to 50% of prostate cancers. Infection-driven inflammation is implicated in the formation of ERG+ fusions, and we hypothesized that these fusions initiate in early inflammation-associated prostate cancer precursor lesions, such as proliferative inflammatory atrophy (PIA), prior to cancer development. We investigated whether bacterial prostatitis is associated with ERG+ precancerous lesions in unique cases with active bacterial infections at the time of radical prostatectomy. We identified a high frequency of ERG+ non–neoplastic-appearing glands in these cases, including ERG+ PIA transitioning to early invasive cancer. These lesions were positive for ERG protein by immunohistochemistry and ERG messenger RNA by in situ hybridization. We additionally verified TMPRSS2:ERG genomic rearrangements in precursor lesions using tricolor fluorescence in situ hybridization. Identification of rearrangement patterns combined with whole-prostate mapping in three dimensions confirmed multiple (up to eight) distinct ERG+ precancerous lesions in infected cases. We further identified the pathogen-derived genotoxin colibactin as a potential source of DNA breaks in clinical cases as well as cultured prostate cells. Overall, we provide evidence that bacterial infections can initiate driver gene alterations in prostate cancer. In addition, our observations indicate that infection-induced ERG+ fusions are an early alteration in the carcinogenic process and that PIA may serve as a direct precursor to prostate cancer.

Abstract Disclosure: A. Cruz Lebron: None. P.A. Balbuena-Almodóvar: None. L. Mummert: None. S.E. Ernst: None. M. Markowski: None. M. Rudek: None. J. Ridlon: None. K.S. Sfanos: None. Background: Advanced prostate cancer is often treated via a combination of androgen deprivation therapy (ADT) and androgen receptor axis-targeted therapy. Unfortunately, most individuals undergoing these therapies develop resistance to treatment, termed “castration resistance”, through an unknown mechanism. Previous studies demonstrated a potential link between the gut microbiota and treatment efficacy in metastatic castration resistant prostate cancer (mCRPC). This may be due in part to gut bacterial communities with the machinery to synthesize androgens using mechanisms distinct from human cells. Therefore, we hypothesized that androgen synthesis by the gut microbiota promotes prostate cancer growth and negatively impacts prostate cancer treatment, leading to non-responsiveness. Aims & Methods: This study aims to i) identify bacterial species responsible for gut androgen biosynthesis, ii) determine if circulating and fecal androgen levels in individuals with mCRPC correlate with treatment response using metagenomics and metabolomic studies, and iii) determine the relationship between gut androgen production and prostate cancer treatment response using in vivo mouse models. Results: Metagenomic sequencing showed an imbalance in microbial communities at the phylum level and identified the presence of androgen-synthesizing bacteria such as Clostridium scindens in fecal samples of individuals undergoing treatment with abiraterone acetate/prednisone (AA/P). Targeted LC/MS/MS analyses of fecal samples demonstrated the presence of testosterone, dihydrotestosterone and Δ1-Androstenedione (Δ1-AT) in the AA/P cohort. Furthermore, we demonstrate that C. scindens converts hydrocortisone and prednisone into the androgen precursor 11β-hydroxyandrost-4-ene-3,17-dione (11OHAD) and Δ1-AT in vitro at 48- and 72h post-treatment. Lastly, we have established a prostate cancer mouse model using a VCaP xenograft in which tumor growth was significantly inhibited by abiraterone acetate in comparison to than those treated with ADT alone. Additional studies will use this mouse model to study the effects of androgen metabolism by gut bacteria on AA/P efficacy. Conclusions: Overall, this study ascertains the ability of the human gut microbiota to harbor androgen-synthesizing bacteria, which in turn can be an alternative source of androgens that could impact prostate cancer treatment responsiveness. Presentation: Saturday, July 12, 2025

Homozygous biallelic inactivation of is thought to be rare in cancer. Herein we evaluate the prevalence of intratumoral (subclonal) complete p27 protein loss (IPPL) in primary prostate cancer. We used immunohistochemistry (IHC) for p27 in a large cohort of whole tissue sections from radical prostatectomy (n=412) and metastases from self-identified African American (AA) and European American (EA) individuals. IPPL was evaluated alongside mRNA hybridization and next generation sequencing of laser captured cancer regions. Cox proportional hazards analyses assessed the association of IPPL with biochemical recurrence and development of metastases after radical prostatectomy. IPPL was detected in 18.1% of AA versus 12.2% of EA cases and was tightly correlated with mRNA loss and biallelic genomic loss. IPPL was associated with ≥pT3 pathologic stage and pN1 disease, however these associations were only significant among AA participants. IPPL was further associated in both univariate and multivariate analyses with the development of biochemical recurrence and metastasis after primary treatment, specifically in AA individuals. The prevalence of p27 genomic alterations in metastatic disease is higher than that of primary prostate cancer in publicly available datasets as well as our analysis of autopsy cases via IHC, indicating that complete p27 loss may be selected for in metastatic disease. Subclonal biallelic loss of resulting in complete p27 protein loss is one of the most commonly occurring biallelic tumor suppressor genomic alterations in primary prostate cancer, and could contribute to worse prostate cancer outcomes, specifically in AA males.

Prostate cancer (PCa) remains a leading cause of cancer-related deaths in American men and treatment options for metastatic PCa are limited. There is a critical need to identify new mechanisms that contribute to PCa progression, that distinguish benign from lethal disease, and that have potential for therapeutic targeting. P2X4 belongs to the P2 purinergic receptor family that is commonly upregulated in cancer and is associated with poorer outcomes. Herein, we report that the P2X4 purinergic receptor is overexpressed in PCa, associated with PCa metastasis, and a driver of tumor development in vivo. We observed P2X4 protein expression primarily in epithelial cells of the prostate, a subset of CD66+ neutrophils, and most CD68+ macrophages. Our analysis of tissue microarrays representing 491 PCa cases demonstrated significantly elevated P2X4 expression in cancer compared to benign tissue spots, in prostatic intraepithelial neoplasia, in cancer from White compared to Black men, and in PCa with ERG positivity or with PTEN loss. High P2X4 expression in benign tissues was likewise associated with the development of metastasis after radical prostatectomy. Treatment with P2X4-specific agonist CTP increased transwell migration and invasion of PC3, DU145, and CWR22Rv1 PCa cells. P2X4 antagonist 5-BDBD treatment resulted in a dose-dependent decrease in viability of PC3, DU145, LNCaP, CWR22Rv1, TRAMP-C2, Myc-CaP, BMPC1, and BMPC2 cells and decreased DU145 cell migration and invasion. Knockdown of P2X4 attenuated growth, migration, and invasion of PCa cells. Finally, knockdown of P2X4 in Myc-CaP cells resulted in significantly attenuated subcutaneous allograft growth in FVB/NJ mice. Collectively, these data strongly support a role for the P2X4 purinergic receptor in PCa aggressiveness and identifies P2X4 as a candidate for therapeutic targeting.

Prostate adenocarcinoma is the second most commonly diagnosed cancer in men worldwide and the initiating factors are unknown. Oncogenic TMPRSS2:ERG (ERG+) gene fusions are facilitated by DNA breaks and occur in up to 50% of prostate cancers. Infection-driven inflammation is implicated in the formation of ERG+ fusions, and we hypothesized that these fusions initiate in early inflammation-associated prostate cancer precursor lesions, such as proliferative inflammatory atrophy (PIA), prior to cancer development. We investigated whether bacterial prostatitis is associated with ERG+ precancerous lesions in unique cases with active bacterial infections at time of radical prostatectomy. We identified a high frequency of ERG+ non-neoplastic-appearing glands in these cases, including ERG+ PIA transitioning to early invasive cancer. We verified TMPRSS2:ERG genomic rearrangements in precursor lesions using tri-color fluorescence in situ hybridization. Identification of rearrangement patterns combined with whole prostate mapping in 3 dimensions confirmed multiple (up to 8) distinct ERG+ precancerous lesions in infected cases. Finally, we identified the pathogen-derived genotoxin colibactin as a potential source of DNA breaks in clinical cases as well as cultured prostate cells. Overall, we provide evidence that bacterial infections initiate driver gene alterations in prostate cancer. Furthermore, infection-induced ERG+ fusions are an early alteration in the carcinogenic process and PIA may serve as a direct precursor to prostate cancer. Competing Interest Statement The authors have declared no competing interest.

Updates of SARS-CoV-2 vaccines are required to generate immunity in the population against constantly evolving SARS-CoV-2 variants of concerns (VOCs). Here we describe three novel in-silico designed spike-based antigens capable of inducing neutralising antibodies across a spectrum of SARS-CoV-2 VOCs. Three sets of antigens utilising pre-Delta (T2_32), and post-Gamma sequence data (T2_35 and T2_36) were designed. T2_32 elicited superior neutralising responses against VOCs compared to the Wuhan-1 spike antigen in DNA prime-boost immunisation regime in guinea pigs. Heterologous boosting with the attenuated poxvirus - Modified vaccinia Ankara expressing T2_32 induced broader neutralising immune responses in all primed animals. T2_32, T2_35 and T2_36 elicited broader neutralising capacity compared to the Omicron BA.1 spike antigen administered by mRNA immunisation in mice. These findings demonstrate the utility of structure-informed computationally derived modifications of spike-based antigens for inducing broad immune responses covering more than 2 years of evolved SARS-CoV-2 variants.