Abstract 3341: Systemic targeted JAK1/2 therapy for mouse Pten-deficient prostate cancer model influences the diversity and composition of the gut microbiome
Authors: De Velasco Marco A. , Sakai Kazuko , Kura Yurie , Ando Naomi , Sako Noriko , Yoshikawa Kazuhiro , Nishio Kazuto , Uemura Hirotsugu 
Published: September 2020

Modulation of immune response by gut microbiota is believed to play a key role in determining response to anticancer therapy. Conversely, anticancer therapies have the potential to alter resident microbiota and the implications are unknown. We previously showed the antitumor efficacy of targeted JAK1/2 inhibition in a preclinical mouse model of prostate cancer and are now exploring its effectiveness as an immune modulator in prostate cancer therapy. We have also shown that androgen withdrawal can turn a poorly inflamed tumor into an inflamed tumor. In this follow-up study, we examine the effects of targeted JAK1/2 cancer therapy on the gut microbiome. For this we utilize 16S rDNA amplicon sequencing to profile the fecal microbiota (proximal and distal colon) of normal wildtype (WT) and tumor bearing conditional Pten-knockout (KO) mice treated for four weeks with the JAK1/2 inhibitor AZD1480 alone or in combination with orchidectomy. Mice treated with AZD1480 had lower tumor burden compared to control mice. Alpha diversity of fecal microbiota was greater in castrated KO mice compared intact WT and KO mice and mice receiving AZD1480 tended to have lower diversity regardless of castration status. Significant compositional differences were observed between the colonic microbiota of all experimental groups. Overall, mice treated with AZD1480, regardless of castration status resulted in decreased abundance of Clostridiaceae, F16, Gemellaceae, Odoribacteraceae, Rikenellaceae, and Lactobacillaceae and an increase of Paraprevotellaceae, Porphyromonadaceae, Verrucomicrobiaceae, Bifidobacteriaceae bacterial families. In the castration-naïve prostate cancer setting, enrichments of Akkermansia, Coprobacillus, Prevotella and Dehalobacterium and decreases of Lactococcus, Bacilli, Gemella, Lactobacillus, Desulfovibrio, and Odoribacter. Bifidobacterium, Desulfovibrio, Allobaculum, and Lactococcus were enriched in androgen deprived AZD1480-treated mice while Ruminococcus, and unclassified Clostridiaceae and F16 were decreased. We further used weighted correlation network analysis (WGCNA) to identify relevant networks of fecal microbiota associated with systemic targeted JAK1/2 inhibition. Using this approach, we have identified clusters of highly correlated taxa in the context of poorly inflamed and inflamed prostate tumors. Our findings show that systemic anticancer therapies can modify host microbiomes and provides insights into interactions between tumor, host microbiomes and immune modulating cancer therapies.

Citation Format: Marco A. De Velasco, Kazuko Sakai, Yurie Kura, Naomi Ando, Noriko Sako, Kazuhiro Yoshikawa, Kazuto Nishio, Hirotsugu Uemura. Systemic targeted JAK1/2 therapy for mouse Pten-deficient prostate cancer model influences the diversity and composition of the gut microbiome [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3341.