The novel, telomerase-directed, telomere-targeted, anticancer agent 6-thio-dG (THIO) demonstrates potent activity and induces antitumor immunity in hepatocellular carcinoma (HCC) models

Background: HCC is one of the leading causes cancer-related deaths worldwide. Low response rates with current treatments for demonstrate an urgent unmet need more effective systemic therapies. However, development novel has been challenging due to a lack functionally druggable targets. The nucleoside prodrug analogue THIO first-in-class telomerase-directed, telomere-targeted, anticancer agent that shown potent activity in other tumor types, including colorectal, lung, melanoma, and brain cancer models. In cells, converted into corresponding 5′-triphosphate, which efficiently incorporated telomeres by telomerase, activating DNA damage responses pro-apoptotic pathways. We hypothesized telomerase-targeting agents may be given high rate mutations telomerase reverse transcriptase (hTERT) promotor. Moreover, since >90% HCCs reactivate drive escape from senescence-induced growth arrest, treatment or second-generation telomere-targeted analogues likely highly selective telomerase-positive cells relative nonmalignant hepatocytes. Material methods: Activity was evaluated vitro using vivo syngeneic mouse models aggressive HCC. treated without were analyzed cell proliferation stained markers replicative stress cycle followed confocal microscopy and/or flow cytometry. Immunophenotyping tumor-infiltrating T mice performed measuring frequencies MDSCs (Ly6C+Ly6G-), NK (NK1+), CD4 (Ki67+/CD4+), CD8 (Ki67+/CD8+). Antitumor assessed serial measurements volume sequentially therapeutically relevant doses ± checkpoint inhibitors compared control mice. Results: induced stress, arrest apoptosis telomerase-reactivated cells. HCC, activated pathways associated innate adaptive immunity (eg, cGAS-STING pathway infiltration CD8+ microenvironment) altered immune-suppressive microenvironment. enhanced inhibitors, yielding complete some model systems no dose-limiting toxicities. Similar results observed analogues. Conclusions: Results this study indicate THIO, agent, its enhance overall therapeutic efficacy immune inhibitor-based Conflict interest: Other Substantive Relationships: JW Shay: I have interest relation organizations could perceived as potential conflict context abstract. relationship summarized below: Scientific Advisory Board member stock/stock options MAIA Biotechnology, Inc. am also named inventor on several patents licensed MAIA. Mender: S Siteni: disclose. M Obrocea: Full-time employee, officer (Chief Medical Officer), V Vitoc: employment, (Founder Chief Executive SM Gryaznov: