MTH1 targeting promotes tumor cell apoptosis without affecting normal cells . Moreover, it reduces ROS levels implying an additional anti-inflammatory and anti-angiogenic role.
Sophia Magkouta1, Apostolos Pappas1, Chrysavgi Kosti1, Marianthi Iliopoulou1, Katherina Psarra2 and Ioannis Kalomenidis1
1"Marianthi Simou Laboratory", 1st Department of Critical Care and Pulmonary Medicine, National and Kapodistrian University of Athens, School of Medicine, Evangelismos Hospital, 10675, Athens, Greece, 2Department of Immunology - Histocompatibility, Evangelismos Hospital, 10675, Athens, Greece
MTH1 enzyme sanitizes oxidized dNTP pools to prevent incorporation of damaged bases during DNA replication. MTH1 targeting promotes tumor cell apoptosis without affecting normal cells . Moreover, it reduces ROS levels implying an additional anti-inflammatory and anti-angiogenic role. Since MPM initiation and progression are associated with oxidative stress and genotoxic damage, we assumed that MTH-1 presents a reasonable target for MPM treatment.
We hypothesized that pharmacological targeting of the protein would abrogate experimental MPM growth in vivo by inducing tumor cell apoptosis, limiting tumor angiogenesis, and reprogramming pro-tumor immune responses. Our hypothesis was tested in a syngeneic AE17 murine model as well as in ZL34 xenographs. The MTH-1 inhibitor (TH1579) abrogated mesothelioma progression in both models. Mesothelioma-associated pleural effusion was also profoundly reduced in treated mice. Tumors of TH1579-treated mice presented enhanced tumor cell apoptosis and reduced angiogenesis compared to control. In addition to this, TH1579 conferred an M1 anti-tumor phenotype of pleural fluid macrophages. In conclusion, MTH-1 inhibition substantially abrogates mesothelioma progression affecting tumor growth, angiogenesis and tumor-associated inflammation.