威尼斯wnsr6662016年度秋季学期学术系列讲座之十一
题目：Poisoning cancer with oxidized nucleotides by targeting MTH1: a general treatment for all cancer?
讲座人：Thomas Helleday, Ph.D.
Torsten and Ragnar Söderberg Professor in Translational Medicine,
Strategic Professor in Chemical Biology,
Head of Division of Translational Medicine and Chemical Biology,
Department of Medical Biochemistry and Biophysics,
Karolinska Institutet, Solna, Sweden
Abstract：
DNA damaging agents, i.e., radio- and chemotherapy, constitute the backbone for treatment of a wide variety of cancers and may result in complete cure from the disease. Here, I will give an overview on how DNA repair can be targeted using completely novel inhibitors and more specifically how cancer cells may require a specific DNA repair pathway to mediate survival to the high load of endogenous DNA damage. Cancers have deregulated levels of reactive oxygen species (ROS), damaging both DNA and free dNTPs. The MTH1 protein sanitises oxidized dNTP pools, converting 8-oxo-dGTP to 8-oxo-dGMP, to prevent incorporation of damaged bases during DNA replication. MTH1 overexpression reverses the mutator phenotype caused by mismatch repair defects and prevents Ras-induced senescence by suppressing the overall level of DNA damage. These data suggest that a majority of damage in cancer cells occur on the free dNTP pool and that this need sanitation for cancer cell survival.  Here we show that cancer cells are dependent on MTH1 activity for survival, due to the effects of MTH1 in preventing incorporation of oxidized dNTPs into DNA to avoid ATM and p53 mediated apoptosis. As MTH1-/- mice are viable and MTH1 is not required for survival of non-transformed cells, targeting MTH1 may selectively cause DNA damage to cancer cells. We validate MTH1 as an anti-cancer target in vivo and describe small molecules, TH287 and TH588 that potently and selectively inhibit MTH1. Protein co-crystal structures demonstrate that the compounds bind as inhibitors in the enzymatic pocket of MTH1. These first-in-class inhibitors of the Nudix hydrolase family cause increased incorporation of oxidized dNTPs in cells subject to high ROS levels, causing DNA damage and cytotoxicity to cancer cells. This study exemplifies a new general therapeutic approach to convert oxidative stress to cytotoxic DNA damage and cancer cell death. Here, I will present the progression of MTH1 inhibitors from pre-clinical development into early clinical trials.
References
Gad et al 2014 Nature. 508(7495):215-21.
Huber et al 2014 Nature. 508(7495):222-7.
Helleday 2015 N Engl J Med. 373(16):1570-1.
时间：2016年11月22日，13:00 - 14:30
地点：威尼斯wnsr666邓祐才报告厅
联系人：吴虹（62754055）
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