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Apr 3, 2014

Swipe Cancer’s Enzymatic Crutch, Watch It Tumble

  • Developers of anticancer agents have made a special target of weaknesses that afflict cancer cells, but not normal cells. Such weaknesses include genetic defects found in specific cancers. Yet, when these defects are subjected to targeted therapies, cancers often manage to develop resistance. Now, however, a team of scientists from Karolinska Institutet and four other Swedish universities are pioneering an alternative approach.

    The new approach still distinguishes between normal cells and cancer cells, and it is still highly targeted. With the new approach, however, the target isn’t a specific genetic defect. Instead, it is an enzymatic activity that appears to be common to multiple cancers.

    The Swedish researchers advocate inhibiting an enzyme called MTH1, which cancer cells require for survival. This enzyme effectively compensates for poor redox regulation, a metabolic fault peculiar to cancer cells that gives rise to reactive oxygen species, which damage both DNA and its building blocks. These building blocks, free bases in the cellular and mitochondrial deoxynucleoside triphosphate (dNTP) pool, are sanitized by MTH1, preventing fatal flaws from entering the DNA of cancer cells.

    According to the researchers, inhibiting MTH1 caused “incorporation of oxidized dNTPs in cancer cells, leading to DNA damage, cytotoxicity and therapeutic responses in patient-derived mouse xenografts.” The researchers attained this result by deploying TH287 and TH588, both small molecules and first-in-class nudix hydrolases that “potently and selectively engage and inhibit the MTH1 protein in cells.”

    The researchers described their work in an article (“MTH1 inhibition eradicates cancer by preventing sanitation of the dNTP pool”) that appeared April 2 in Nature.

    In this article, the authors wrote that “targeting MTH1 constitutes a novel cancer phenotypic lethal anticancer therapeutic approach targeting nononcogene addiction, which converts deregulated metabolism and ROS levels present in cancer into toxic DNA damage.” While the authors advocate accelerating the development of their approach (they have set us an open innovation model), they also caution that “cancer cells may adapt to imbalanced redox status and activate powerful antioxidant mechanisms to allow survival.”

    As part of their drive toward clinical applications, the researchers have produced a potent MTH1 inhibitor that selectively kills cancer cells in the tumors that have been surgically removed from skin cancer patients. With respect to this work, Dr. Roger Olofsson Bagge, a surgeon at Sahlgrenska University Hospital, said, “When we saw that the tumor from one of my melanoma patients who has developed resistance to all the current treatment actually responded very well to the treatment, we were extremely happy. It's rare that you get to experience and witness such a breakthrough.”

    The study leader, Thomas Helleday, Ph.D., holder of the Söderberg Professorship at Karolinska Institutet, added, “That existing anticancer agents hit the MTH1 shows that the concept really works. Now that we understand the mechanism, we can develop very selective inhibitors.”

    To follow up on this suggestion, the Swedish researchers have already joined colleagues in Austria and the United Kingdom to assess previously identified cancer-cell-killing substances for anti-MTH1 activity. This work, also published April 2 in Nature (“Stereospecific targeting of MTH1 by (S)-crizotinib as anticancer strategy”), used a chemical proteomic approach to identify MTH1 as a target of SCH51344, another small molecule. “Loss of function of function of impaired growth of KRAS tumor cells,” wrote the authors, “whereas MTH1 overexpression mitigated sensitivity toward SCH5144.” 



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