Title: Redox protection of the nucleotide pool as key mechanism of maintaining genomic DNA integrity in cancer cells

By Dr.  Priyamvada Rai

Professor, Department of Radiation Oncology, Miller School of Medicine at University of Miami

Director, UMMSOM Summer Undergraduate Research Fellowship (SURF) Program

Graduate faculty member, Cancer Biology and Molecular and Cellular Pharmacology

Co-leader, Tumor Biology Program, Sylvester Comprehensive Cancer Center

Affiliate faculty, Center for Aerosol Science and Technology, College of Engineering

Abstract

The holy grail of cancer therapeutics is to target a pathway that is elevated in tumor cells but not in normal tissues. We identified the mammalian 8-oxodGTPase, MTH1, as a key upregulated pathway in aggressive cancers, with low levels of its expression and activity found in normal tissues. This 8-oxodGTPase function is essential to remove oxidized guanine nucleotides prior to their incorporation into genomic DNA by polymerases, where their in situ repair can compromise genomic integrity and cell survival. Thus, elevated MTH1 levels can protect cancer cells from oxidative stress-induced DNA breaks and tumor suppression. Subsequent small molecule inhibitor development against MTH1 led to much controversy and confusion in the field as the outcomes from the highly effective first-in-class inhibitors could not be replicated by second generation inhibitors, casting doubt on MTH1 as a bonafide cancer target. Partnering with a chemistry lab, we helped validate a unique probe, ARGO, to measure endogenous 8-oxodGTPase activity in cells and tissues. Using this probe, we have shown that the first-in-class MTH1 inhibitor effects are off-target and that the second-generation MTH1 inhibitors, while more specific, are ineffective as there is redundancy in MTH1 function not targeted by the current inhibitors. Elucidating the mechanisms of endogenous 8-oxodGTPase activity has yielded new insights into how redox maintenance of the nucleotide pool occurs in normal vs. cancer cells, opening avenues for exploiting these differences towards targeting aggressive, treatment-resistant cancers.

Bio

Dr. Rai received her Bachelor of Science degree with honors from the California Institute of Technology. She conducted her PhD research at the University of California, Berkeley, in the field of biophysics, with Dr. Stuart Linn and Dr. David Wemmer as her co-advisors. She was a Leukemia and Lymphoma Society postdoctoral fellow in the lab of Robert Weinberg at the Whitehead Institute for Biomedical Research/MIT. She began her independent career at the University of Miami Miller School of Medicine in 2008 and is currently a tenured full professor in the Department of Radiation Oncology. She is the co-leader for the Tumor Biology program at the NCI-designated Sylvester Comprehensive Cancer Center. She is also the Director of the Medical School Summer Undergraduate Research Fellowship (SURF) program and the PI of the NCI R25 grant that funds the CREATE component of the SURF program. Her research, investigating the redox vulnerabilities of cancer cells as therapeutic targets, has been continuously funded since 2009 by the NCI, DOD, and the Florida Department of Health.

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