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BCRF Grantee Since

2012

Donor Recognition

The RGS Labs International Award

Area(s) of Focus

David Cortez, PhD

Ingram Professor of Cancer Research
Professor of Biochemistry
Vanderbilt University School of Medicine
Nashville, Tennessee

Current Research

Triple negative breast cancer (TNBC) comprises approximately 25 percent of breast cancer deaths. There is currently no proven targeted therapy for this disease subtype; thus, there is a critical need to develop better therapeutic options. Dr. Cortez hypothesizes that at least a subset of these cancers are especially dependent on DNA repair mechanisms that are coordinated by the ATR checkpoint kinase signaling pathway. He is working to develop small molecule inhibitors of the ATR pathway in collaboration with other researchers at the Vanderbilt-Ingram Cancer Center. Dr. Cortez has concentrated on two targets, ATR and RPA, since they are essential nodes in the pathway. His studies of an ATR selective inhibitor indicate that it kills cells due to a requirement for ATR signaling to complete DNA replication. ATR inhibition is synergistic with other chemotherapeutic agents such as platinum crosslinking drugs. Screening approaches have also identified small molecule inhibitors that are being optimized. Finally, Dr. Cortez completed a synthetic lethal screen to identify cancer contexts where anti-ATR pathway drugs would be particularly useful. This screen indicates that BRCA mutations do not sensitize to ATR inhibitors, but loss of function of several other genes including ATM, ERCC1, and RNR do cause hypersensitivity. Dr. Cortez is also investigating the mechanism by which changes in other DNA damage response protein expression alter the cellular effects of ATR inhibitors. These studies will help direct clinical trials of ATR pathway inhibitors.

Mid-Year Summary

Dr. Cortez and his team are working to develop small molecule inhibitors of the ATR pathway in collaboration with other researchers at the Vanderbilt-Ingram Cancer Center. Their studies of an ATR selective inhibitor indicate that it kills cells due to a requirement for ATR signaling to complete DNA replication. ATR inhibition is synergistic with other chemotherapeutic agents such as platinum cross-linking drugs. In the past six months the researchers completed two synthetic lethal screens to identify cancer contexts where anti-ATR pathway drugs would be particularly useful. These screens identified a number of genetic interactions that might be useful in the cancer clinic. As expected, cancer cells with defects in the ATM pathway are hyper-sensitive to ATR inhibitors. ATM is mutated in about 5% of breast cancer cases. The largest number of genetic interactions identified are in the ATR pathway itself, indicating that reduced function of this pathway due to mutations in many genes could create a circumstance in which the ATR-targeted inhibitors would be useful. Indeed, the Cortez team verified that loss of a single ATR allele in cancer cells is sufficient to cause hypersensitivity to ATR inhibitors. ATR pathway mutations are found in only 3% of breast cancers but as many as 10-15% of other cancers. The other major genetic interaction they identified was with ERCC1/XPF. Decreases in expression of this protein complex cause hypersensitivity in both triple negative breast cancer (TNBC) and small cell lung cancer cell lines. We found that 19 of 30 TNBC cell lines have reduced expression of the complex making it a potential biomarker for ATR-targeted therapies. Finally, in the second synthetic lethal screen which was completed just this past month the researchers found that loss of several protein kinases potentiate the effects of ATR inhibitors for killing cancer cells. They will continue to analyze these screen results as well as follow-up these interesting hits to understand whether they will be useful in either understanding how the ATR pathway functions or how it may be targeted in the cancer clinic.

Bio

Dr. Cortez graduated summa cum laude from the University of Illinois at Champaign-Urbana with Highest Honors in Biology and Biochemistry. He received his doctorate in 1997 in Molecular Cancer Biology from Duke University. After post-doctoral training as a Jane Coffin Childs Fellow at the Baylor College of Medicine, Dr. Cortez joined the Vanderbilt faculty in 2002. He was promoted to Associate Professor in 2007 and Professor of Biochemistry and Ingram Professor of Cancer Research in 2009. Dr. Cortez is Director of Graduate Studies in the Department of Biochemistry, and a member of the Editorial Boards of the journals Cell Reports, Molecular and Cellular Biology, and Journal of Biochemistry. He became co-leader of the Genome Maintenance Program in the Vanderbilt-Ingram Cancer Center upon its inception in 2007.

Dr. Cortez’s research focuses on the mechanisms that maintain genome integrity. His research has been published in journals including Science, Genes and Development, Cell Reports, Molecular and Cellular Biology, Journal of Biological Chemistry, Proceedings of the National Academy of Sciences, Cancer Research, and Molecular Cell. He has received several awards recognizing his scientific achievements including the Howard Temin Award from the National Cancer Institute, the Wilson S. Stone Memorial Award, and a Pew Scholar Award from the Pew Charitable Trusts.