Vanderbilt University School of Medicine
Richard Armstrong Professor for Innovation in Biochemistry
Chair, Department of Biochemistry
Vanderbilt-Ingram Cancer Center
Understanding the defects in DNA damage response to develop more effective treatments for triple-negative breast cancer.
Targeting DNA, DNA repair, and DNA replication is a widely used strategy for cancer therapies including radiation and most chemotherapies. These therapies work by increasing DNA damage, which is particularly lethal to cancer cells. Cells with deficient DNA repair, like those with mutations in BRCA genes, rely on a protein called PARP to compensate for this deficiency. Blocking PARP in these cells results in cell death and inhibitors of PARP (e.g., oloparib/Lynparza® and talazoparib/Talzenna®) have been approved to treat cancers with defects in genes required for DNA repair such as BRCA1 and BRCA2. Unfortunately, PARP inhibitors do not work for all patients and drug resistance is a problem. Dr. Cortez is seeking to understand resistance mechanisms—specifically how the DNA repair process provides opportunities for improved therapies like olaparib—in order to identify new drug targets and strategies that will allow more patients to benefit from olaparib and other drugs like it.
Precise replication of DNA requires specific dynamics at the replication fork, a fork-like structure that both stabilizes the DNA and aligns the separated strands with the replication machinery. Dr. Cortez and his colleagues have identified RADX, a protein involved in replication fork dynamics, as an important factor in DNA damage repair and consequently DNA-damaging cancer treatments. While inactivation of RADX and other replication fork proteins causes genome instability and tumorigenesis, it also makes the tumor cells vulnerable to combination DNA-damaging therapies. Dr. Cortez and his team discovered two pathways that regulate how cells respond to chemotherapeutic agents that damage DNA and interfere with the process of DNA repair. They also discovered that three genes—ATR, BRCA2, and RAD51—play a role in controlling these pathways. In the last year, his team made a major discovery about the function of RAD51 during DNA replication, results that are slated for publication in the prestigious journal Science. His results represent a paradigm shift in the way researchers think about this process with insights that may prompt a rethinking of how cells respond to DNA damaging chemotherapies and newer agents like PARP and ATR inhibitors.
Building on his findings, Dr. Cortez will continue to study these replication stress response pathways with an emphasis on defining how they determine the fate of cancer cells treated with PARP inhibitors, chemotherapeutic, and other agents. In related work with his clinical colleagues, his team will also investigate drug combinations that can work to overcome PARP inhibitor resistance mechanisms.
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 postdoctoral 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.
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