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David Cortez, PhD
Interim Chair, Department of Biochemistry
Richard Armstrong Ph.D. Chair for Innovation in Biochemistry
Professor of Biochemistry
Associate Director of Basic Sciences,
Vanderbilt-Ingram Cancer Center
Vanderbilt University School of Medicine
Goal: To identify new strategies that would improve outcomes for patients with triple-negative breast cancer (TNBC).
Impact: Dr. Cortez is developing strategies to overcome resistance to a targeted therapy (olaparib) for BRCA-mutation associated cancers. These cancers have a higher likelihood of also being triple-negative (TNBC). His findings could expand the number of patients who may benefit from olaparib and improve outcomes for more patients with TNBC.
What’s next: He and his team will continue to investigate resistance mechanisms and, more generally, to understand how tumor cell defects in DNA repair provide opportunities for other therapies like olaparib.
In 2017, the first targeted therapy for BRCA mutation-associated cancers, olaparib (Lymparza®), was approved by the FDA. This was followed by approval of a second targeted therapy in the same class called talazoparib (Talzenna®). These drugs are in a class of drugs called PARP-inhibitors which work by targeting a protein called PARP. Cells with deficient DNA repair, like those with mutations in BRCA genes, rely on PARP to compensate for this deficiency. Blocking PARP in these cells results in cell death. Unfortunately, as with most therapies, resistance to PARP inhibitors can arise. Dr. Cortez is developing strategies to overcome resistance to olaparib and other drugs like it so that more patients can benefit from this therapy.
Full Research Summary
Research area: Understanding the defects in DNA damage response that cause cancer and to develop methods to target this response and develop more effective treatments for patients with triple-negative breast cancer (TNBC).
Impact: Defects in the BRCA1, BRCA2, and other DNA repair genes cause inherited breast cancer. BRCA-associated cancers have a higher likelihood of also being triple-negative (TNBC), a subset of breast cancer with fewer treatment options and higher mortality. The first targeted therapy for BRCA-driven breast cancers, olaparib, was approved in 2017. Olaparib targets an enzyme called PARP which is used by cells to repair DNA damage. Unfortunately, as with most therapies, resistance can arise. Dr. Cortez is seeking to understand resistance mechanisms and specifically to understand how the DNA repair process provides opportunities for improved therapies like olaparib. They hope to identify new drug targets and to develop new strategies that will allow more patients to benefit from olaparib and other drugs like it.
Current investigation: Dr. Cortez is defining the DNA repair mechanisms that impact the efficacy of anti-DNA damage response treatments such as olaparib. In addition, he and his team will identify drug targets that may provide new opportunities for targeted therapies.
What he’s learned so far: 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 as a protein involved replication fork dynamics, making it an important factor in DNA damage repair and sensitivity to PARP-inhibitors and DNA-damaging cancer treatments. While inactivation of RADX and other fork protection proteins causes genome instability and tumorigenesis, it also provides opportunities for combination anti-DNA damage response therapies.
What’s next: He and his team will continue their studies to understand the mechanisms of DNA repair, which is essential for understanding the vulnerabilities of cells that are deficient in this process. Specifically, they will continue to investigate the proteins and pathways involved as potential biomarkers and new therapeutic targets. They plan to translate their findings into clinically useful information in collaboration with clinicians conducting ongoing clinical trials.
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.