David Cortez, PhD
Ingram Professor of Cancer Research
2012-2013 BCRF Project:
Professor of Biochemistry
Vanderbilt University School of Medicine
Triple negative breast cancer comprises approximately 25 percent of breast cancer deaths. Women with triple negative breast cancer have an increased likelihood of distant recurrence and death compared to other types of breast cancer. There is currently no proven targeted therapy for this disease subtype; thus, there is a critical need to develop better therapeutic options.
Several observations suggest that the DNA damage response may be a useful target in triple negative breast cancer, which often has a good initial response to chemotherapy including platinum drugs. These agents work by increasing the DNA damage burden in the cancer cells thereby placing a greater dependency on repair mechanisms. Mutations in the BRCA1 and BRCA2 DNA repair genes are associated with triple negative breast cancer. Finally, genomic studies indicate that a large proportion of triple negative breast cancers are highly genetically unstable, suggesting defects in genome maintenance activities. These observations suggest that defects in DNA repair are common in triple negative breast cancer. Dr. Cortez hypothesizes that triple negative breast cancer is especially dependent on the remaining, intact DNA repair mechanisms. Thus, his team proposes that synthetic lethal approaches targeting these DNA damage response pathways will be a therapeutic approach of high impact against this subtype of breast cancer.
To test this hypothesis and identify drug targets, Dr. Cortez's team has performed a series of tests including screening for essential genes in the survival and proliferation of triple negative breast cancer cells. Their preliminary data has identified several possible genes, as well as the ATR checkpoint kinase pathway, as critical for cell survival. Dr. Cortez, based on his own preliminary data as well as data from others, believes that this pathway may be a useful therapeutic target in breast cancers with TP53, ATM, or BRCA mutations.
In addition, working in collaboration with other researchers including Drs. Carlos Arteaga at Vanderbilt University School of Medicine, Dr. Cortez's team is developing inhibitors to critical nodes in the ATR pathway. They are working to understand the synthetic lethal relationships between the ATR pathway and common genetic alterations in triple negative breast cancer (such as mutations in TP53, BRCA, and PTEN) using selective ATR inhibitors. These studies include the testing of biomarkers that would allow Dr. Cortez's team to identify tumors dependent on ATR function as well as identify whether these drugs engage their molecular target. This information is critical for the early phase I development of these drugs and for the selection of patients likely to benefit from this targeted approach. Dr. Cortez's team in the upcoming year will further elucidate ATR function and continue to develop novel therapies targeting the ATR-dependent DNA damage response pathway.
Mid-year Progress: Dr. Cortez's team hypothesized that triple negative breast cancer is especially dependent on DNA repair mechanisms that are coordinated by the ATR checkpoint kinase signaling pathway. They are working to develop small molecule inhibitors of the ATR pathway in collaboration with other researchers at the Vanderbilt-Ingram Cancer Center. In the past few months, they have characterized how an ATR kinase specific inhibitor kills cancer cells. They also are working to identify in which cellular contexts this inhibitor may be most useful by examining synthetic lethal relationships. These relationships will allow targeting of ATR pathway drugs to the right patient populations with the help of specific biomarkers.
Also, Dr. Cortez has identified and characterized small molecule inhibitors of a key protein-protein interaction in the ATR pathway mediated by the RPA DNA binding protein. Biochemical experiments indicate these inhibitors are potent molecules that bind a specific cleft of the RPA molecule thereby disrupting protein-protein interactions without interfering with protein-DNA interactions. Dr. Cortez's team continues their work on understanding the specificity of these small molecules, testing their cell permeability characteristics, and using them in target validation studies, which is critical for the early phase I development of these drugs and for the selection of patients likely to benefit from this targeted approach.