David Cortez, PhD

Understanding the defects in DNA damage response to develop more effective treatments for triple-negative breast cancer.

Impact

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 tackles this challenge by mapping the full network of DNA repair pathways and finding new ways to block cancer cell growth. By seeking to understand resistance mechanisms, specifically how the DNA repair process provides opportunities for improved therapies like olaparib, he hopes to identify new drug targets and strategies that will allow more patients to benefit from olaparib and other drugs like it.

Progress Thus Far

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. His team’s discovery about the function of RAD51 during DNA replication 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. In related studies, as in the last year, Dr. Cortez examined another protein critical for the regulation of DNA damage response, poly(ADP-ribose) glycohydrolase (PARG). His team found that blocking PARG stops cancer cells from copying their DNA. In addition, they identified another group of proteins that may also make good drug targets, especially in BRCA1-mutant cancers and discovered that blocking one specific protein in the group, FEN1, can damage cancer cell DNA and might work even better when combined with existing treatments.

What’s next

They will complete their PARG findings to help guide future clinical trials and explore how these drugs work in different types of breast cancer. In partnership with Blacksmith Medicine, they will keep studying FEN1 inhibitors and test how they perform alone and in combination with other treatments. They will also continue work on a newly discovered protein to determine if it could be a new drug target. Together, Dr. Cortez’s studies will help deepen our understanding of DNA repair and improve DNA repair targeted therapies.