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. Dr. Cortez is seeking to understand resistance mechanisms– specifically how the DNA repair process provides opportunities for improved therapies like olaparib–in orderto identify new drug targets and strategies that will allow more patients to benefit from olaparib and other drugs like it.

Progress Thus 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, 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. In his most recent work, Dr. Cortez discovered that a family of proteins called FET proteins form gel-like, condensed structures at replication forks when DNA is damaged, acting like a speed bump that slows DNA copying to allow time for repair. In breast cancer cells lacking BRCA1, this protective slowing becomes lethal. The team also identified SAMHD1 as a protein cancer cells rely on to survive treatment with chemotherapy drugs including doxorubicin, and mapped how blocking FEN1, a key replication enzyme, reshapes the molecular environment at replication forks and synergizes with PARP inhibitors already approved for breast cancer.

What’s next

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, chemotherapy, and other agents. In the next year, his team will continue analyzing specific, targetable, pathways using a variety of genetic, biochemical, and cell biological approaches. Together, Dr. Cortez’s studies will help deepen our understanding of DNA repair and improve DNA repair targeted therapies.