Understanding the defects in DNA damage response that cause cancer for the development of 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 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. 

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 as a protein involved in replication fork dynamics, making it 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 anti-DNA damage response 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.  

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, chemotherapeutic, and other agents. In ongoing work with his clinical colleagues, his team will also investigate drug combinations that can work to overcome PARP inhibitor resistance mechanisms.