Andrea Richardson, MD, PhD

Determining which breast cancer patients will respond to PARP inhibitors and identifying strategies to improve PARP inhibitor effectiveness for more patients.

Impact

BRCA-driven breast cancers have a distinctive feature associated with defects in DNA repair. This leads to frequent DNA damage events resulting in genomic instability, which makes tumors very aggressive. While this feature makes the tumor cells very mutable and thus adaptable, it also makes them vulnerable to a class of drugs called PARP inhibitors as well as other DNA damaging agents, because the cells cannot repair the DNA damage. Unfortunately, tumors develop resistance to these drugs by activating alternative DNA repair pathways. Dr. Richardson’s research is focused on understanding how defects in different DNA repair pathways cause either sensitivity or resistance to anti-cancer drugs like PARP inhibitors. This research could lead to a new way to test mutations in other rare DNA repair genes and prognostic biomarkers to predict sensitivity to particular drugs.

Progress Thus Far

Dr. Richardson and her team examined how specific mutations in the BRCA1 gene affect a tumors cell’s response to PARP inhibitor treatment. They found that mutations in one of the 3 regions of the BRCA1 gene that does not correspond to its DNA repair function may present an opportunity for new targeted drugs that are resistant to PARP inhibitors. This finding may help us better predict drug sensitivity in patients with different types of BRCA mutations. They also found a new role for BRCA1, the ability to bypass problems in DNA replication by filling gaps in DNA that remain after replication. This BRCA1 function is not targeted by PARP inhibitors but may provide a new drug target in tumors that are PARP inhibitor resistant. Finally, they completed a study on the role of acetaldehyde exposure in mutagenesis. Acetaldehyde is a downstream product of alcohol and is thought to be how drinking alcohol leads to increased cancer risk. They found that exposing normal cells to acetaldehyde does not increase DNA base mutations but does lead to large genomic alterations. This effect of acetaldehyde is more prominent in cells that have defects in some of the DNA repair genes.

What’s next

In the coming year, Dr. Richardson plans to extend her studies to examine the roleBRCA1 plays in genomic instability and continue to drill down on different parts or domains of the BRCA1 protein and their roles in the development of PARP inhibitor resistance. Other studies will examine how BRCA1 works with other proteins to bypass errors in DNA replication by filling gaps in DNA generated in the process. This research will inform our understanding of how inherited mutations in DNA repair genes lead to further mutations in tumor DNA and potentially reveal new ways to target this function and hinder breast cancer formation.