Breast cancer is not one singular disease; there are many variations in how those cancer cells rewrite normal functions to fuel their growth and spread. This ability to rapidly adapt leads to cancer spreading throughout the body and becoming resistant to existing treatment methods.
Wei Xu, PhD, co-director of Carbone Cancer Center’s Genetic and Epigenetic Mechanism Program and associate director of McArdle Laboratory for Cancer Research, examines those cell processes in all subtypes of breast cancer so her lab can develop new precision treatments that interrupt new cell growth and overcome treatment resistance.
One of those projects is developing a new treatment for patients with metastatic estrogen receptor positive, HER2-positive breast cancer — a subtype that makes up about 15-20% of breast cancer diagnoses in the U.S. This means the breast cancer cells use estrogen to fuel growth and overproduce the protein HER2, which typically supports normal breast cell growth.
“HER2-positive cancer is an understudied cancer. It’s correlated with poor prognosis because the cancer cells kind of rewire their signal pathway [to resist treatments],” Xu said.
Research done over the past five years by Xu’s lab shows that Aurora A kinase, an enzyme that plays a role in cell reproduction, is involved in the signaling pathway that this form of breast cancer uses for cell growth when they become resistant to treatments.
To examine the specific cell mechanisms at play in these cancer cells, she partnered with Huy Dinh, PhD, an assistant professor in McArdle Laboratory and Carbone researcher with bioinformatics expertise, to perform single-cell RNA sequencing of these cancer cells. This provides a precise snapshot of the gene expression in an individual cell, allowing Xu’s team to determine aspects of cell signaling that they can disrupt with targeted drugs to stop cell growth and reproduction.
“We really make use of cutting-edge technology,” Xu said. “We used single-cell RNA sequencing to identify what the real drivers [of cell growth] are, like when you inhibit one pathway [that regulates cell growth and division], another one gets activated. Using this analysis, we identified a driver that is responsible for that therapeutic-resistant type of cell.”
With these findings, Xu’s lab began pre-clinical testing of a new combination approach using two existing FDA-approved drugs: an anti-HER2 drug with a drug that blocks the activity of Aurora A kinase.
“We show, using a number of preclinical models, that if you target that new driver, the cancer cell becomes sensitized to the anti-HER2 treatment,” said Xu. “So we think this combination will give a better result than just anti-HER2 treatment for cancers expressing both estrogen and HER2.”
Xu is now working with Dr. Kari Wisinski, a Carbone breast cancer medical oncologist, on logistics to open a clinical trial to validate this new approach.