Titles and Affiliations
Pittsburgh Foundation Chair and Director, Institute for Precision Medicine
Professor, Pharmacology & Chemical Biology, and Human Genetics
UPMC Hillman Cancer Center
Research area
Improving treatment for invasive lobular breast cancer by inhibiting tumor growth.
Impact
Invasive lobular cancer (ILC) accounts for 10-15% of all breast cancers. While an estrogen receptor (ER)-positive breast cancer, the unique biology of ILC distinguishes it from other ER-positive diseases. As a discrete breast cancer subtype, ILC is the sixth most common cancer in women. The major feature of ILC is mutation and subsequent loss of E-cadherin, a cell adhesion protein important to normal breast tissue architecture. Dr. Lee and his team study the unique features of ILC.
Progress Thus Far
Using large patient datasets, Dr. Lee and his team have found that mutations in the HER2 gene are more common in metastatic ER-positive, HER2-negative ILC and are linked to worse outcomes. They built new laboratory models carrying these HER2 mutations and discovered that the mutations change how the HER2 protein behaves on the cell surface, causing it to be rapidly pulled inside the cell rather than remaining stable. This turns out to help explain why a HER2-targeted drug called trastuzumab deruxtecan (T-DXd, Enhertu®) works well in HER2-mutant ILC, since the drug relies on being drawn into the cell alongside HER2 to deliver its payload. The team also found that a related protein, HER3, is unusually active in these HER2-mutant tumors, and that a drug targeting HER3, patritumab deruxtecan (P-DXd), enhances T-DXd’s effects in their models. While each drug alone was effective at first, resistance eventually developed in laboratory models. Combining the two produced tumor control that lasted well beyond the treatment period.
What’s next
Dr. Lee and his team will continue to investigate novel treatment combinations for HER2-mutant ILC, building on the evidence supporting the combination of T-DXd and P-DXd. They will also study how HER2 mutations emerge and change over time in patients using liquid biopsies, tracking blood samples from patients with metastatic breast cancer to understand which prior treatments may drive these mutations and help inform when HER2-targeted therapies should be used. The team is also investigating why ILC cells tend to have elevated HER2 protein levels even before mutations develop and has identified a molecular switch that appears to drive this. This finding may offer a new way to lower HER2 levels and delay treatment resistance. Together, this research aims to uncover the molecular vulnerabilities unique to ILC and translate them into better, more targeted treatments for patients with this distinct type of breast cancer.
Biography
Adrian Lee, PhD is the Pittsburgh Foundation Chair and Director of the Institute for Precision Medicine at the University of Pittsburgh and UPMC. He is Professor of Pharmacology and Chemical Biology, and Professor of Human Genetics, at UPM Hillman Cancer Center and Magee Women’s Research Institute. Dr. Lee received his BSc and PhD in England and came to San Antonio for his postdoctoral studies. He was subsequently recruited to Baylor College of Medicine and now the University of Pittsburgh.
The goal of Dr. Lee’s laboratory is to translate basic cell and molecular research findings into the understanding and treatment of breast cancer. Dr. Lee serves on numerous other national peer-review committees and is on the Scientific Advisory Board for Susan G. Komen for the Cure.
