Naoto T. Ueno, MD, PhD

Developing novel therapies that will improve outcomes for patients with inflammatory breast cancer, a rare and very aggressive form of the disease.

Impact

Inflammatory breast cancer (IBC) is the most lethal and aggressive form of breast cancer. Although the disease affects only two to four percent of breast cancer patients, it is responsible for about 10 percent of breast cancer deaths in the United States. Thus, new treatment strategies to reduce IBC recurrence and metastasis are urgently needed. Dr. Ueno and his team showed that a drug targeting the cell-surface protein called EGFR could improve response to immunotherapy in laboratory models of IBC. His team is investigating the effectiveness of combining EGFR-targeted therapy with immunotherapy for the treatment of these breast cancers. Dr. Ueno is also developing novel therapies to prevent the spread of IBC to the skin and lymph vessels surrounding the breast. He hopes these studies will help to identify biomarkers for selecting IBC patients who will benefit from EGFR-targeted therapy and strategies to enhance the effectiveness of these drugs and ultimately improve outcomes for patients.

Progress Thus Far

Their laboratory studies have shown that an anti-EGFR drug called panitumumab increased the infiltration of immune cells into the microenvironment and tumor, effectively reducing tumor growth. They did not see similar activity, however, when used in combination with immunotherapy in patients with triple-negative IBC. Dr. Ueno and his colleagues continue to screen compounds that can inhibit the activity of EGR1 in IBC and have identified another target called TBK1 that may be effective in triple-negative breast cancer (TNBC). For EGR1, they created a new type of treatment called O’PROTACs, which can eliminate EGR1 from cancer cells. After testing them in IBC and TNBC models, promising candidates were identified and the team worked to improve their stability and effectiveness. They also tested a drug that blocks CREB, a protein that controls EGR1, and demonstrated that it successfully reduced EGR1 levels and cancer cell growth. In the TBK1 studies, several drugs were tested and one, BX795, effectively reduce TBK1 activity in cancer cells and slowed tumor growth.

What’s next

In the coming year, Dr. Ueno’s team will identify other drugs that could boost BX795’s effectiveness. In addition to drug development, they devised a new tissue staining method that allows examination of 28 different markers on a single tumor slide—this technology is critical for studying how immune cells and cancer cells interact within the tumor environment. In aggregate, Dr. Ueno’s studies will advance strategies that target both cancer cells and their surroundings, with the goal of improving outcomes for patients with IBC and TNBC.