The following is an update from Naoto T. Ueno, M.D., Ph.D. Executive Director, The University of Texas MD Anderson Cancer Center Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, Houston, TX
Inflammatory breast cancer (IBC) is the most lethal and aggressive form of breast cancer; it is highly likely to spread to other sites in the body. Although the disease affects only 2-4% of breast cancer patients, it causes an alarmingly disproportionate 10% of breast cancer deaths in the U.S. There is an urgent need to establish novel treatment strategies to reduce IBC recurrence and metastasis. One of our group’s efforts is to identify the molecules that make IBC so aggressive. Identification of such molecules will help us diagnose IBC early and develop new treatments for patients with this disease.
With your generous support, our group has focused on the role of the protein molecule Axl in IBC. Axl is found on the cell membrane and is part of an essential signaling pathway in cancer. We have shown that 1) reducing the amount of Axl protein in IBC cells reduced IBC cell growth and 2) reducing the activity of Axl signaling using drugs called small molecule Axl inhibitors reduced the growth and the spread of IBC cells. We then examined why reducing Axl signaling reduced the growth and spread of IBC cells. We found that the reason was related to the impact of Axl on cells called M2 macrophages.
Recent studies have indicated that cells surrounding IBC tumors, including M2 macrophages, contribute to IBC tumor growth and progression. We have found that reducing the activity of Axl signaling using a small molecule Axl inhibitor can reduce the percentage of M2 macrophages. We have also found that another signaling pathway, the STAT6 signaling pathway, affects the impact of Axl on M2 macrophages. Further, in studies in mice, we have shown that a small molecule Axl inhibitor decreased not only the percentage of M2 macrophages but also the percentage of regulatory T cells, a type of cell that suppresses the immune response. These results indicate that reducing Axl signaling could reduce the extent to which cells surrounding IBC tumors promote IBC tumor growth. We are currently continuing to study how Axl regulates IBC tumor growth through affecting the cells surrounding IBC tumors.
Our team is also investigating whether Axl inhibitors in combination with drugs targeting other proteins would have increased efficacy against IBC and triple-negative breast cancer. Finally, we are evaluating the efficacy of Axl inhibitors in combination with immune checkpoint inhibitors (including anti-PD1 and anti-CTLA4) against IBC in studies in mice.