Enhancing Axl-Targeted Therapy in Inflammatory Breast Cancer
Abstract
Inflammatory breast cancer (IBC) is a rare type of breast cancer. During the years 1973 to 2015, only 2.76 cases of IBC were diagnosed each year per every 100,000 people. IBC is the most lethal and aggressive form of breast cancer. Although the disease causes only 2%-4% of breast cancers, it causes an alarmingly disproportionate 10% of breast cancer deaths in the United States. Many types of cancer can be treated successfully with targeted therapy, which attacks cancer cells while doing less harm to normal cells. However, no targeted therapies have been approved by the Food and Drug Administration specifically for IBC. There is an urgent need to establish novel targeted therapy to improve the outcomes of patients with IBC. The objective of the proposed project is to reduce IBC patient death by developing a novel therapy targeting Axl, a protein that promotes cancer aggressiveness. In our previous work, we showed that Axl promotes IBC tumor growth by regulating the cellular environment surrounding the tumor (cancer microenvironment). The rationale for the proposed project is that if we learn how Axl regulates the cancer microenvironment, we can develop an effective new targeted therapy for patients with IBC and prolong their survival. In the proposed project, we will find out how Axl regulates IBC tumor growth by regulating the cancer microenvironment by interacting with another important protein, called TBK1, in tumor cells. Like Axl, TBK1 also regulates the cellular environment surrounding the tumor. By targeting Axl and TBK1, we expect that we will be able to suppress a component in cancer microenvironment that contributes to IBC aggressiveness (Aim 1). We will also use experimental models that closely mimic human IBC to determine whether targeting Axl and TBK1 or other newly identified molecules works better than targeting Axl alone in reducing IBC tumor growth (Aim 2). Therefore, the proposed research addresses two of the Fiscal Year 2020 Rare Cancers Research Program Focus Areas: (1) biology and etiology and (2) therapy. The completion of the proposed research will help IBC patients, who have a rare and aggressive disease without an effective targeted therapy for many years, by establishing an effective therapeutic approach. Our Morgan Welch Inflammatory Breast Cancer Research Program and Clinic will soon start a clinical study of TP-0903, a drug that inhibits Axl, for patients with metastatic IBC (this clinical trial is supported by separate funding). TBK1 inhibitors are currently being developed by several pharmaceutical companies. Once we establish that a combination of TP-0903 and TBK1 inhibitor is effective against IBC as proposed in this study, we will be well positioned to test the combination in a clinical trial quickly. We anticipate achieving a clinically relevant outcome in about 3 to 5 years after the completion of the proposed research. Further, we will share the newly created experimental disease models of IBC with other investigators who conduct IBC research. This will accelerate understanding of IBC biology and development of drugs for this disease. In summary, our proposed work will have a substantial positive impact on improving the outcome of patients with IBC and benefit the IBC research community.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110559
Entities
People
- Xiao-Ping Wang
Organizations
- The University of Texas MD Anderson Cancer Center
- United States Army