Developing Rationalized Therapeutic Strategy to Target Advanced Stage Triple-Negative Breast Cancer
Abstract
Triple-negative breast cancers (TNBC) lack hormone receptors and expression of the human epidermal growth factor receptor 2 (HER2). This subtype of breast cancer is the most challenging type of breast cancer to treat. The only medicine for treating early and advanced TNBC is chemotherapy, which produces significant adverse effects and negatively impacts quality of life. TNBC constitutes 10%-20% of all breast cancers, and it is more frequent in young women and in African American women. TNBC tumors are generally larger and have more aggressive behavior compared to other types of breast cancer. Despite having high rates of initial response to chemotherapy, these tumors have the highest chance of spreading to distant organs. Among patients with advanced breast cancer, women with TNBC tend to have the shortest survival. Due to the lack of molecular therapeutic targets, all available options for treating TNBC with medicine include chemotherapy. There is an urgent need to find the molecular pathways that are activated in TNBC and allow it to grow rapidly and spread so that the treatments can be developed that target these pathways. This type of targeted therapy has proven to be very effective for other subtypes of breast cancer and is associated with fewer side-effects and dramatically improved quality of life compared to treatment with chemotherapy. For these reasons, there is an urgent need to develop targeted, non-chemotherapy treatment options for patients with TNBC. We have identified a new target known as Mixed Lineage Kinase 3 (MLK3) that is highly active in TNBC. An orally administered inhibitor of MLK3 was developed to treat certain neurologic diseases, and in those studies it had very few side-effects. We found that treating human-derived breast TNBC tumors with MLK3 inhibitors caused many tumors to dramatically shrink, however, some of the tumors were non-responsive to single agent. We then discovered that MLK3 inhibitor treatment in a resistant TNBC cell population and non-responder tumors resulted in upregulation of MLK4 (another MLK family member) and an additional protein, CD70. Interestingly, CD70 upregulation has been shown to be associated with cisplatin resistance in ovarian cancer. We found that targeting with an agent that inhibits MLK3 and MLK4 together (pan-MLK inhibitor) along with inhibition of CD70 reduced the TNBC cell population that behaves like stem cell. We believe that for successful treatment of TNBC, both tumor and stem cells need to be targeted, which can be achieved by using pan-MLK inhibitors along with CD70 antagonist. Interestingly, the CD70 antagonistic antibody Cusatuzumab has been used in human with hematological cancer and can be used for TNBC without delay. CD70 is similarly an emerging drug target in cancer, and the inhibitor of CD70, Cusatuzumab, is under clinical trial (NCT03030612). Cusatuzumab has recently been used for acute myeloid leukemia (AML), a disease that is driven by stem cells and resists conventional chemotherapy, which is the major cause of relapse, similar to TNBC. The response rate of Cusatuzumab in patients with AML has been very encouraging, with 12 patients enrolled, including 8 in complete remission, 2 in complete remission with incomplete blood count recovery, and 2 in partial remission. We also plan to develop rationalized therapy that can eliminate both TNBC cells and any cancer stem cells present within the TNBC tumors. We want to see if the combination of a pan-MLK inhibitor plus CD70 blocker may work better than either targeted drug alone. Our proposed experimental plan addresses three very important overarching challenges: (1) Identify what drives breast cancer growth; determine how to stop it; (2) Identify why some breast cancers become metastatic; (3) Revolutionize treatment regimens by replacing them with ones that are more effective, less toxic, and impact survival. It is our expectation that after completing this study, we
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210051
Entities
People
- Ajay Rana
Organizations
- United States Army
- University of Illinois at Chicago