Role of DKK3 in Triple-Negative Breast Cancer Tumor Progression and Resistance to Therapy
Abstract
Triple negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, and for the majority of patients with TNBC, chemotherapy will not be an effective cure. Unfortunately, the outcome for patients whose tumors do not respond well to chemotherapy is poor since currently there are no other effective treatments for this disease. In addition, there is no reliable method to identify which patients will respond to chemotherapy. For these reasons, there is an urgent unmet need to develop markers that can predict which patients with TNBC will respond to chemotherapy and to develop novel effective therapies for TNBC. While most cancer researchers are focused on targeting the tumor cells, my lab is interested in how the other cells in the tumor microenvironment (cancer-associated stroma) affect the cancer cells. We and others have shown that the stromal cells are important partners in crime that produce factors that increase the aggressiveness of their neighboring cancer cells and make them more resistant to chemotherapy. We recently showed that Dikkopf 3 (DKK3) is a factor produced by the stromal cells in pancreatic cancer that promote tumor progression, metastasis, and resistance to chemotherapy. We developed a blocking antibody to DKK3 (anti-DKK3 monoclonal antibody mAb) that was highly effective in treating pancreatic cancer in mouse models and more than doubled survival, which is unprecedented for this disease, which has no effective cure. We have filed for a nonprovisional patent for the DKK3-mAb and are actively working toward further development toward clinical trial. I am a clinically active breast cancer surgeon and the Associate Medical Director for Breast Surgery at the Nellie B. Connally Breast Center at MD Anderson Cancer Center, which is one of the largest of its kind in the world, treating more than 40,000 breast cancer patients per year. I treat TNBC patients every week and because I’ve seen far too many patients who fail standard therapy, I was interested in whether DKK3 has a similar role in breast cancer as it does in pancreatic cancer. Our preliminary data shows that, indeed, high expression of DKK3 is strongly associated with poor outcome in patients with TNBC (but not other types of breast cancer). We found that the stromal cells in TNBC express high levels of DKK3 that stimulate TNBC cancer cell activity, similar to what we observed in pancreatic cancer. We hypothesize that DKK3 promotes TNBC tumor growth and metastasis and contributes to resistance to therapy. Our long-term objective is to develop therapeutic DKK3 mAb for use as a single targeted agent or in combination with chemo- or immunotherapy for the treatment of patients with TNBC. To accomplish this goal, we will determine the role of DKK3 in TNBC using patient tumor samples that have been collected in a highly innovative clinical trial for TNBC at our institution (ARTEMIS trial). The ARTEMIS trial has enrolled over 360 TNBC patients with extensive tumor molecular data, which will be analyzed to determine whether DKK3 expression is associated with clinical outcome or response to chemotherapy and also to identify which patients might be good candidates for DKK3-targeted therapy. We will also evaluate whether DKK3 is associated with an immunosuppressive profile, which would suggest that DKK3 blockade could improve the response to immunotherapy. Using TNBC cells and mouse models of TNBC, we will investigate molecular mechanisms of action of DKK3. We will then test our anti-DKK3 mAb as a single agent in mouse models of TNBC, including a model that uses tumor samples from patients (PDX), which may be a more accurate representation of human disease. We will then test the efficacy of anti-DKK3 mAb for its ability to improve response of TNBC to chemotherapy and immunotherapy. For this proposal, we have assembled a highly qualified team of investigators that have the expertise to complete the aims of our project
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210097
Entities
People
- Rosa Hwang
Organizations
- The University of Texas MD Anderson Cancer Center
- United States Army