Targeting CysLTR1 in Triple-Negative Breast Cancer
Abstract
Triple-negative breast cancer (TNBC) is the most aggressive type of breast cancer, with a high chance for metastasis and poor prognosis. Unfortunately, the current treatment of TNBC is limited by the lack of effective systemic therapy. Immune-regulatory mechanisms are often utilized by cancer to escape from the host immune system. Recent advances and in-depth understanding of the biology of TNBC and its interaction with the immune system have led to a paradigm shift in TNBC treatment using targeted therapies and immunotherapies. Our proposal will develop a feasible and rational strategy to overcome resistance to chemotherapies and increase the proportion of responders to immunotherapies. We hope to rapidly translate this knowledge into novel combinatorial approaches for improving the survival of patients with TNBC. Central problem addressed in the proposed research: Chemotherapy and targeted therapy are relatively ineffective and have generally failed to reduce severe sickness and death of TNBC patients. Recent immune checkpoint blockade has emerged as an exciting approach for cancer treatment. However, checkpoint blockade only benefits a limited subpopulation of TNBC patients. Therefore, there is an urgent clinical need to enhance the efficacy of checkpoint blockade immunotherapy and improve patient survival. Our objective is to decipher the largely unknown tumor immunity in TNBC and to develop novel treatment strategies by rationally design immunotherapy in combination with clinically available CysLTR1 antagonist treatment. The scientific premise for this application is evidence-based and target-driven mechanistic research. Thus, our proposal is directed to address the “Revolutionize treatment regimens by replacing them with ones that are more effective, less toxic, and impact survival” Overarching Challenge. How the proposed study would advance the field of breast cancer research and/or patient/survivor care: The immune status of breast cancer (especially TNBC) is largely unknown, and how the immune system will be affected by targeted therapy using CysLTR1 antagonist is also unclear. Our preliminary data showed that CysLTR1 expressed highly in TNBC facilitated tumor accumulation of myeloid-derived suppressor cells (MDSCs) to counteract the antitumor immune responses. Therefore, by deciphering how targeted therapy may affect the immune system in TNBC with high CysLTR1 expression, rational design of clinical trials by combining clinically available CysLTR1 antagonist and immunotherapy will be possible to improve TNBC patient survival. Novelty and potential impact of the proposed research: Despite the increased acknowledgment that inflammatory lipid mediators and their receptors in the pathophysiology of various inflammatory disorders, there are currently no data available regarding the role of CysLTs and their receptors in tumor-induced immune escape. Successful completion of the proposed studies will for the first time elucidate the novel molecular mechanisms underlying chronic inflammation in promoting TNBC progression and immunosuppression, thereby expanding our understanding of TNBC pathogenesis and provide new insights into applying CysLTR1 inhibitors in treating TNBC. More importantly, our investigations using both preclinical mouse tumor models and human specimens on the combined clinically available CysLTR1 antagonist + PD1/PD-L1 mAb treatment in TNBC tumors will shed new lights into a new immune-oncology treatment strategy for TNBC patients. In addition, our study may also indicate CysLTR1 expression as a biomarker to predict TNBC patient responses to immune checkpoint inhibitors, and it provides a strong rationale to apply a newly combined CysLTR1 inhibitor+PD-1/PD-L1 mAb therapy to treat TNBC patients with high CysLTR1 expression in clinic. In the long term, our study may expand treatment options for solid cancer patients with high CysLTR1 expression in general.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010024
Entities
People
- Bin Zhang
Organizations
- Northwestern University
- United States Army