Targeting Endoplasmic Reticulum Protein Quality Control Mechanism to Overcome Chemotherapy Resistance
Abstract
Breast cancer is the most common cancer affecting women. Despite the significant advances in breast cancer biology, there has been limited progress in the treatment of advanced breast cancer, with little change in the overall survival for women with treatment-resistant triple-negative breast cancer (TNBC) over the last several decades. TNBC is very aggressive and more likely to relapse and metastasize than the other breast cancer subtypes. Consequently, there is an unmet and urgent need to find targeted therapies for these patients. Oncogene MYC is one of the most common drivers of human cancer. MYC is overexpressed in TNBC and has been reported as a key driver of this disease. Our recent studies reveal IRE1/XBP1 pathway as a therapeutic vulnerability for MYC-driven TNBC. IRE1/XBP1 is part of an intricate signaling network of the stress-sensing and adapting mechanism called the Unfolded Protein Response. Cancerous cells are under numerous intra- and extracellular stresses, and they remain alive by adapting to these stresses through hijacking the adaptation mechanisms. We found MYC-high TNBC tumors are particularly sensitive to the perturbation of IRE1/XBP1 pathway. Remarkably, a combination of chemotherapy and a novel drug that inhibits this pathway is overwhelmingly better than chemotherapy alone. The novel combination therapy was able to rapidly and completely eradicate MYC-high TNBC tumors. Strikingly, the tumors did not come back after treatment in preclinical models. These exciting data strongly suggest that the IRE1/XBP1 pathway is a highly valuable drug target to overcome chemotherapy resistance for patients with MYC-driven TNBC. This proposal will validate this hypothesis and uncover the underlying mechanism. The proposed studies will address the overarching challenges of ?Identify what drives breast cancer growth; determine how to stop it? and ?Revolutionize treatment regimens by replacing them with ones that are more effective, less toxic, and impact survival.? This study will highly likely advance the field of breast cancer research by elucidating an unprecedented therapy resistance mechanism and revolutionize the treatment regimens for patients with MYC-driven TNBC. With the overwhelming enthusiasm from our clinical collaborators, this novel combination therapy is expected to move into clinical trial within 2 years and substantially prolong patient survival. MYC is one of the most common drivers of human cancers; however, direct targeting of MYC has not been achieved yet. Successful completion of this unprecedented study will likely lead to the first effective therapy for patients with MYC-driven breast cancer. If proven effective, the impact of this proposal may extend well beyond TNBC and will offer a new therapy for other MYC-driven malignancies such as Burkitt?s lymphoma and neuroblastoma. My long-term career goal is to become an independent Principal Investigator (PI) and a leader in the field of basic and translational breast cancer research, focusing on metastasis and therapy resistance mechanisms and to develop mechanism-based therapies to end breast cancer. I have acquired extensive experience on genetics, genomics, animal model, molecular biology, biochemistry, and signal transduction during my Ph.D. training, which resulted in seven first and co-first author publications. Focusing on the proposed research, this grant will be critical for me to acquire new knowledge/expertise in breast cancer research and leadership skills to achieve my career goal. My training in the Chen Lab at the Department of Molecular and Cellular Biology, the Lester and Sue Smith Breast Center, and the Dan L. Duncan Cancer Center of Baylor College of Medicine (BCM) provides me a uniquely supportive environment for my career. I have extensive interaction with integrated breast cancer program researchers with clinical, basic, and epidemiologic experiences. I participate in the weekly joint lab meeting
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 05, 2019
- Source ID
- W81XWH1910035XX0
Entities
People
- Xiangdong Lv
Organizations
- Baylor College of Medicine
- United States Army