Targeting LKB1-YAP/TAZ Axis: An Effective Way to Block AA-TNBC Progression
Abstract
Overarching challenge(s): This study will address two overarching challenges: (1) "Identify what drives breast cancer growth; determine how to stop it" and (2) "Revolutionize treatment regimens." What types of patients will it help and how will it help them? Among all ethnic groups, women of African American (AA) origin have highest breast cancer-related mortality rates. This difference is observed even in places where the standard of care is the same. It has been shown that higher numbers of AA women are diagnosed with triple-negative breast cancer (TNBC) in comparison to European American (EA) women. More importantly, TNBC tumors in AA women exhibit higher rate of growth and metastasis in comparison to TNBC tumors in European American (EA) women. Five-year relative survival for AA is only 14% compared to 36% for EA. Currently, TNBC has limited therapeutic options as it lacks the expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). We believe that AA-TNBC have unique biology that results in aggressive progression of these tumors. Our study is designed to understand the unique biology of AA-TNBC, and we plan to exploit this knowledge to develop effective therapy against AA-TNBC tumors. In our initial studies, we observed that AA-TNBC cells have higher invasion and migration potential in comparison to EA-TNBC cells, showing the inherently aggressive nature of AA-TNBC. Also, our preliminary studies show that a large percentage of AA-TNBC tumors show loss of an important tumor suppressor gene-Liver Kinase B1 (LKB1). Our preliminary findings also discovered that LKB1-null AATNBC cells acquire higher expression of oncogenes and are more aggressive. Encouraged with our novel preliminary findings, we propose to investigate how loss of LKB1 leads to acquisition of higher expression of the oncogenes YAP-TAZ and drives growth and metastasis of AA-TNBC cells. We have planned to exploit our valuable cohort of clinical samples and analyze AA-TNBC and EA-TNBC tumors to establish LKB1-loss and elevated YAP/TAZ as biomarkers of aggressive progression of AA-TNBC. We will utilize these biological insights to test safe and effective therapeutic strategies to target AA-TNBC. In fact, we have screened the Johns Hopkins Drug library, a collection of >3300 Food and Drug Administration (FDA)-approved drugs and drugs being tested in Phase II clinical trials to identify clinically viable drugs to effectively inhibit YAP-TAZ in AA-TNBC and have already selected two most-effective drugs (Dasatinib and Verteporfin). In addition, we have also screened ~30 known bioactive compounds to discover a natural compound, Honokiol, a bioactive agent from Magnolia Grandiflora, which is orally available, non-toxic, and most-effective to inhibit YAP-TAZ. We have also developed novel analogs of Honokiol with increased lipophilicity. Based on these important developments, we propose to conduct mouse-trials using patient-derived xenografts (PDX) from AA-TNBC. Blocking the overexpressed YAPTAZ as a strategy to inhibit AA-TNBC is a therapeutic approach that is based on the unique biology of AA-TNBC and will significantly impact AA-TNBC treatment. Potential clinical applications and projected time to patient-related outcome: The proposed studies will provide new molecular understanding regarding AA-TNBC and establish key molecular nodes that drive the aggressive progression of AA-TNBC. Defining the utility of Dasatinib and Verteporfin for AA-TNBC will move the field in a new direction to repurpose these drugs and potentially providing new therapeutic options for AA-TNBC based on their unique biology. Also, future translation of our preclinical findings can move faster (within 3 years) as both Dasatinib and Verteporfin are FDA-approved, clinically available drugs, and a clinical trial is expected to start at the end of this project to treat AA-TNBC patients with high YAP-TAZ wit
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1710034
Entities
People
- Dipali Sharma
Organizations
- Johns Hopkins University
- United States Army