A Novel Therapeutic Strategy Targeting BACH1 for Triple-Negative Breast Cancer
Abstract
Which overarching challenge(s) does this research address? The research I propose here addresses two overarching challenges: (1) to develop therapeutic intervention with the approved drugs that are less toxic and (2) to maximize the efficacy of the approved drug with a combinational treatment that targets a metabolic regulator. To address these questions, I will focus on a novel target, BACH1, that regulates breast cancer metabolism. My study will identify the mechanism by which BACH1 regulates metabolism. In addition, I will take advantage of an US Food and Drug Administration (FDA)-approved drug that breaks down BACH1 to improve treatment with currently used drugs such as metformin that target cancer cell metabolism. The goal of this research is to provide a novel therapeutic regimen to benefit the highest risk patients with triple-negative breast cancer (TNBC). What types of patients will it help and how will it help them? Currently women have a 12% chance of developing breast cancer during their lifetime. The most aggressive and lethal subtype of breast cancer is TNBC, yet there is no approved targeted therapy for this group. Recent clinical trials are ongoing to use metformin, a diabetic drug, as a therapeutic to cure breast cancer. Metformin is safe and is mostly used for the patients with type II diabetes. Unfortunately, metformin has limited efficacy, targeting only about 16% of cancer types because of their altered metabolism. However, we propose to reprogram metabolic pathways in TNBC cancer cells in order to increase metformin responses. We will reprogram the cells by targeting BACH1, a protein that controls the way that energy is generated in cells. We hypothesize that removing BACH1 with the drug panhematin can drive cancer cells to depend on mitochondrial respiration, which is a target of the anti-diabetic drug metformin. This combination of panhematin and metformin as targeted therapy should help cure TNBC patients as well as save many women from undergoing nonproductive therapies. What are the potential clinical application, benefits, and risks? Metformin is the most commonly used drug and is known to be safe when used to treat patients with type II diabetes mellitus. Panhematin is a drug used to treat acute porphyrias, which is a metabolic disorder. Panhematin is also approved by the FDA and used for patients as a short-term treatment. These approved drugs are relatively safe to use individually because the function of these drugs when administered to people has already been examined. Our preliminary data suggest that TNBC cells treated with panhematin are more sensitive to metformin treatment than the tumors treated with metformin alone. Therefore, this study will indicate whether the combination treatment using panhematin and metformin will benefit patients with TNBC. Although each drug is safe to use, the interactive cytotoxicity of both drugs when treated together should be examined to prevent any unknown risks. What is the projected time if may take to achieve a patient-related outcome? The big advantage of this study is that the two drugs we plan to use for treatment, panhematin and metformin, are already approved by the FDA. Thus, they can, in principle, be used within a short time as a treatment regimen, and clinical trials using a combination treatment could be conducted immediately. What is the likely impact of this study on ending breast cancer? The research I propose is to develop a novel therapeutic intervention by using the drug panhematin to rewire metabolism in breast cancer. Importantly, this research provides preclinical information to maximize the efficacy of metformin, which is already in clinical trials for breast cancer. If successful, our results could have immediate impact and improve significantly the survival of patients with high-risk TNBC.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710261
Entities
People
- Jiyoung Lee
Organizations
- United States Army
- University of Chicago