Epigenetic Heterogeneity and Targets in Triple-Negative Breast Cancer
Abstract
Scientific Objective and Rationale: Breast cancer is not a single disease, but rather a diverse collection of diseases. Triple-negative breast cancer (TNBC) is one of the molecular subsets of breast cancers. TNBC stands for lack of targetable hormonal receptors such as estrogen (ER), progesterone (PR), and human epidermal growth factor receptor 2 (HER2). Due to the absence of the above-mentioned hormonal receptors, treatment of TNBC patients has been extremely challenging. In addition, recent studies have demonstrated that TNBC is highly heterogeneous disease, making it even more difficult to pinpoint a well-defined molecular target and align it with appropriate therapeutic intervention. As a result, the only treatment option TNBC patients have access to is chemotherapy, which unfortunately is not effective in the majority of patients. Due to lack of targeted therapies and the aggressive biology of this disease, TNBC patients in general have poorer prognosis. Thus, TNBC patients are in great need for more effective treatment options. We are committed to identify new targets in TNBC. We plan to achieve this by focusing our efforts on studying the epigenetic heterogeneity of TNBCs. This means that we will focus on studying factors that regulate the features and gene expression patterns in TNBC instead of genetics driven by heritable or acquired changes within DNA sequence (especially as recent studies have failed to discover any novel mutations). The proposal is comprised of two approaches dedicated to understanding epigenetic heterogeneity in TNBCs. The first approach is to evaluate epigenetic heterogeneity between TNBCs in different patients. Our previous work suggests that TNBCs display higher degree of epigenetic heterogeneity compared to luminal breast tumors. Our preliminary data also suggest that by analyzing the epigenetic profiles of TNBCs we can identify novel therapeutic vulnerabilities. The second approach in this proposal is to gain better understanding of the intratumor (within a single tumor) cellular epigenetics and phenotypic heterogeneity in TNBCs. We plan to analyze TNBC cell lines and patient samples to evaluate the degree of epigenetic heterogeneity at the single cell level. Heterogeneity of cancer cells within tumors is a driver of tumor progression and therapeutic resistance. Thus, better understanding of the underlying processes is key to our ability to improve treatment outcomes. The cumulative results of this proposal will provide insight into the epigenetic heterogeneity of TNBCs and its prognostic and therapeutic utility. The proposed experiments will further us towards better clinical management of TNBC patients. Applicant’s Career Goals in Breast Cancer: My long-term career goal is to become an independent investigator leading my own research team towards impactful performance in science relevant to improving public health by eradicating cancer. As a graduate student co-mentored by Drs. Moses and Pietenpol, I had a unique opportunity to be trained in the areas of basic science, translational, and clinical research. This combined experience along with my close work with clinicians has engraved in me a deep passion for translational research, specifically, research of TNBCs. The defining moment was seeing patients we accrued to our trial poorly respond to the treatments, dropping out due to severe side effects, and worst of all feeling helpless due to lack of alternatives ultimately leading to losing them to this terrible disease. This experience made me realize that I needed to dedicate all I have to try to make a difference in the lives of these and any future victims of TNBC. I feel it is my responsibility to use my skills and develop new ones to give these women alternatives. I made a decision to reach out to Dr. Kornelia Polyak for a post-doctoral position, as her works in tumor heterogeneity contained, in my mind, the alternative skills I was looking for. I am gra
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810027
Entities
People
- Bojana Jovanovic
Organizations
- Dana–Farber Cancer Institute
- United States Army