Approximately 70% of breast cancers express the estrogen receptor (ER). Although ER inhibitors such as tamoxifen have saved the lives of millions of breast cancer patients, development of resistance to tamoxifen occurs in ~40-50% patients receiving hormone therapy. Thus, there is an unmet need to develop novel therapies targeting hormone refractory breast cancers to improve patient survival. One of the major mechanisms of developing hormone refractoriness is protein kinase-driven signaling pathways becoming pathologically activated and circumventing the dependence on ER signaling. Given the availability of pharmacological inhibitors targeting a large spectrum of protein kinases, kinases have become most attractive therapeutic targets in many diseases particularly in cancer. In this proposed study, we will use advanced high- resolution and high-accuracy proteomic approaches to systematically identify novel protein kinases that are activated in hormone-refractory breast cancers. To keep our study relevant to the clinical setting, instead of using in vitro cultured cell lines, our discovery efforts will instead employ breast tumor samples from patients with different responses to hormonal therapy. We will validate the therapeutic potential of candidate kinases discovered in these studies in xenograft tumors directly derived from hormone refractory metastatic tumors. We will also validate our discoveries on breast cancer tumor microarrays (TMA) comprising >800 breast cancer tumor cores with clinical outcomes. This strategy will help us discern kinases that are required for hormone refractoriness observed in ER-positive breast cancer. In order to shorten the path from bench to bedside, we have recruited a highly qualified multidisciplinary team of investigators capable of ultimately translating these pre-clinical discoveries to clinical trials. A successful outcome of or proposed studies will not only identify kinases with therapeutic potential but also set the stage for initiating clinical trials to test promising drugs in patients with hormone refractory breast cancer.

Public Health Relevance

Development of resistance to hormonal therapy is the most common cause of breast cancer death. In this proposed study, we will use advanced proteomic approaches to identify pathologically activated kinases that drive development of hormone refractoriness. Our clinical resources and experienced multidisciplinary team increase the likelihood that our discoveries will be translated into novel therapeutic options for patients.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA184165-04
Application #
9458124
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Forry, Suzanne L
Project Start
2015-04-01
Project End
2020-03-31
Budget Start
2018-04-01
Budget End
2019-03-31
Support Year
4
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Genetics
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21205
Wu, Xinyan; Zahari, Muhammad Saddiq; Renuse, Santosh et al. (2017) The non-receptor tyrosine kinase TNK2/ACK1 is a novel therapeutic target in triple negative breast cancer. Oncotarget 8:2971-2983
Kim, Min-Sik; Zhong, Jun; Pandey, Akhilesh (2016) Common errors in mass spectrometry-based analysis of post-translational modifications. Proteomics 16:700-14
Wu, Xinyan; Zahari, Muhammad Saddiq; Renuse, Santosh et al. (2015) Phosphoproteomic Analysis Identifies Focal Adhesion Kinase 2 (FAK2) as a Potential Therapeutic Target for Tamoxifen Resistance in Breast Cancer. Mol Cell Proteomics 14:2887-900