10 Dec Mt. Sinai Researcher Discusses Emerging Therapeutic Approach For Triple-Negative Breast Cancer
MedicalResearch.com Interview with:
Jian Jin, Ph.D.
Mount Sinai Endowed Professor in Therapeutics Discovery
Professor, Department of Pharmacological Sciences
Professor, Department of Oncological Sciences
Director, Mount Sinai Center for Therapeutics Discovery
Co-leader, Cancer Clinical Investigation Program, Tisch Cancer Institute
Icahn School of Medicine at Mount Sinai
MedicalResearch.com: What is the background for this study?
Response: Triple-negative breast cancer (TNBC), a subtype of breast cancer that lacks estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2), represents 12-20% of all breast cancers. TNBC has poor prognosis, high recurrence, a low survival rate, and has higher incidence in African-American and Hispanic women. Currently, there are no effective therapies for treating a substantial portion of TNBC patients.
Enhancer of zeste homolog 2 (EZH2) is the main enzymatic subunit of the polycomb repressive complex 2 (PRC2) which catalyzes trimethylation of histone H3 lysine 27 (H3K27me3) to promote transcriptional silencing. EZH2 is overexpressed in multiple types of cancer including triple negative breast cancer (TNBC) and high expression levels correlate with poor prognosis. Several EZH2 inhibitors which inhibit the enzymatic activity of EZH2 have shown promise in treating sarcoma and follicular lymphoma in clinics. However, current EZH2 inhibitors are ineffective at blocking proliferation of TNBC cells even though they effectively inhibit the enzymatic activity of EZH2. While the proteolysis targeting chimera (PROTAC) technology for selective degradation of the target protein has been rapidly gaining momentum in the drug discovery field, the hydrophobic tagging approach for selective protein degradation has received considerately less attention from the scientific community.
MedicalResearch.com: What are the main findings?
Response: Using the hydrophobic tagging approach, the research team led by Drs. Jian Jin and Ramon Parsons created an innovative first-in-class EZH2 selective degrader, MS1943, which effectively reduces EZH2 levels in a variety of cancer cell lines including multiple TNBC cell lines. Importantly, MS1943 has a profound cytotoxic effect in multiple TNBC cell lines, while sparing normal cells, and is efficacious in in vivo TNBC mouse models, suggesting that pharmacologic degradation of EZH2 can be advantageous for the treatment of EZH2-depedent TNBC.
MedicalResearch.com: What should readers take away from your report?
Response: This study is the first to discover an EZH2 selective degrader and demonstrate that EZH2 selective degraders, but not EZH2 inhibitors, are effective in treating triple negative breast cancer in preclinical models. Our findings suggest that EZH2 selective degraders such as MS1943 may provide a novel therapeutic strategy for the treatment of triple-negative breast cancer.
MedicalResearch.com: What recommendations do you have for future research as a result of this work?
Response: It has been reported that EZH2 also plays an important role in driving proliferation of other cancers including prostate cancer. We therefore hypothesized that pharmacological degradation of EZH2 could also be effective in treating these tumors. The EZH2 selective degrader reported in this study is an invaluable tool to test this therapeutic hypothesis.
MedicalResearch.com: Is there anything else you would like to add?
Response: Nothing else to add. Several authors of this paper including Drs. Jian Jin and Ramon Parsons are inventors of a patent application filed by the Icahn School of Medicine at Mount Sinai. Dr. Jin is an equity shareholder and consultant of Cullgen, Inc.
Ma, A., Stratikopoulos, E., Park, K. et al. Discovery of a first-in-class EZH2 selective degrader. Nat Chem Biol (2019) doi:10.1038/s41589-019-0421-4
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