funded investigators
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| Arthur Zelent, Ph.D. | Ming-Ming Zhou, Ph.D. | Samuel Waxman, M.D. |
| Institute of Cancer Research | Mount Sinai School of Medicine | Mount Sinai School of Medicine |
Modulating Transcription Repressor Sin3 for Targeted Epigenetic Cancer Therapy
Mortality from breast cancer has recently declined, however, the impact of conventional cytotoxic treatment has contributed little to breast cancer survival rates, particularly in advanced stages of this disease. Recent studies have demonstrated that multiple epigenetic programs creating abnormal gene function contribute to the development of breast cancer. Epigenetics is the study of heritable chromatin traits that are not encoded in the DNA sequence and epigenetic mechanisms are a critical factor in the regulation of many cellular processes, including gene expression and DNA replication. As in the longestablished case with gene mutations, epigenetic changes are a driving force in carcinogenesis. In contrast to gene mutations, however, epigenetic modifications can be manipulated by targeting factors that are responsible for their establishment and maintenance. This reversibility of potentially harmful epigenetic changes has made the development of drugs targeting these modifications, so-called epidrugs, an attractive avenue of research in cancer therapeutics.
Triple negative breast cancer (lacking receptors for estrogen, progesterone and Her2) accounts for 10 percent to 20 percent of the overall total of breast cancer cases. This particular type of breast cancer, which generally has a poor prognosis, is more common in young African American and Hispanic women. In triple negative cancer there is a group of epigenetically silenced genes essential for normal growth, function and death
control and switching off these genes makes a key contribution to the prognostically unfavorable basal phenotype that characterizes this disease. Thus far, there has been modest clinical response from drugs designed to correct these abnormal epigenetic defects and restore essential gene function in breast cancer.
We believe that more specific epigenetic targets that contribute to the development of breast cancer, once identified, will lead to novel approaches to the treatment of triple negative breast cancer and potentially other cancers. To this end Dr. Zelent in collaboration with Drs. Waxman and Farias (Mount Sinai School of Medicine) designed a targeted disruption of a small group of proteins that contribute to gene silencing in breast cancer using a small decoy, which we call SID, to restore essential gene function. The proposed collaborative multi-disciplinary research (also involving the teams of Waxman and Farias as well as a collaboration with Prof. Alan Ashworth at the Institute of Cancer Research) is to develop small molecule inhibitors with the biological properties of SID and evaluate their therapeutic potential in a large number of breast cancer cell lines.
Additionally, we will dissect the mechanisms of SID decoy action. Results of these more basic studies should offer new insights into the epigenetic bases of breast cancer development and help in the optimization of small molecular SID decoys for anticancer therapy. Successful SID decoy development will offer novel therapeutic options for triple negative breast cancer.
*Arthur Zelent is also collaborating with Frank Rauscher III, on a collaborative grant project. Click here to read more.
