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CRCHD Grantee Michelle Stewart Discovers New Strategy to Combat Cancer Drug Resistance

CRCHD F31 Grantee Michelle L. Stewart, of the Dana-Farber Cancer Institute and Harvard University, has discovered a new approach to disable a key protein in cancer cells that otherwise enables them to resist cancer drugs.

By targeting the protein MCL-1, which helps cancer cells survive, and by using a sophisticated technique known as "peptide stapling," Stewart has discovered how to inhibit and block MCL-1 activity thus allowing cancer drugs to effectively kill tumor cells by apoptosis, or programmed cell death, Stewart said. This in turn will allow Stewart and coworkers to advance new therapeutic strategies to thwart drug resistance in cancer patients.

According to Stewart, MCL-1 is a member of the BCL-2 Family, a group of survival proteins (which include: BCL-2, BCL-XL, BCL-W, MCL-1, and BFL-1/A1). When overproduced, all of these proteins can act as "blockades" against powerful cancer drugs, thus "securing the cancer cell's immortality." Stewart and her colleagues began their research because MCL-1 had emerged as a formidable resistance factor in cancer, eluding drug development efforts.

Stewart , her Lab Chief, Loren Walensky, M.D., Ph.D. and colleagues produced a series of stapled BH3 peptides, corresponding to the natural domains found in cells, to search for one that might bind exclusively to MCL-1 itself. It turned out to their surprise that the BH3 domain of MCL-1 was exactly what they were looking for. Was it possible that MCL-1's own death domain could selectively inhibit its pro-survival behavior? The finding enabled Stewart and Walensky, in collaboration with the laboratory of Dr. Amy Keating of the Massachusetts Institute of Technology, to analyze the three dimensional structure of the docking mechanism of MCL-1 BH3 on MCL-1 and discover molecular basis for the exclusive targeting.

The structural data that emerged allowed Stewart and colleagues to create a blueprint for the development of new drugs to overcome MCL's ability to make cancer cells drug resistant.

Stewart's research has important implications for combating drug resistance in cancer patients, said Stewart's Lab Chief Loren Walensky, MD. PhD, of the Dana-Farber Cancer Institute in Boston. The discovery could help advance the development of new drugs to treat a broad range of cancers in which MCL-1 overexpression has been linked to cancer pathogenesis, including leukemia, lymphoma, multiple myeloma, melanoma, and some forms of poor-prognosis breast cancer, Walensky said.

"Michelle is a simply remarkable young scientist who has harnessed her cross-training in chemistry, structural biology, and cancer medicine to successfully address a pressing biomedical challenge of our field," Walensky said. "I am hopeful that her work will directly impact patient care and serve as a shining example of the transformational potential of cancer chemical biology research."

Stewart's lab results were published as a cover article in the August 2010 issue of Nature Chemical Biology (Volume 6, page 595). Stewart's findings , which will also form the basis for her Ph.D. dissertation at Harvard University , is being funded by an F31 Ruth L. Kirschstein National Research (pre-doctoral fellowship) Service Award initiated by the NCI's Center to Reduce Cancer Health Disparities. The award is given to outstanding young scientists to promote diversity in health-related research. She is a graduate student in Dr. Walensky's lab. The MCL-1- blocking compound that Stewart and Walensky developed are now being tested in animal models.

Currently, the National Cancer Institute's Laboratory of Cell Biology is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize compounds that demonstrate cytotoxicity against multi-drug resistant (MDR) cancer cells.

One of the main causes of failure in the treatment of cancer is when cancer cells become resistant to powerful anti-cancer agents. At first the cancer treatments may be working. But the body sees the cancer drugs as foreign invaders and the kidneys pump the cancer drugs out of the body faster than doctor's can put the medicine in. Other reasons include gene amplification. A cancer cell may produce hundreds of copies of a particular gene. This gene triggers an overproduction of protein that renders the anticancer drug ineffective. Cancer cells may stop taking in the drugs because the protein that transports the drug across the cell wall stops working. Similarly, the cancer cells may learn how to repair the DNA breaks caused by some anti-cancer drugs.

Stewart will graduate in the spring with a Ph.D. in Biological Chemistry and Molecular Pharmacology from Harvard University in Cambridge, Massachusetts. She currently holds a 3.8 grade point average at Harvard. The author of six scientific papers and four U.S. patents, she has received five professional honors including: a Goldwater Scholarship in Mathematics, Science and Engineering in 2002, an American Institute of Chemists Award in Biochemistry in 2003, and she was a Milliken Research Scholar in 2002.

Stewart graduated with a Master's of Science degree in Chemistry from Furman University, Greenville, South Carolina in August 2004, and her Bachelors of Science degree from the same university in June 2003. From 2004-2006, Michelle worked as a chemist at Vertex Pharmaceuticals, Inc., in Cambridge, where she designed and synthesized small molecule protein kinase inhibitors for new medicines. Her hobbies include: cooking, nature photography and hiking. "In order to be a good cook, you have to be a good chemist," she said.

Updated: 01/10/14