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CURE Scholar Spotlight - Dr. Donita Colette Brady

, by CRCHD Staff

Investigating Copper as a Means to Slow Cancer Growth

Skin cancer is the most common type of cancer in the U.S. and melanoma is the most dangerous form of skin cancer, killing an estimated 10,000 people a year, according to the National Cancer Institute.  The pioneering efforts of a CRCHD Continuing Umbrella of Research Excellence (CURE) scholar may help unravel one of the mysteries of melanoma.

Donita C. Brady, a research associate Senior at the Department of Pharmacology and Cancer Biology at Duke University, is investigating the role that copper plays in cell growth and tumor biology. Inspired by mentors Christopher Counter, a cancer biologist, and Dennis Thiele, a copper biologist, at Duke University, Brady has a unique interest in the way copper interacts with protein pathways, such as the BRAF (a human gene that directs cell growth)-MEK-ERK pathway, which is a major target for targeted cancer therapies because the BRAF gene is mutated in 60 percent of melanoma cases.

Brady explains, “copper is an essential metal in terms of biological life.” In the human body, copper is found in the liver, muscle and bone. Sources of copper come from the dietary intakes of certain foods like nuts and shellfish. Under CRCHD’s funded K01 Mentored Research Scientist Development Award, Brady discovered that copper is a key element required in oncogenic BRAF signaling (which directs the creation of certain cancer tumors). In the case of cancer cells, mutated BRAF continually sends signals switching on the cells to grow causing tumors. “In cancers with mutations in BRAF, the protein is always on so it’s a little like driving a car where the accelerator is stuck and there are no brakes,” Brady says. “There is no signal to the cancerous cell to stop growing.”

What was particularly unique in Brady’s research was her discovery that during BRAF activation (when proteins signal to cells to grow, for example), copper can reduce the activity of the proteins MEK1 and MEK2 that BRAF signals to, which then effectively slows down cancer growth. Her findings were published in the prestigious scientific journal Nature (see Copper is required for oncogenic BRAF signaling and tumorigenesis). Brady presented her research findings to CRCHD’s CURE Program Directors at the Annual Professional Development Workshop in late June 2014.

Brady says the CRCHD K01 Award played an instrumental role in her career allowing her to commit time to this novel research and to fund the necessary resources to pursue her research. Brady also says that the K01 award allows her to be “connected with CRCHD staff that have been and will continue to be very instrumental in my career as to pursue a full time tenured assistant professor position.”

Brady’s finding has far reaching potential to direct future cancer research. “There are obvious offshoots to this research," she says. "We can use similar experimental approaches to find out what other cancer types may or may not respond to these copper lowering drugs in combination with current standards of care and/or experimental drugs for cancer treatment (such as the combination therapy of trientine with vemurafenib to treat BRAF mutated metastatic melanoma).” The Duke University Comprehensive Cancer Center is currently testing Brady’s concept of copper reduction for the treatment of BRAF-mutation positive melanoma in a trial led by Dr. April Salama, she says.

There are also hints that lower levels of the protein important for copper uptake in African Americans can predispose them to different responses to the chemotherapy cisplatin. While this is not one of Brady’s research focuses, she says, “While not directly related to copper itself, it has been found previously that CTR1, the major transporter for copper uptake, is lower in African Americans compared to Caucasians and this may correlate with a decrease in tumor response to chemotherapy.” The disparities research and diversity training team at CRCHD, along with Brady, are excited to see where her research will lead.

Brady credits her high school chemistry teacher for having “spurred my interest in science during my senior year of high school and urged me to pursue a B.S. in chemistry while attending Radford University.” She participated in the University of North Carolina at Chapel Hill Department of Pharmacology Carolina Summer Fellowship Program, and she graduated Magna Cum Laude with a B.S. in chemistry from Radford University, VA. She earned her Ph.D. in pharmacology at the University of North Carolina at Chapel Hill.

During postdoctoral studies in the laboratory of Dr. Christopher Counter at Duke University, she began investigating the molecular mechanisms by which the aberrant activation of the small GTPase RAS promotes cancer by dissecting the signaling pathways downstream of oncogenic RAS, including the RAL GTPases and the RAF-MEK-ERK cascade.

Among many awards, Brady earned the James Lewis Howe Award for Outstanding Achievement in Chemistry from the American Chemical Society in 2003. She also received the AACR Annual Meeting Minority Scholar in Cancer Research Award two years in a row in 2013 and 2014. Brady is a member of the American Association for Cancer Research, the American Chemical Society, and the International Biometals Society.

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