I looked at the ornaments on the desk. Everything standard and all copper. A copper lamp, pen set and pencil tray, a glass and copper ashtray with a copper elephant on the rim, a copper letter opener, a copper thermos bottle on a copper tray, copper corners on the blotter holder. There was a spray of almost copper-colored sweet peas in a copper vase. It seemed like a lot of copper.”
― Raymond Chandler, The High Window
Too much copper seems to be a problem for Los Angeles private investigator Philip Marlowe in the novel The High Window, the 1942 crime drama about the search for the rare and valuable Brasher Doubloon. In a real-life mystery, copper also plays a central role for cancer biologist Donita Brady, PhD. She is searching for answers about the role of this “transition metal” in normal cell physiology, as well as out-of-control cancer cells.
Brady looks for weak points in the protein signaling path of the RAS protein, which is mutated in 30 percent of cancers. She calls these metal-related chinks in the signaling chain “novel vulnerabilities.” In fact, RAS is the most mutated gene in cancers overall. However, small molecule inhibitors of the RAS pathway have not been working as clinicians had hoped. This is where Brady’s work, starting with her doctoral research at the University of North Carolina, Chapel Hill, continuing at Duke University for her postdoc, and now here at Penn, comes in. Brady is the Presidential Assistant Professor of Cancer Biology in the Perelman School of Medicine.
Copper is an integral part of many human enzymes, transport proteins, and cell components. Specific to Brady’s work, copper plays an important role in the communication from one molecule to the next in the RAS pathway, from RAS to RAF to MEK to ERK. Overall, when RAS is switched on by incoming molecules, it then turns on other proteins, which ultimately activate genes involved in cell replication, differentiation, and survival.
Transition metals like copper are not made by the body and need to be part of a person’s diet via nuts, shellfish, and leafy green plants. Copper is important for donating and accepting electrons in energy-producing reactions in the cell, mainly within the mitochondria.
Two rare diseases have also informed scientists about the role of copper in the body. Menkes disease is a genetic disorder in which the body does not have enough copper and is diagnosed in children less than one year old. On the other hand, in Wilson disease, copper accumulates in the liver and brain over decades. It is usually diagnosed when people are in their preteens to twenties and can be treated with chemicals called chelators that bind to and “mop up” the excess copper.
Working in fruitflies, Brady’s colleagues at Duke were studying the role of copper in cell growth through a protein called CTR1, which brings copper into our cells and is easily manipulated. When they decreased CTR1, less copper was imported into cells. In fact, these researchers tested the relationship in a fly eye in which RAS was mutated and showed that when copper transport was decreased the fly eye developed normally, but not the reverse.
Copper is also known to be elevated in some cancer patients. The metal promotes blood vessel growth, so tumors rely on it to form a network to bring nutrients to their ever-growing masses. Because of all of these ties to copper, Brady and her colleagues are looking at the role of copper in relation to the proteins downstream of RAS -- RAF, MEK, and ERK.
Brady and others found that if CTR1 was decreased then RAS signaling is also dampened, especially in quieting MEK’s “talking” to ERK. This happens because MEK “talks” more loudly to ERK if more copper is available in the cell. Knowing this, Brady asked if this could be used to treat RAS cancers: “If we decrease copper, can we make MEK talk less to ERK and therefore decrease signals to the cell cycle and reduce the rate of replication?”
She and colleagues are probing this specifically in BRAF mutations, which account for 60 percent of metastasized melanoma cases. U.S. Food and Drug Administration-approved drugs that inhibit MEK and BRAF do work to slow down cell replication and tumor growth, but only for a few weeks to months. Then the body becomes resistant to the drugs’ effects.
Cancer cells are basically addicted to the MEK part of the pathway to stay alive, so another approach was needed. In the spring of 2014, Brady was first author on a paper in Nature that described how, by getting rid of CTR1 in a mouse model or using a copper chelator to decrease copper uptake in cells, tumor growth was slowed.
Looking towards the future, Brady is now working on why copper is so essential for MEK kinases and why this chemical pairing has been evolutionally conserved from fruitflies to humans. She also plans to take this basic science knowledge and translate it into the clinic to make better treatments for metal-sensitive cancers.
Since Brady’s arrival at Penn in the summer, she has been setting up her lab and enlisting other medical detectives to help her solve her own true-life, copper-filled whodunit.
Photo: schizoform via Flickr Creative Commons