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Depleting copper levels may reduce the production of energy cancer cells need to travel and establish themselves in other parts of the body through a process called metastasis, according to a new study by researchers at Weill Cornell Medicine and Memorial Sloan Kettering Cancer Center (MSK).

Uncovering the underlying mechanisms of how copper depletion may help reduce metastasis in breast cancer will help inform the design of future clinical trials.

In a series of research papers from 2013 to 2021, researchers at Weill Cornell Medicine showed that in a phase II clinical trial, when patients with high-risk triple negative breast cancer (TNBC) were treated along with a drug that lowers the copper levels in their body, it extended the period of time before their cancer came back and spread or metastasized. In the current study, published Dec. 15 in Nature Communications, and led by first author Divya Ramchandani, cardiothoracic surgery research associate at Weill Cornell Medicine, investigators used animal models to take a closer look at why it was the case.

“One of the defining characteristics of TNBC is that it is a very aggressive and difficult form of the disease to treat, with a high rate of metastatic recurrence and few treatment options,” said the co- principal author Vivek Mittal, research director at Neuberger Berman Lung. Cancer Center and Ford-Isom Research Professor of Cardiothoracic Surgery at Weill Cornell Medicine. “Even after surgery and other treatments, recurrence rates are high, which tends to happen early. As a result, better treatments that focus specifically on this type of cancer are needed. “

Many biological processes that take place inside cells require metal atoms. Although iron is perhaps more well known, copper has started to become an important player. Copper is needed for a process called oxidative phosphorylation (OXPHOS), which cells use to generate energy in organelles called mitochondria. Mittal showed that metastatic cancer cells in TNBC had high levels of intracellular copper and high levels of OXPHOS compared to non-metastatic cells.

Researchers hypothesized that metastatic cells may require a lot of energy to spread to other parts of the body and take hold, blocking the availability of copper, thus cutting off their power source, could be a good way to prevent these cells from traveling.

To reduce copper levels, researchers from the previous clinical trial and recent animal research used a drug called tetrathiomolybdate (TM), which is in development to treat a copper storage disorder called Wilson disease. In mouse models of TNBC, they found that when they depleted copper levels in the body, primary tumors continued to grow while the cancer’s ability to metastasize significantly reduced.

Further examination of cancer cells treated with TM revealed that these cells altered their metabolism in ways that made it more difficult for them to produce energy. Interestingly, this failing energy status triggered an AMP-activated protein kinase (AMPK) from the crucial energy sensor. In a separate study, researchers also found that lowering copper levels affected collagen remodeling in the so-called premetastatic niche – areas of the body where unwanted cancer cells are easier to establish. This has helped explain how TM can make it more difficult for the colonization of distant organs by itinerant TNBC cells.

“This article is based on research that started in the clinic, which we brought back to the lab,” said co-lead author Dr Linda Vahdat, professor of medicine at Weill Cornell Medicine, medical oncologist at MSK and chief of medical oncology and clinical director of cancer services at Norwalk Hospital. “Now that has turned into a very interesting science that we can move forward into a larger clinical trial.”

“We can use this information to plan our large randomized breast cancer trial,” Mittal said. The trial, which will be a Phase II trial involving 177 patients, will examine the use of TM as an adjuvant therapy (one treatment given after the other treatment is completed) to reduce the risk of cancer coming back in patients with the disease. from TNBC. The study is expected to begin enrolling patients in the fall of 2022 through the Translational Breast Cancer Research Consortium, supported by the Breast Cancer Research Foundation, with additional support from the NCI NExT program.

In the previous trial, Vahdat said, patients had very few side effects from MT, which is taken two to three times a day in pill form. “We are depleting copper in patients to the level where normal cellular functions can still take place, but tumor-related processes not,” she said.

Laboratory research will be an important part of the upcoming trial, as the goal is to find the right treatment for the right patient at the right time. Researchers will study patient tissues to analyze metabolic aspects of tumor and healthy tissue. Mittal and Vahdat plan to expand these findings using a recently awarded price of $ 2. NCI $ 8 million grant to study copper-mediated metabolic reprogramming and ECM alterations in TNBC metastases.

Julie Grisham is a freelance writer for Weill Cornell Medicine.

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