Dr Vahdat on Research Supporting Copper Depletion for Breast Cancer Management

“We remodel the collagen microenvironment because cancer cells put a moat around themselves as native collagen. We inhibit a copper-dependent enzyme, which enables that moat formation, so immune cells and chemotherapy can transverse that now smooth road [of the] collagen environment to get to the cancer.”

Linda T. Vahdat, MD, MBA, section chief of Medical Oncology and interim section chief of Hematology at Dartmouth Health, as well as a professor of medicine at the Darthmouth College Geisel School of Medicine, detailed the science behind therapeutic copper depletion as a strategic intervention to prevent cancer metastasis in patients with triple-negative breast cancer (TNBC).

These findings supported the initiation of an ongoing phase 2 trial (NCT06134375) investigating copper depletion in patients with high-risk TNBC. Vahdat argued that by manipulating the body’s systemic copper levels, oncologists can effectively starve dormant cancer cells before they develop into lethal secondary tumors. This biological approach serves as the foundation for a shift in how researchers view the relationship between the tumor microenvironment and the nutrients that fuel disease progression.

According to Vahdat, the systemic distribution of copper can be envisioned as a communal pool from which various cells drink based on their metabolic needs and biological hierarchy. In this conceptual model, healthy cells are positioned at the front of the line, whereas cancer cells wait at the rear, she explained. By strategically depleting the available pool of copper, Vahdat noted that the resource is exhausted by the time cancer cells attempt to access it. This method ensures that although the body’s normal physiological functions are maintained, the cancer cells are deprived of the essential mineral required for their survival and expansion, she reported.

To validate this strategy, Vahdat and colleagues completed a pilot phase 2 clinical trial (NCT00195091), which established copper depletion as both a safe and effective intervention. The scientific framework supporting this trial revealed that copper depletion functions through several distinct biological pathways, she said. Primarily, the process inhibits a specific copper-dependent enzyme responsible for remodeling the collagen microenvironment, she continued. She noted that cancer cells typically construct a protective layer of native collagen around themselves to evade treatment. By preventing the formation of this barrier, the collagen environment allows immune cells and traditional chemotherapy agents to more easily transverse the space and infiltrate the tumor, she stated.

The research also indicated that copper depletion augments the body’s natural defenses by altering the immune microenvironment, Vahdat added. Furthermore, the strategy was shown to decrease the concentration of cancer stem cells within primary tumors, which are often the primary drivers of recurrence and treatment resistance, she concluded.