By reducing copper levels with TM, we aim to cut off the essential resources cancer cells need, making it difficult for the tumor to grow and spread.
Linda Vahdat, MDA promising multi-site clinical trial that has just opened at lead site Dartmouth Cancer Center looks to bring an innovative treatment strategy to one of the most challenging forms of breast cancer.
But to Principal Investigator Linda Vahdat, MD, the trial is not “new.” A prominent breast cancer medical oncologist, clinical researcher, and Deputy Director of Dartmouth Cancer Center, Dr. Vahdat’s pioneering work in metals and cancer has been paving the way toward new hope in triple-negative breast cancer treatment for more than 10 years.
No targets, no arrows
Triple-negative breast cancer (TNBC) sets itself apart as it lacks three receptors known to fuel most breast cancers: estrogen, progesterone, and the HER2 protein. The absence of targets makes standard hormonal therapies such as tamoxifen and anastrozole, as well as Herceptin for HER2+ cancers ineffective, narrowing treatment options for patients.
"Triple-negative doesn't follow the typical patterns, which presents unique challenges that require unique approaches," Dr. Vahdat says. "We’re exploring the potential of copper depletion as one of these novel strategies."
From the Lab: The Close-up on How it Works
Tetrathiomolybdate (TM) is a copper chelation (bonding) compound used to treat Wilson's disease, a hereditary copper metabolism disorder. Early studies of breast cancer showed that depleting copper with TM prevents creation of the local “neighborhoods” in the body that cancer cells need in order to grow and spread. These neighborhoods are created by bone marrow cells called HPCs (hematopoietic progenitor cells), which prepare sites in distant organs to receive migrating cancer cells. HPCs also recruit other cells called EPCs (endothelial progenitor cells) that activate an “angiogenic switch” that establishes blood vessels at the new site to feed the cancer cells.
Early research showed that immediately before cancer recurrence, levels of both HPCs and EPCs spike. However, copper is critical to mobilizing these cells, suggesting that copper depletion should be studied. Copper is also used to produce the fuel that allows cancer cells to travel to other sites, and it helps to create a welcoming environment for cancer cells by remodeling the collagen microenvironment.
Copper depletion appears to inhibit the production, release, and mobilization of EPCs from the bone marrow, leading to a suppressed angiogenic switch and promotion of tumor dormancy.
“I love metals”
Dr. Vahdat’s career work focuses on the premise that copper, an essential mineral in all body tissues, plays a key role in cancer's ability to spread, or metastasize. Her current research centers around Tetrathiomolybdate (TM), an investigational anti-copper drug compound previously seen to keep tumors in a dormant state by disrupting the cancer growth environment and preventing the spread.
"By reducing copper levels with TM, we aim to cut off the essential resources cancer cells need, making it difficult for the tumor to grow and spread," Dr. Vahdat explains. In this particular trial, she will build on previous success of proving this concept by comparing the addition of TM to standard-of-care therapy. Eligible patients are those with triple-negative breast cancer who have residual disease after completing standard neoadjuvant therapy, or treatment given as a first step to shrink the tumor before surgery.
Building blocks
The registered name of the trial is “Novel Targeting of the Microenvironment to Decrease Metastatic Recurrence of High-Risk TNBC: A Randomized Phase II Study of Tetrathiomolybdate (TM) Plus Capecitabine in Patients with Breast Cancer at High Risk of Recurrence.” The “TM Copper Trial” as it’s casually known, builds on the insights gained from a successful Phase II trial led by Dr. Vahdat a decade ago at Weill Cornell Medicine, which showed extended periods without cancer recurrence in patients who underwent copper depletion.
"Our earlier efforts have been foundational," Dr. Vahdat reflects. "We now have a trial enrolling patients at multiple leading cancer centers that seeks to deepen and broaden our understanding of how copper depletion can be harnessed in treating TNBC."
With the green light from the FDA in June of this year, the trial is set to enroll participants over the next five years, focusing on the safety, effectiveness, and overarching goal of preventing metastasis of TNBC.
There is still a long journey ahead, but the “TM Copper Trial” represents a significant leap forward in the quest to uncover effective treatments for TNBC. “Our aim transcends managing the condition,” says Vahdat. “We're striving to outpace it."
Those facing triple-negative breast cancer have a new glimpse into a future where more effective treatment strategies are within reach. We are moving closer to a day when TNBC can be effectively managed, and its spread effectively prevented.
For questions and inquiries about the trial, please contact CopperStudyTNBC@hitchcock.org.