Working primarily in mouse models of disease and also in people (through a phase I clinical trial), researchers have shown that triple-negative breast tumors might one day be treated with a drug that cuts the connection between normal cells and tumor cells.
The findings stem from a collaboration between researchers at the Garvan Institute of Medical Research (Sydney), the Centre for Cancer Biology (Adelaide), and GEICAM, Spain's leading breast cancer research group (Nat Commun 2018;9:2897).
Aurélie Cazet, PhD, and Mun Hui, PhD, worked with Alex Swarbrick, PhD, (all from Garvan) to investigate the role of non-cancerous cells. The researchers analyzed the genetic output of thousands of individual cells within the tumor.
Importantly, they found that cancer cells send signals to neighboring non-cancerous cells (cancer-associated fibroblasts or CAFs). And CAFs talk back: they send back their own signals that help the cancer cells become drug-resistant and enter a dangerous state the researchers noted as “stem-like.”
The researchers disrupted the hotline between CAFs and cancer cells by using a drug called SMOi, which targets CAFs and stops them from pushing tumor cells towards a “stem-like” state. In mouse models of triple-negative breast cancer, treatment with SMOi reduced the spread of cancer, slowed tumor growth, increased sensitivity to chemotherapy, and improved survival.
Phase I Results
Following the success in mice, Swarbrick worked with GEICAM to carry out a phase I clinical trial in 12 advanced triple-negative breast cancer patients who had relapsed after previously being treated with chemotherapy. Patients were given SMOi together with docetaxel to determine whether the combination was tolerated by patients.
While the combination treatment did not halt cancer progression in nine patients, disease was stabilized in two patients and tumors fully disappeared in one patient.
“The combination of SMOi plus docetaxel produced a tumor shrinkage in some individuals with triple-negative breast cancer who were not expected to have such responses with docetaxel alone,” noted Miguel Martin, MD, PhD, Chairman of GEICAM and principal investigator of the trial. “The challenge now is the identification of the molecular characteristics of the patients most likely to respond to the combination.”
“We observed that the trial participants who responded best to the treatment were the ones with evidence of the highest levels of chatter between CAFs and tumor cells,” Hui remarked. “This is a preliminary finding, but is exciting, because it suggests that it might be possible in the future to identify patients who would respond best to this approach.”
Swarbrick, who led the research, noted it has led to a major step forward in the understanding of how CAFs can drive aggressive cancer.
“It's the stem-like cells in breast tumors that are particularly bad players, as they can travel to distant parts of the body to create new tumors and are resistant to treatment,” he stated. “We knew that CAFs played a role in turning cancer cells into a stem-like state, but now we know one way in which they communicate with tumors—and how to stop them talking to one another.”
Michael Samuel, PhD, Associate Professor at the Centre for Cancer Biology, worked with Swarbrick, Cazet, and Hui on the new research.
“We found that when they received signals from cancer cells, CAFs produced large amounts of collagen, a protein that forms a dense scaffold in the tumor, which increased its stiffness and helped to maintain the stem-like state of the cancer cells. When we disrupted the hotline in our models, collagen density was reduced and the cancer cells weren't as stem-like anymore,” Samuel said.
The breadth of this study, from cutting-edge single cell genomics (which explores which genes are turned on and off in thousands of individual cells) through to human clinical trials, has painted a comprehensive picture of how CAFs and tumor cells communicate to drive breast cancer progression and how this knowledge may be used to design more effective treatment.
“Single-cell genomics was crucial for this research,” Cazet added. “We were able to take a tumor, separate out the cancer cells from the CAFs, and look in detail at the genes that were switched on and off in each cell type. In this way, we were able to uncover their communication strategy, and found the first ever evidence that we may be able to target this communication channel to improve outcomes in triple-negative breast cancer.”
Next Steps in Research
Phase I clinical trials in a small number of patients are now complete, and Swarbrick and his medical collaborators are currently working on designing and funding phase II trials to test the effectiveness of this treatment in a larger group of patients. In parallel, Swarbrick has plans to investigate prostate cancer, where the same communication may be happening.
“We have preliminary clinical evidence that targeting the hotline between cancer cells and CAFs may be effective in breast cancer,” Swarbrick noted, “but we certainly hope that this strategy will have applications in other cancer types. We also hope this story will encourage others to look for answers outside the box, or rather, outside the tumor cell.”