Researchers at the Baylor College of Medicine and the collaboration institutions have identified a combination therapy for treating triple-negative breast cancer (TNBC) that results in a long-term tumor regression in an animal model of the condition.
On two fronts, the chemotherapy drug cyclophosphamide eliminated tumor cells, while on the other side, another medication inhibited tumor-associated cells called macrophages, which block the body''s immune response against the tumor. This two-front strategy successfully treated several highly aggressive TNBC primary tumors and metastasis. The study was published in the journalCancer Research.
TNBC is an aggressive breast cancer type with a lesser prognosis than other breast cancer subtypes, according to a co-corresponding authorDr. Jeffrey Rosen, a Distinguished Service Professor of molecular and cellular biology at Baylor.
Although treating the tumors with cyclophosphamide initially eliminated the tumor, the disease reintroduced its growth gradually. A closer look into the tumor microenvironment revealed that the tumors that returned often had very little macrophages.
We investigated the possibility that eliminating both the tumor cells and the macrophages would improve the chances of eliminating the tumor for a long time, according to Sirwarnima Singh, the first author of the paper and a student from the Baylors graduate school of biomedical sciences working together in the Rosen and Zhang laboratories. We eliminated macrophages with either a small molecule inhibitor or a monoclonal antibody toward CSF1R, a marker on these cells.
The team administered the tumors with a combination of medications for several months. Eventually, they stopped treatment and monitored tumor progression in the treated animals.
Singh said the results were very positive. Typically, a month after discontinuing the combined therapy, the tumors returned. We were very pleased to see that the tumors did not return again a month after discontinuing the combination therapy. We observed a long-term response in two animal models of TNBC.
Interestingly, animals with a durable response were able to prevent new tumors from growing. We challenged these animals with fresh tumor cells, and 40% of them rejected them. These animals were not susceptible to new tumor growth. This showed that the animals had an immune system capable of alleviating new tumor growth. We also treated lung tumor metastasis with combination therapy and found that it greatly reduced cancer growth.
With a durable response, Rosen and his friends investigated how the tumor microenvironment had improved in animals.
Our co-author said that when we treated the tumors with one of the two medications, which did not provide a viable response, immune B and T cells involved in the treatment failed to enter the tumor mass, and that their cells remained in the periphery of the tumor, according to Zhang, who is also a member of the Dan L Duncan Comprehensive Cancer Center and a McNair Scholar at Baylor.
Both B and T cells remained close to each other on the other hand, suggesting that they were able to intercede tumor elimination in a long-term way.
Researchers examined whether the macrophage signature they had observed in animal models was found in TNBC from patients. Similarly, tumors from patients with the worse prostate showed a high number of macrophages, according to Rosen. This signature may, therefore, help us identify individuals who might be candidate for combination therapy.
The researchers are planning to conduct a clinical trial to assess the effectiveness of their approaches in treating humans like TNBC.