Many patients with triple-negative breast cancer (TNBC) have recurrence of their disease after an initial response to chemotherapy because the cancer cells have become resistant to treatment. TNBC has a lower survival rate because of this pattern of resistance and there are no targeted agents to treat this form of breast cancer.
A new study by Vanderbilt-Ingram Cancer Center (VICC) investigators suggests drugs that block or inhibit the TGF-b signaling pathway in cancer cells enhance the effect of chemotherapy and may prevent recurrences of treatment-resistant TNBC.
The study, led by post-doctoral research fellow Neil Bhola, Ph.D., was published online in the Feb. 8 issue of the Journal of Clinical Investigation.
Bhola is funded by the Komen Foundation and works in the laboratory of Carlos Arteaga, M.D., associate director for Clinical Research and director of the Breast Cancer Program at VICC, and principal investigator for the study.
Chemotherapy drugs are designed to attack fast-dividing cancer cells. Recent research suggests that after an initial response to chemotherapy a small population of slower growing cells known as cancer stem-like cells (CSCs) survives and regenerates, causing metastatic tumor recurrences.
In this study, the VICC investigators sought to identify clinically targetable molecules or pathways driving the survival of chemotherapy-resistant CSCs in triple-negative breast cancer.
This subtype of breast cancer is called triple-negative because it does not have detectable estrogen or progesterone receptors or large amounts of the HER2/neu protein.
The VICC team tested paclitaxel, one of the most commonly used chemotherapy drugs in breast cancer, in triple negative breast tumor cell lines and mouse models.
The investigators found that treatment with paclitaxel actually increased the cancer stem-like cells making it more likely that these cells would survive and spread to distant sites.
Previous studies have linked the TGF-b molecule to cancer invasion and metastasis.
In this study, the VICC investigators found genes associated with this pathway were increased in patients who had been treated with chemotherapy. This suggested an association between TGF-b and resistance to chemotherapy.
Next, using a TGF-b type I receptor kinase inhibitor drug as well as a TGF-b type II receptor neutralizing antibody they identified the role of TGF-b in chemotherapy-induced growth of drug-resistant stem-like cancer cells in TNBC.
“We had to hit the cancer with chemotherapy to get rid of the fast-dividing cells and then hit them with the TGF-b inhibitor to target the slower-dividing cancer stem cell population,” explained Bhola.
He said the results were highly encouraging.
“We found that in combination with chemotherapy, the TGF-b inhibitor decreased tumor volume in mice and it significantly decreased the population of cancer stem cells.
“We used multiple cell lines where the cancer stem cells are defined by different markers and we saw that the combination actually decreased all those markers across multiple TNBC cell lines.”
According to Arteaga, “The results strongly support the use of anticancer chemotherapy in combination with drugs that block TGF-b in order to limit tumor recurrences in TNBC.”
Investigators in the VICC Breast Cancer Program plan to test such combinations promptly after the Phase I studies with the type II receptor antibody are completed.
Other VICC investigators who participated in the study include Justin Balko, Pharm.D., Ph.D., Teresa Dugger, B.S, María Gabriela Kuba, M.D., Violeta Sánchez, A.S.CP, Melinda Sanders, M.D., Jamie Stanford, Ph.D., and Rebecca Cook, Ph.D.
This work was supported by the Breast Cancer Specialized Program of Research Excellence (SPORE) grant P50 CA98131 from the National Cancer Institute — a division of the National Institutes of Health, Susan G. Komen for the Cure Foundation Grant SAC100013, and the Susan G. Komen Postdoctoral Fellowship PDF12227859.
