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William J. Gradishar, MD, FACP, FASCO
William J. Gradishar, MD, FACP, FASCO
Posted: Friday, May 5, 2023
Current therapies for triple-negative breast cancer do not tend to facilitate long-lasting responses. To improve this treatment gap, Jasmine M. Manouchehri, PhD, of The Ohio State University Comprehensive Cancer Center, Columbus, and colleagues hypothesized that heparanase inhibitors might change the extracellular ATP concentrations in triple-negative breast cancer by increasing heparan sulfate in the tumor microenvironment, resulting in a response to chemotherapy. Their study findings were presented during the American Association for Cancer Research (AACR) Annual Meeting 2023 (Abstract 397/23).
Heparan sulfate has been shown to play a role in several cancer-related processes such as neoangiogenesis, Hedgehog signaling, cell adhesion, and fibroblast growth factor signaling. This study discovered an additional mechanism for the tumor suppression role of heparan sulfate using the heparanase inhibitor OGT 2115 to inhibit extracellular ATPases.
To assess cell viability and extracellular ATP levels, triple-negative breast cancer cell lines MDA-MB 231, Hs 578t, and MDA-MB 468, as well as the nontumorigenic immortal mammary epithelial cell line MCF-10A, were treated with increasing concentrations of paclitaxel in the presence of heparan sulfate and/or OGT 2115. Furthermore, specific antagonists to the purinergic receptors P2RX4 and P2RX7 were used to confirm the effects of OGT 2115 were mediated through extracellular ATP. The effects of this combination on the breast cancer–initiating cell population were evaluated, and heparanase protein expression was compared.
“In our previous research, we discovered that augmenting the concentration of extracellular ATP greatly enhances the chemotherapeutic response of triple-negative breast cancer cell lines by activating purinergic receptors, leading to cell death,” the authors explained. “This strategy could potentially be used to induce deeper and more durable responses in triple-negative breast cancer patients.”
Disclosure: The study authors reported no conflicts of interest.
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