@article{10.1172/jci.insight.92928, author = {Nathaniel H. Boyd AND Kiera Walker AND Joshua Fried AND James R. Hackney AND Paul C. McDonald AND Gloria A. Benavides AND Raffaella Spina AND Alessandra Audia AND Sarah E. Scott AND Catherine J. Landis AND Anh Nhat Tran AND Mark O. Bevensee AND Corinne Griguer AND Susan Nozell AND G. Yancey Gillespie AND Burt Nabors AND Krishna P. Bhat AND Eli E. Bar AND Victor Darley-Usmar AND Bo Xu AND Emily Gordon AND Sara J. Cooper AND Shoukat Dedhar AND Anita B. Hjelmeland}, journal = {JCI Insight}, publisher = {The American Society for Clinical Investigation}, title = {Addition of carbonic anhydrase 9 inhibitor SLC-0111 to temozolomide treatment delays glioblastoma growth in vivo}, year = {2022}, month = {3}, volume = {2}, url = {https://insight.jci.org/articles/view/92928}, abstract = {Tumor microenvironments can promote stem cell maintenance, tumor growth, and therapeutic resistance, findings linked by the tumor-initiating cell hypothesis. Standard of care for glioblastoma (GBM) includes temozolomide chemotherapy, which is not curative, due, in part, to residual therapy-resistant brain tumor-initiating cells (BTICs). Temozolomide efficacy may be increased by targeting carbonic anhydrase 9 (CA9), a hypoxia-responsive gene important for maintaining the altered pH gradient of tumor cells. Using patient-derived GBM xenograft cells, we explored whether CA9 and CA12 inhibitor SLC-0111 could decrease GBM growth in combination with temozolomide or influence percentages of BTICs after chemotherapy. In multiple GBMs, SLC-0111 used concurrently with temozolomide reduced cell growth and induced cell cycle arrest via DNA damage in vitro. In addition, this treatment shifted tumor metabolism to a suppressed bioenergetic state in vivo. SLC-0111 also inhibited the enrichment of BTICs after temozolomide treatment determined via CD133 expression and neurosphere formation capacity. GBM xenografts treated with SLC-0111 in combination with temozolomide regressed significantly, and this effect was greater than that of temozolomide or SLC-0111 alone. We determined that SLC-0111 improves the efficacy of temozolomide to extend survival of GBM-bearing mice and should be explored as a treatment strategy in combination with current standard of care.}, number = {24}, doi = {10.1172/jci.insight.92928}, url = {https://doi.org/10.1172/jci.insight.92928}, }