Abstract 255: Antagonizing Na-K-Cl cotransporter NKCC1 impairs medulloblastoma cell viability

Medulloblastoma, a common pediatric brain cancer, is comprised of four molecular subgroups: Wnt-activated; Shh-activated; group 3; and group 4. Group 3 subgroup patients have the lowest survival rate and the highest rates of relapse and metastasis [1]. The standard-of-care for medulloblastoma consists of surgical removal of the tumor, radiation, and chemotherapy [1]. However, the standard-of-care poses many risk factors including hearing loss, permanent damage to endocrine and neurocognitive function, and secondary tumors [1]. There is a high demand for new treatment options for medulloblastoma. Interestingly, group 3 medulloblastoma tumors have high expression of GABRA5 and SLC12A2, which code for the α5-subunit of the ligand-gated ionotropic γ-aminobutyric acid type A receptor (GABAAR) and the sodium-potassium-chloride cotransporter isoform-1 (NKCC-1), respectively [2]. Several recent studies have provided evidence that ion channel activity contributes to brain cancer progression [3]. If so, then modulating ion channel(s) function may impair cancer cell viability. We have already shown that use of a positive allosteric modulator of the GABAAR can impair viability of group 3 medulloblastoma cells in vitro and in vivo and with greater specificity and potency than standard-of-care chemotherapeutic [4, 5]. Others have shown that inhibition or down-regulation of NKCC-1 can reduce cell viability, increase apoptosis, and decrease migration and invasion of cells derived from various cancer types [3]. We have examined how modulating NKCC-1 and GABAAR alone and simultaneously impacts the viability of group 3 medulloblastoma cells. We find that there is a synergistic effect in the inhibition of NKCC-1 and positive modulation of GABAAR. We will report on these observations and our model for the mechanism of action. References1.Sengupta, S., Pomeranz Krummel, D., Pomeroy, S. (2017) The evolution of medulloblastoma therapy to personalized medicine. F1000Research 6, 490.2.Cho, Y.J., Tsherniak, A., Tamayo, P., Santagata, S., Ligon, A., Greulich, H., et al. (2011) Integrative genomic analysis of medulloblastoma identifies a molecular subgroup that drives poor clinical outcome. J. Clin. Oncol. 29, 1424-1430.3.Cong, D., Zhu, W., Kuo, J.S., Hu, S., Sun, D. (2015) Ion transporters in brain tumors. Curr. Med. Chem. 22, 1171-81.4.Sengupta, S., Weeraratne, S.D., Sun, H., Phallen, J., Rallapalli, S.K., Teider, N., et al. (2014) α5-GABAA receptors negatively regulate MYC-amplified medulloblastoma growth. Acta Neuropathol. 127, 593-603.5.Jonas, O., Calligaris, D., Methuku, K.R., Poe, M.M., Francois, J.P., Tranghese, F., et al. (2016) First in vivo testing of compounds targeting group 3 medulloblastomas using an implantable microdevice as a new paradigm for drug development. J. Biomed. Nanotechnol. 12, 1297-1302. Citation Format: Andre Burnhamm, Milota Kaluzova, Laura Kallay, Gaunguan Li, Taukir Ahmed, Farjana Rashid, Andrew Jenkins, James Cook, Danial Pomeranz Krummel, Soma Sengupta. Antagonizing Na-K-Cl cotransporter NKCC1 impairs medulloblastoma cell viability [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 255.