MEDU-33. PLK1 INHIBITION IN COMBINATION WITH STANDARD THERAPIES FOR MYC-DRIVEN MEDULLOBLASTOMA

摘要

In the recent past, polo-like kinase (PLK1) has gained considerable attention as a potential therapeutic target in medulloblastoma. Volasertib (BI6727), highly specific and potent PLK1 inhibitor, is under clinical trials. However, volasertib exhibits varied clinical efficacies and only few patients respond well to single-agent volasertib. Therefore, we tested whether combination of BI6727 with other standard chemotherapy drugs could show promise in the treatment of highly aggressive Myc driven medulloblastoma. We evaluated the cellular effects of BI6727 in combination with other drugs in a panel of high and low cMyc expressing medulloblastoma cell lines. Of all the drugs tested, we found pairing the kinase inhibitor, BI6727, with the topoisomerase inhibitor, topotecan, showed synergistic effect in inhibiting tumor cell growth and enhanced tumor cell killing. Combination treatment resulted in a significant increase in apoptosis when compared with either drug alone. BI6727 in combination with topotecan induced both S and G2/M phase cell cycle arrest. In addition, BI6727 treatment caused a marked induction of tumor suppressor proteins, p53 and p21, when combined with topotecan. Interestingly we found that high-myc expressing medulloblastoma cell lines displayed increased sensitivity to BI6727 in combination with topotecan treatment when compared to low-myc cell lines. Using ChIP-PCR we found that Myc binds to the PLK1 promoter to induce expression of PLK1 and conversely volesertib suppresses Myc driven transcriptomic programs suggesting a positive feedback loop between PLK1 and Myc. In summary our study suggests that a combination, topotecan, and volasertib will synergize to potentiate cell death in high-Myc medulloblastoma patients.