LAUSR

Diffuse Midline Gliomas (DMGs) are devastating and incurable pediatric brain tumours. DMGs are characterised by epigenetic aberrations in the form of histone modifications, coupled with mitotic abnormalities, which together drive a stem-like transcriptional cell state that is critically dependent on the cell cycle. Polo-like kinase 1 (PLK1) is a pivotal regulator of mitosis and cell cycle progression. To determine an effective therapeutic strategy against DMG, we characterised the anti-tumour potential of PLK1 inhibition, either alone or in combination with radiotherapy. We show that targeting PLK1 with small molecule inhibitors BI2536 and BI6727 (volasertib) reduced DMG colony formation and cell proliferation, and induced G2/M checkpoint arrest and apoptosis in vitro at physiologically achievable, clinically relevant concentrations. When combined with radiotherapy, PLK1 inhibitors acted as potent radiosensitisers with synergistic suppression of DMG survival. We further show that PLK1 inhibitors exert potent anti-tumour effects in highly aggressive orthotopic DMG models, effectively extending the median survival of tumour harbouring mice both as a single agent and enhanced in combination with radiotherapy. We further demonstrate a potential novel role for PLK1 in defining an oncogenic transcriptional state in DMG by acting as a conduit between cell cycle progression and the DMG epigenome through modulation of polycomb repressive complex 2 (PRC2) activity and its resultant histone methyltransferase function. Together, these data indicate that targeting PLK1 is a highly promising therapeutic strategy to arrest DMG tumorgenicity. This data has formed the basis for a planned international Phase 1/2 trial of the PLK1 inhibitor volasertib in combination with radiotherapy in paediatric patients with DMG. Citation Format: Elisha Hayden, Laura Franshaw, Dannielle Upton, Jie Liu, Hieu Nguyen, Swapna Joshi, Maria Tsoli, Emmy Dolman, Benjamin Rayner, David Ziegler. Preclinical examination of PLK1 inhibitors for the treatment of diffuse midline gliomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1561.