Abstract 3174: PLK4 is a rational target for very high-risk medulloblastoma

Abstract

Abstract Medulloblastoma (MB) is the most common malignant pediatric brain tumor. Despite aggressive therapy (maximal safe surgical resection, craniospinal irradiation and/or chemotherapy) only 65% of patients survive, and survivors are left with severe neuro-cognitive sequelae. MB is comprised of at least four distinct molecular subgroups (SHH, Wnt, Group 3 and Group 4). Within the Sonic hedgehog (SHH) subgroup, a subset harboring inactivating mutations within TP53 represent a very high-risk group with almost universally fatal outcome. TP53 mutated SHH tumors have a high degree of genomic instability with frequent chromothripsis and are resistant to the current generation of SHH pathway inhibitors. The protein PLK4 has a key role in the maintenance of chromosome numeral integrity and as such dysregulation of PLK4 expression causes genomic instability. The PLK4 inhibitor (CFI-400945, produced by the Campbell Family Institute for Breast Cancer Research) was shown to increase genomic instability in aneuploid cells from adult solid tumors and induce these cells to die through mitotic catastrophy. Here we leverage a sporadic transposon based metastatic mouse model (Ptch+/-/Math1-SB11/T2Onc) that faithfully mimics very high-risk MB in children. In order to mimic treatment in children, tumors are microsurgically subtotally resected, followed with the oral administration of CFI-400945 and cranial MRI to monitor response. Blood brain barrier penetration of CFI-400945 was confirmed using mass spectroscopy, specifically pharmacokinetics study revealed an expected availability of CFI-400945 in the circulating blood and concentrated compound in the tumor compared to the normal brain. The administration of CFI-400945 confers an advantage of survival to the mice in this model, median of 18.5 days for surgery group and 49 days for surgery plus CFI-400945 group (p=0.005). In human tumor datasets PLK4 is highly expressed across a variety of malignancies, including MB. Specifically, across two independent, non-overlapping datasets higher PLK4 levels correlate with a trend toward worse outcome, however, when restricting this analysis only to SHH tumors, there is a significant survival difference between high and low PLK4 expression (p=0.012). In paired primary-metastatic MB PLK4 expression is retained at the time of recurrence, specifically in metastatic recurrences, suggesting PLK4 inhibition is a suitable treatment option at the time of recurrence. Taken together, the data reveals PLK4 inhibition as a novel and rational therapeutic target for a subset of very high risk MB and a broad range of other pediatric cancers. Citation Format: Carolina Nor, Mark Bray, Tak Mak, Michael Taylor. PLK4 is a rational target for very high-risk medulloblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3174.