Project 463551

Meningiomas are the most common brain tumour and the WHO grade and extent of resection guide adjuvant radiotherapy (RT). However, up to 40% of all meningiomas progress despite RT. Recently, we developed a novel molecular group (MG) classification of meningiomas based on multi-omic analysis and capture of cell-free meningioma DNA in the plasma. We aim to extend these findings towards the determination of response to RT through the following: Aim 1: Establish DNA methylation signatures of response to RT in tumour tissue and plasma. We developed a DNA-methylation based model that predicts recurrence post-RT. We aim to externally validate this using cohorts from other institutions (Tubingen, Seattle, Indiana) and samples from the phase 2 RTOG-0539 clinical trial. Tumour signatures of RT-responsiveness will be correlated with plasma signatures for non-invasive prognostication. Aim 2: Uncover the biology of RT-resistant meningiomas through multi-omic analysis. We will build off our previous work that defined unique meningioma MG by performing RNAseq and whole-exome sequencing on RT-treated meningiomas to determine transcriptomic signatures, copy number alterations, mutations, and MG associated with RT-responsiveness. Single-cell RNAseq(scRNAseq) will assess the contribution of tumour heterogeneity and microenvironment to RT responsiveness. Pathway analysis of RNA and phosphoproteomic data will yield targetable pathways for novel therapies in RT-resistant meningiomas. Aim 3: Mechanistic studies of RT resistance and targeted radio-sensitizing drugs in preclinical models. Candidate therapies from Aim 2 will undergo drug screen on meningioma cell lines across MG with and without RT. Successful compounds will be applied to our patient-derived xenograft(PDX) meningioma mice model to confirm the therapeutic value. DNA methylation, RNAseq, scRNAseq will be performed on PDX before- and after- treatment to ascertain RT and treatment effects on the epigenome and gene expression.