Chromosomal instability and radiation sensitivity in meningioma

Project Summary: Meningiomas are the most common primary intracranial tumors. Two key clinical challenges face meningioma patients and clinicians. First, no reliable biomarkers beyond WHO grade exist to predict outcomes after surgery and select patients for adjuvant radiation (RT). Second, many high-grade meningiomas are resistant to RT and result in significant morbidity and mortality, and medical therapies remain ineffective or experimental. To help address this, my prior work identified a transcriptomic meningioma biomarker correlated with aneuploidy, which outperforms WHO grade for risk stratification and identifies patients most likely to benefit from RT, but further validation in clinical FFPE samples is needed. Our data from this biomarker and from multiplatform characterization of human meningiomas and cell lines indicate that aneuploidy and chromosomal instability (CIN) correlates with progression and RT resistance. My central hypothesis is that CIN is a key driver of meningioma tumorigenesis, and that pathways of adaptation to CIN mediate cell-intrinsic resistance to RT. I propose to validate my aneuploidy-correlated transcriptomic assay to establish a clinical biomarker for risk stratification (Aim1), to utilize novel mouse and in-vitro models of meningioma to define contribution of CIN to tumorigenesis and RT resistance (Aim 2), and to test the vulnerability of meningiomas harboring CIN (CINhigh) to inhibition of key adaptive pathways in combination with RT (Aim 3). Successful completion of these aims would result in the first clinically available biomarker of meningiomas with elevated aneuploidy and risk of recurrence and provide strong evidence for the first time of the key role of CIN in meningioma tumorigenesis. It will also identify key alterations in adaptive pathways and provide preclinical rationale for targeting of CIN mediated RT resistance in meningiomas using existing medical therapies, yielding new therapeutic strategies to overcome radiation resistance in the most common primary intracranial tumor.