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.

Grant Number: 1K99CA296996-01
NIH Institute/Center: NIH
Principal Investigator: William Chen