New Investigator Grant Awarded to Vivekanand Yadav

Diffuse intrinsic pontine gliomas (DIPGs) are lethal pediatric brain tumors with no effective therapies other than radiation. As such, most of the patients die within 1.5 years of diagnosis (1). Thus, there is an urgent need for new therapies for DIPG. Inhibitor of DNA-binding (ID) proteins are key transcriptional regulators of tissue and lineage-specific gene differentiation during embryogenesis (2). Higher expression of ID1 is associated with aggressive and invasive behavior of tumor cells, correlating with poor clinical outcomes of multiple human cancers (3, 4). Over 80% of DIPGs harbor K27M mutations in the genes encoding histone H3.1 (H3F3A) or H3.3 (HISTIH3B) variants and often with concurrent mutation in Activin A receptor, type I (ACVR1) (5). Previous reports show upregulation of ID1 with H3K27M and ACVR1 mutations (1, 6). However, the impact of ID1 on DIPG tumorigenesis has not yet been validated in human DIPG samples and no attempts have been made to target this pathway in DIPG. Our preliminary data suggest that the ID1 gene is epigenetically activated in DIPG and ID1 is upregulated in human DIPG tumor cells and tissues. We observed that genetic knockdown of ID1 reduces DIPG cell invasion and migration while significantly improving the survival of DIPG tumor-bearing mice, indicating that ID1 upregulation is essential for primary features of DIPG. We found that cannabidiol (CBD), a clinically available non-toxic and non-psychotropic cannabinoid, is effective in reducing ID1 levels and viability of cultured DIPG cells(7-9). Importantly, CBD treatment (off trial, non-prescribed) is an increasingly popular and controversial therapy among DIPG patients. However, it is entirely un-studied in this setting, with no pre-clinical efficacy data or understanding of its potential mechanism in targeting DIPG cells. Therefore, the underlying mechanisms of ID1-driven invasion/migration in DIPG and the impact of patient-specific genetic features (e.g. H3 or ACVR1 mutation) on CBD efficacy need to be investigated. The overall objective of this proposal is to determine: (i) the epigenetic mechanism of ID1 activation and its role in DIPG invasiveness and (ii) the impact of H3F3A/ACVR1 mutation on CBD-mediated ID1 inhibition in DIPG. This study will lay the groundwork for potential future clinical trials for testing the efficacy of CBD treatment in a rational manner.