Abstract
Brain tumors account for the most cancer-related deaths among children. MYC is one of the key oncogenes implicated in the tumor pathogenesis, and MYC (c-MYC, MYCN, and MYCL) deregulation is common in various types of malignant brain tumors in children, including those with the worst prognoses. Subsets of pediatric glioblastoma (GBM), medulloblastoma, diffuse intrinsic pontine glioma (DIPG), and atypical teratoid rhabdoid tumor (ATRT) have been shown to harbor MYC overexpression, amplification, and chromosomal translocation. Cyclin-dependent kinase 9 (CDK9) is a key regulator of transcription via its substrate, RNA polymerase II, and with CDK9 inhibition, very short-lived proteins are rapidly depleted, resulting in caspase activation and subsequent apoptosis. MYC is a short-lived protein that plays a prominent role in cancer cell survival signaling and has been shown to be depleted with CDK9 inhibition. TG02, a novel, orally-bioavailable CDK9 inhibitor, which also inhibits other CDKs (1, 2, 5, 7), works at clinically-achievable exposures and has demonstrated anti-tumor activity in vitro and in vivo. TG02 significantly reduced MYC in cell lines, primary cells, and mouse models of adult glioblastoma, though has not yet been evaluated with pediatric brain tumors. We tested the efficacy against a panel of pediatric brain tumors, both cell lines and primary cells. While treatment with TG02 universally resulted in decreased cell viability, TG02 was selectively more potent in cells with high levels of c-myc expression as compared to those with low levels of expression, with mean IC50 values of 82 nM and 575 nM, respectively. The greatest efficacy in reduction of cell proliferation with TG02 treatment was shown in c-myc-amplified medulloblastoma. Downregulation of c-myc in treated cells was confirmed by immunoblot. This work provides rationale for pursuing in vivo studies testing the efficacy of TG02 in pediatric brain tumors that express MYC.