pha-848125 and Medulloblastoma

Medulloblastoma (MB) is the most common malignant brain tumor in children. Current treatment for MB includes surgical resection, radiotherapy and chemotherapy. Despite significant progress in its management, a portion of children relapse and tumor recurrence carries a poor prognosis. Based on their molecular and clinical characteristics, MB patients are clinically classified into four groups: Wnt, Hh, Group 3, and Group 4. With our increased understanding of relevant molecular pathways disrupted in MB, the development of targeted therapies for MB has also increased. Targeted drugs have shown unique privileges over traditional cytotoxic therapies in balancing efficacy and toxicity, with many of them approved and widely used clinically. The aim of this review is to present the recent progress on targeted chemotherapies for the treatment of all classes of MB.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Cerebellar Neoplasms; Humans; Medulloblastoma; Protein Kinase Inhibitors

Medulloblastoma (MB) is the most common malignant brain tumor in children. MYC genes are frequently amplified and correlate with poor prognosis in MB. BET bromodomains recognize acetylated lysine residues and often promote and maintain MYC transcription. Certain cyclin-dependent kinases (CDKs) are further known to support MYC stabilization in tumor cells. In this report, MB cells were suppressed by combined targeting of MYC expression and MYC stabilization using BET bromodomain inhibition and CDK2 inhibition, respectively. Such combination treatment worked synergistically and caused cell cycle arrest as well as massive apoptosis. Immediate transcriptional changes from this combined MYC blockade were found using RNA-Seq profiling and showed remarkable similarities to changes in MYC target gene expression when MYCN was turned off with doxycycline in our MYCN-inducible animal model for Group 3 MB. In addition, the combination treatment significantly prolonged survival as compared to single-agent therapy in orthotopically transplanted human Group 3 MB with MYC amplifications. Our data suggest that dual inhibition of CDK2 and BET bromodomains can be a novel treatment approach for suppressing MYC-driven cancer.

Topics: Azepines; Cell Line, Tumor; Cell Proliferation; Cell Survival; Cerebellar Neoplasms; Cyclin-Dependent Kinase 2; Drug Synergism; Female; Humans; Medulloblastoma; Piperazines; Protein Kinase Inhibitors; Protein Stability; Proto-Oncogene Proteins c-myc; Pyrazoles; Pyridines; Quinazolines; Sequence Analysis, RNA; Signal Transduction; Triazoles; Xenograft Model Antitumor Assays