panobinostat 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) patients with MYC oncogene amplification or overexpression exhibit extremely poor clinical outcomes and respond poorly to current therapies. Epigenetic deregulation is very common in MYC-driven MB. The bromodomain extra-terminal (BET) proteins and histone deacetylases (HDACs) are epigenetic regulators of MYC transcription and its associated tumorigenic programs. This study aimed to investigate the therapeutic potential of inhibiting the BET proteins and HDACs together in MB.. Using clinically relevant BET inhibitors (JQ1 or OTX015) and a pan-HDAC inhibitor (panobinostat), we evaluated the effects of combined inhibition on cell growth/survival in MYC-amplified MB cell lines and xenografts and examined underlying molecular mechanism(s).. Co-treatment of JQ1 or OTX015 with panobinostat synergistically suppressed growth/survival of MYC-amplified MB cells by inducing G2 cell cycle arrest and apoptosis. Mechanistic investigation using RNA-seq revealed that co-treatment of JQ1 with panobinostat synergistically modulated global gene expression including MYC/HDAC targets. SYK and MSI1 oncogenes were among the top 50 genes synergistically downregulated by JQ1 and panobinostat. RT-PCR and western blot analyses confirmed that JQ1 and panobinostat synergistically inhibited the mRNA and protein expression of MSI1/SYK along with MYC expression. Reduced SYK/MSI expression after BET (specifically, BRD4) gene-knockdown further confirmed the epigenetic regulation of SYK and MSI1 genes. In addition, the combination of OTX015 and panobinostat significantly inhibited tumor growth in MYC-amplified MB xenografted mice by downregulating expression of MYC, compared to single-agent therapy.. Together, our findings demonstrated that dual-inhibition of BET and HDAC proteins of the epigenetic pathway can be a novel therapeutic approach against MYC-driven MB.

Topics: Animals; Apoptosis; Azepines; Cell Cycle Proteins; Cell Line, Tumor; Cell Proliferation; Cerebellar Neoplasms; Epigenesis, Genetic; Histone Deacetylases; Humans; Medulloblastoma; Mice; Nuclear Proteins; Panobinostat; Proto-Oncogene Proteins c-myc; Transcription Factors; Triazoles

Mutations in the gene encoding for the histone acetyltransferase (HAT) CREBBP are common driver events in multiple types of human cancer, such as small cell lung cancer (SCLC) or Sonic Hedgehog medulloblastoma (SHH MB). Therefore, therapeutic options targeting such alterations are highly desired. We used human cell lines from SCLC as well as primary mouse tumor cells and genetically engineered mouse models for SHH MB to test treatment options with histone deacetylase inhibitors (HDACi) in CREBBP wild-type and mutated tumors. In contrast to CREBBP wild-type SCLC cells, CREBBP-mutated SCLC cells showed significantly lower IC

Topics: Animals; Basic Helix-Loop-Helix Transcription Factors; Cell Line, Tumor; Cell Proliferation; Cerebellar Neoplasms; CREB-Binding Protein; Disease Models, Animal; Drug Screening Assays, Antitumor; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Medulloblastoma; Mice; Mice, Transgenic; Panobinostat; Primary Cell Culture; Smoothened Receptor