sr-1078 and Neuroblastoma

MYCN activation is a hallmark of advanced neuroblastoma (NB) and a known master regulator of metabolic reprogramming, favoring NB adaptation to its microenvironment. We found that the expression of the main regulators of the molecular clock loops is profoundly disrupted in MYCN-amplified NB patients, and this disruption independently predicts poor clinical outcome. MYCN induces the expression of clock repressors and downregulates the one of clock activators by directly binding to their promoters. Ultimately, MYCN attenuates the molecular clock by suppressing BMAL1 expression and oscillation, thereby promoting cell survival. Reestablishment of the activity of the clock activator RORα via its genetic overexpression and its stimulation through the agonist SR1078, restores BMAL1 expression and oscillation, effectively blocks MYCN-mediated tumor growth and de novo lipogenesis, and sensitizes NB tumors to conventional chemotherapy. In conclusion, reactivation of RORα could serve as a therapeutic strategy for MYCN-amplified NBs by blocking the dysregulation of molecular clock and cell metabolism mediated by MYCN.

Topics: Animals; Antineoplastic Agents; ARNTL Transcription Factors; Benzamides; Cell Line, Tumor; Cell Survival; Humans; Lipogenesis; Mice; N-Myc Proto-Oncogene Protein; Neuroblastoma; Nuclear Receptor Subfamily 1, Group F, Member 1; Promoter Regions, Genetic; Xenograft Model Antitumor Assays

Autism is a developmental disorder of the nervous system associated with impaired social communication and interactions as well excessive repetitive behaviors. There are no drug therapies that directly target the pathology of this disease. The retinoic acid receptor-related orphan receptor α (RORα) is a nuclear receptor that has been demonstrated to have reduced expression in many individuals with autism spectrum disorder (ASD). Several genes that have been shown to be downregulated in individuals with ASD have also been identified as putative RORα target genes. Utilizing a synthetic RORα/γ agonist, SR1078, that we identified previously, we demonstrate that treatment of BTBR mice (a model of autism) with SR1078 results in reduced repetitive behavior. Furthermore, these mice display increased expression of ASD-associated RORα target genes in both the brains of the BTBR mice and in a human neuroblastoma cell line treated with SR1078. These data suggest that pharmacological activation of RORα may be a method for treatment of autism.

Topics: Animals; Ataxin-2; Autism Spectrum Disorder; Autophagy-Related Protein-1 Homolog; Benzamides; Brain; Cell Adhesion Molecules, Neuronal; Cell Line, Tumor; Disease Models, Animal; Dose-Response Relationship, Drug; Gene Expression Regulation; Grooming; HEK293 Cells; Humans; Inositol 1,4,5-Trisphosphate Receptors; Intracellular Signaling Peptides and Proteins; L-Lactate Dehydrogenase; Mice; Mice, Inbred Strains; Neuroblastoma; Nuclear Receptor Subfamily 1, Group F, Member 1; REM Sleep Behavior Disorder