Targeting splicing vulnerability of neuroblastoma

St. Jude Children'S Research Hospital, Memphis TN

Investigators

Abstract

ABSTRACT Neuroblastoma is responsible for 15% of cancer related deaths in childhood cancers. Although intensive combined chemotherapy and immunotherapy has improved the outcomes to 50% for high-risk patients, it comes at the expense of significant long-term side effects. Thus, safer and more effective therapies are badly needed for improving survival and life quality of high-risk cancer patients. Pre-mRNA splicing is a process coupled with active gene transcription and catalyzed by spliceosome for production of mature mRNAs. The dysregulated pre- mRNA splicing existing across all types of cancer including neuroblastoma, which acts as a critical pathway in tumorigenesis and may consequently create vulnerabilities for cancer cells. Our recent studies revealed that the splicing factor RBM39 is exquisitely essential to neuroblastoma. Indisulam, a “molecular glue” that selectively recruits RBM39 to the CRL4-DCAF15 E3 ubiquitin ligase for proteasomal degradation, is highly efficacious against neuroblastoma, leading to significant responses in multiple high-risk disease models, without overt toxicity. We hypothesize that disruption of the dysregulated spliceosome by targeted degradation of RBM39 is a promising therapeutic strategy against neuroblastoma. Our major goal is to extensively test this hypothesis for a near future clinical trial through the following Specific Aims: 1) To investigate the efficacy of chemoimmunotherapy in combination with indisulam in preclinical NB models; 2) To determine the mechanism by which indisulam induces durable and complete responses in immune competent setting; 3) To determine the mechanism of disease relapse after indisulam therapy in the immune-deficient setting. Our studies will be a deeper understanding of the splicing dependency of cancers driven by oncogenic transcription factors and the identification of novel therapeutic approaches against them. Our proposed research will establish the foundation to translate our findings to a near-term clinical trial, which has the potential to have a significant impact on high- risk neuroblastoma patients who run out of therapy options.