Monday, December 30, 2024
12/30/2024
Project Summary: High-risk neuroblastoma (NB) is responsible for ~15% of pediatric cancer-related deaths, with nearly half of these characterized by MYCN amplification. The addition of anti-GD2 antibodies and retinoids to maintenance therapy has improved the outcomes of these patients, but still more than 50% perish. Omics studies in NB tumors has revealed that most NBs are driven by an adrenergic (ADRN) core regulatory complex (CRC) of transcription factors that can be driven by MYCN and includes GATA-3, TBX2, HAND2, PHOX2B, ISL1 and ASCL1. Genomically targeting the CRCs has been demonstrated to be highly effective, however a pharmaceutical way to target the CRCs and in particular one that would be tolerated by the patient has not been developed. Here we demonstrate a remarkable therapeutic vulnerability of MYCN-amplified NB to SUMOylation inhibition. We provide evidence that toxicity involves disruption of the ADRN CRC which requires the presence of MYCN. This pathway has become actionable, with the advent of the SUMOylation inhibitor, TAK-981 (Subasumstat) now in multiple clinical trials. Thus, we propose we have uncovered an ADRN CRC inhibition strategy that is effective in MYCN-amplified NB, suggesting a real therapeutic window. Specific Aims Specific Aim 1: Test a diverse set of well-annotated high-risk patient-derived xenograft (PDX) models for efficacy and safety of SUMOylation inhibition in neuroblastoma alone and combined with maintenance therapy Specific Aim 2: Investigate the mechanism of adrenergic (ADRN) core regulatory complex (CRC) disruption following SUMOylation targeting Study Design: We will further characterize the high sensitivity of TAK-981 in high-risk MYCN-amplified NB patient-derived xenograft (PDX) models either alone or in combination with the anti-GD2 therapy, dinutuximab. Through a series of genomic and proteomic studies, we will further categorize the mechanism of sensitivity to SUMOylation inhibition. As TAK-981 induces NK cell activation, it is a rational inducing partner with the anti- GD2 immunotherapy, dinutuximab. We will also investigate this combination in NB mouse models. In all, we will attempt to gather the preclinical evidence that TAK-981 should be clinically evaluated in MYCN-amplified NB patients.
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