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Principal Investigator: Anthony Charles Faber
Organization: VIRGINIA COMMONWEALTH UNIVERSITY
Fiscal Year: 2024
Award: $434,312
Funding agency: National Cancer Institute
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.
Terms: <0-11 years old><ACSL1><ACSL1 Gene><ASCL1><ASCL1 gene><ASCL1 protein><ASH1><ATRA><Achaete-Scute Complex Homolog-Like 1 Protein><Achaete-Scute Complex-Like 1 Protein><Achaete-Scute Homolog 1 Protein><Adrenergic Agents><Adrenergic Drugs><Adrenergics><Age><Allergy><Antibodies><Applications Grants><Basal Transcription Factor><Basal transcription factor genes><Basic Mechanisms of SUMOylation><Cancers><Categories><Cell Death><Cessation of life><Child><Child Youth><Childhood><Childhood Cancers><Childhood Neoplasm><Childhood Tumor><Children (0-21)><Clinic><Clinical><Clinical Evaluation><Clinical Testing><Clinical Trials><Combined Modality Therapy><Complex><Cytotoxic cell><Data><Death><Disease><Disorder><Down-Regulation><Drug Targeting><Gene Transcription><General Transcription Factor Gene><General Transcription Factors><Genetic Alteration><Genetic Change><Genetic Transcription><Genetic defect><Genomics><Goals><Grant><Grant Proposals><HASH1><HASH1 protein><Hypersensitivity><Immune mediated therapy><Immunologically Directed Therapy><Immunotherapy><In Vitro><Investigators><K lymphocyte><Kinases><MASH 1 protein><MASH1><MASH1 protein><MYCN><MYCN gene><Maintenance Therapy><Malignant Childhood Neoplasm><Malignant Childhood Tumor><Malignant Neoplasms><Malignant Pediatric Neoplasm><Malignant Pediatric Tumor><Malignant Tumor><Malignant childhood cancer><Mammalian Achaete-Scute Homolog 1><Mediating><Modeling><Multimodal Therapy><Multimodal Treatment><Mutation><NK Cell Activation><NK Cells><NMYC><NMYC Gene><Natural Killer Cell Activation><Natural Killer Cells><Neuroblastoma><Oncogenic><PDX model><Pathway interactions><Patient derived xenograft><Patient outcome><Patient-Centered Outcomes><Patient-Focused Outcomes><Patients><Pediatric Neoplasm><Pediatric Tumor><Pharmaceutical Agent><Pharmaceuticals><Pharmacologic Substance><Pharmacological Substance><Phosphotransferase Gene><Phosphotransferases><Proteomics><RNA Expression><Relapse><Research Design><Research Personnel><Researchers><Retinoic Acid><Retinoic Acid Agent><Retinoic Acid and Derivatives><Retinoids><SUMOylation><Safety><Series><Study Type><Sumoylation Pathway><Surface><Testing><Therapeutic><Time><Toxic effect><Toxicities><Trans Vitamin A Acid><Transcription><Transcription Factor Proto-Oncogene><Transcription factor genes><Transphosphorylases><Tretinoin><Tretinoinum><Vitamin A Acid><addiction><addictive disorder><ages><all-trans-Retinoic Acid><all-trans-Vitamin A acid><cancer in a child><cancer in children><child with cancer><childhood malignancy><clinical test><clinically actionable><combat><combination therapy><combined modality treatment><combined treatment><disease risk><disorder risk><effective therapy><effective treatment><efficacy testing><genome mutation><global gene expression><global transcription profile><high risk><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based therapies><immune-based treatments><immuno therapy><improved outcome><in vivo><inhibitor><kids><malignancy><mouse model><multi-modal therapy><multi-modal treatment><murine model><necrocytosis><neoplasm/cancer><neuroblastoma cell><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><participant enrollment><pathway><patient derived xenograft model><patient enrollment><patient oriented outcomes><pediatric><pediatric cancer><pediatric malignancy><pharmaceutical><pre-clinical><pre-clinical study><preclinical><preclinical study><programs><research clinical testing><study design><trans-Retinoic Acid><transcription factor><transcriptome><tumor><tumors in children><weapons><youngster>