# COMBINATION HIGH-LET MOLECULAR RADIOTHERAPY OF RELAPSED REFRACTORY NEUROBLASTOMA

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2024 · $600,079

## Abstract

PROJECT SUMMARY
There is a critical need for more effective treatments for metastatic and relapsed neuroblastoma
(NB), the most commonly diagnosed extracranial solid cancer in children and the most common
cancer in infancy. Following years of advancement of multimodal therapies, 60 % of high risk NB
will recur after treatment, resulting in a 5% survival rate at 5 years. Conventional regimens now
include targeted radiotherapy to the norepinephrine transporter (NET). This is a well-validated
biomarker expressed in >90% of patients, and is targeted by 131I-MIBG – a beta particle emitting
NET substrate. SSTR2 is another important neuroendocrine specific target, which is also highly
expressed in >70% of NB. FDA-approved SSTR2 radiopeptides, 68Ga/177Lu-DOTA-TATE have
showed some efficacy in investigational use in pediatrics. However, both 131I-MIBG and 177Lu-
DOTA-TATE are low linear energy transfer, beta particle-emitting agents, which lack the capacity
to ablate cancer cells or occult small lesions. 131I-MIBG treatment only achieves a long-term
response in about 30% of NB patients, which is far lower than NET expression incidence. High
linear energy transfer emissions have the capacity to eliminate microscopic occult disease sites,
while sparing distant tissues from the long path lengths of conventional beta-emitting treatments.
In this application we put forwards a combination treatment strategy with novel ligands to address
multiple failure points of conventional targeted radiotherapy for this devastating disease. To NET,
we target 77Br-MBBG (a highly chemically stable, auger emitting meta-bromobenzylguanidine)
and to SSTR2 we have developed 227Th-L804-LM3 (a best-in-class Thorium-227 alpha emitter-
conjugated antagonist for SSTR2). These high LET agents will selectively kill cancer cells with
definitive anticancer effects; and the synergistic elimination of low expressors of either target will
be compensated by the combination approach. We deploy and characterize these next generation
agents to advance NB care in standard xenografts and advanced patient derived models of NB.
We monitor treatment efficacy of 77Br-MBBG, 227Th-L804-LM3 and their combinations, and
compare to conventional 131I-MIBG and 177Lu-DOTA-TATE treatment. We monitor tumor
response; target expression using quantitative molecular imaging analogs; DNA damage and
repair; and genomic profiles of NB in the de novo and post-treatment states. Through these
studies, we anticipate to optimize novel treatment approach that can undergo near term
translation at Washington University in St. Louis Children’s Hospital.

## Key facts

- **NIH application ID:** 10979741
- **Project number:** 1R01CA285959-01A1
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Frederick Szujuei Huang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $600,079
- **Award type:** 1
- **Project period:** 2024-09-17 → 2029-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10979741

## Citation

> US National Institutes of Health, RePORTER application 10979741, COMBINATION HIGH-LET MOLECULAR RADIOTHERAPY OF RELAPSED REFRACTORY NEUROBLASTOMA (1R01CA285959-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10979741. Licensed CC0.

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