# PARP-1 as a novel target for alpha-particle therapy in high-risk Neuroblastoma

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2022 · $577,080

## Abstract

High-risk neuroblastoma (NB) is a deadly pediatric malignancy with less than 20% long term survival. Current
therapeutic approaches rely on intensive chemotherapy, radiotherapy and radiotherapeutics. Despite its high
relapse rate, high risk NB is a radiosensitive disease amenable to therapeutic radiopharmaceuticals. This has
been shown clinically in multiple trials where the beta-emitting Iodine-131-metaiodobenzylguanidine
([131I]MIBG) showed the highest response rate of any tested single agent. However, the physical
characteristics of beta particles makes them inefficient in the setting of micrometastatic disease. This is
particularly relevant to high risk NB as it has been postulated that relapsed NB is caused primarily by residual
micrometastatic disease in the bone marrow. The short path length and high relative biological effectiveness of
alpha particles have the potential to overcome the limitations of beta particles and eradicate micrometastatic
disease. Poly(ADP-ribose) Polymerase 1 has a variety of biological functions and is specifically located in the
nucleus, directly on the chromatin. Furthermore, PARP-1 was shown to be overexpressed in high-risk NB and
combined with its subcellular localization it is a unique therapeutic target for alpha-particle therapy. Through
the functionalization of a small molecule PARP inhibitor with astatine-211 (²¹¹At), we have developed a novel
PARP-1 targeted alpha-emitting radiotherapeutic [(²¹¹At]MM4). We hypothesize that delivering alpha-particles
directly to the genome of NB cancer cells through targeting differential PARP-1 expression patterns in cancer
vs. non-cancer tissue will be safe and effective at selectively destroying macro- and microtumors while sparing
normal tissue. Through this proposal, we will fully characterize [²¹¹At]MM4 for cellular lethality and potential
mechanisms of resistance in high-risk NB using state-of-the-art CRISPR/Cas9 genome editing technology. In
addition, using patient derived xenograft (PDX) models of NB we will perform the molecular characterization of
NB PDX models and novel image guided therapy and survival studies.

## Key facts

- **NIH application ID:** 10375475
- **Project number:** 5R01CA219006-05
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Daniel A. Pryma
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $577,080
- **Award type:** 5
- **Project period:** 2018-05-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10375475

## Citation

> US National Institutes of Health, RePORTER application 10375475, PARP-1 as a novel target for alpha-particle therapy in high-risk Neuroblastoma (5R01CA219006-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10375475. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*