# Optimizing Theranostic Dosimetry and Kidney Biomarkers for Alpha-Emitter Radioligand Therapy in Neuroendocrine Tumors

> **NIH NIH R01** · RESEARCH INST NATIONWIDE CHILDREN'S HOSP · 2024 · $627,573

## Abstract

SUMMARY
The somatostatin subtype 2 receptor (SSTR2) is expressed in 80-100% of NETs. SSTR2 targeted alpha-emitter
radioligand therapy (α-RLT) is emerging as an exciting alternative to beta-emitter radiopharmaceuticals due to
the higher linear energy transfer and dense ionization tracks that result in enhanced formation of double stranded
DNA (dsDNA) damage with up to 80% tumor response rates in early clinical studies. However, preclinical studies
show that α-RLTs can cause a dose dependent late nephrotoxicity characterized by late tubular injury, fibrosis,
and inflammation. Building on recent breakthrough from our group we will test the overall hypothesis that
[212Pb]Pb-VMT-α-NET (212Pb-VMT) tumor responses can be maximized through a treatment scheme that
incorporates biomarkers of tubular injury, dosimetry, dose fractionation, and a nephroprotective superoxide
dismutase mimetic to mitigate nephrotoxicity. In Aim 1, we will develop a detailed understanding of the role of
superoxide dismutation in tubular dsDNA repair following [212Pb]Pb-VMT-α-NET treatment. In Aim 2, we will
identify [212Pb]Pb-VMT-α-NET dosing regimens to achieve maximal tumor responses and reduce nephrotoxicity
using a superoxide dismutase mimetic. We will incorporate the following innovative methods: (1) a novel α-RLT
[203Pb/212Pb]Pb-VMT-α-NET theranostic pair targeting SSTR2; (2) innovative SSTR2 expressing tumor models;
(3) urine biomarkers for non-invasive detection of tubular injury; (4) dsDNA injury/repair tools to study mechanism
of early subclinical tubular dsDNA damage following α -RLT; and (5) a novel nephrotoxicity mitigation strategy
based on superoxide scavenging that shows promising tumor response improvement to external beam radiation.
If successful, we expect these findings and advances be transferable to a broad range of α-RLTs, not only for
pancreatic NETs and neuroblastoma, but also for prostate, breast, melanomas, and other difficult to treat cancers
amenable to α-RLT.

## Key facts

- **NIH application ID:** 10942787
- **Project number:** 1R01CA291827-01
- **Recipient organization:** RESEARCH INST NATIONWIDE CHILDREN'S HOSP
- **Principal Investigator:** Diana Zepeda-Orozco
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $627,573
- **Award type:** 1
- **Project period:** 2024-07-01 → 2029-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10942787

## Citation

> US National Institutes of Health, RePORTER application 10942787, Optimizing Theranostic Dosimetry and Kidney Biomarkers for Alpha-Emitter Radioligand Therapy in Neuroendocrine Tumors (1R01CA291827-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10942787. Licensed CC0.

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