# Development of a theragnostic radiopharmaceutical for pancreatic cancer

> **NIH NIH R01** · STANFORD UNIVERSITY · 2024 · $637,798

## Abstract

Abstract
Pancreatic adenocarcinoma (PDAC) is the third leading cause of cancer mortality, reflecting the fact that only
9% of patients present with tumor localized to the primary site, so that the vast majority of patients with pancreatic
cancer are unresectable at the time of diagnosis. We have created a program that spans the identification of
new molecular targets by spatial transcriptomics, the identification of peptide/small molecule ligands, and the
preclinical and eventual clinical evaluation of these therapies. Peptide targeted radionuclide therapy (PTRT) is a
molecularly targeted treatment strategy that uses radiolabeled peptides as biological targeting vectors designed
to deliver cytotoxic levels of radiation dose precisely to cancer cells that overexpress specific receptors. Peptides
with high receptor affinity are conjugated with a chelator for diagnostic imaging using positron emission
tomography (PET) for patient staging, selection of suitable candidates for PTRT, and subsequent treatment
monitoring. In turn, peptides are then stably radiolabeled with the intermediate-energy β-emitter lutetium-177
(177Lu). Peptides are superior for delivery due to the ease of synthesis, comparable potential affinity and
specificity, improved pharmacokinetic profiles, and low immunogenicity. We now have 40 spatially sequenced
pancreatic cancer samples, each with 4000 locations sequenced at a depth of 18,000 genes. Across all of these
samples, we have identified Claudin-4 (CLDN4) as a particularly promising target; CLDN4 is the top target from
our analysis as it 1) is a tight junction protein that is not accessible in normal tissue, and 2) is overexpressed
(~16x) in all patients and in 97% of the cancer cluster spatial regions we have sequenced. Peptides have been
identified with nanomolar affinity for CLDN4 and we have demonstrated specific accumulation of ~20%IA/cc in
tumor and peritoneal metastases in a PDAC model. Our spatial analysis of these samples indicates that if we
can deliver a peptide carrying a beta-emitter to all CLDN4 expressing cells, all cancer cells could receive a
therapeutic dose of radiation. Further, we have developed the first computational method to generate cyclic
peptides to specific binding domains and have now generated peptides against the tight junction region of
CLDN4. Clostridium perfringens enterotoxin (Cpe) is a natural ligand to CLDN4, and we evaluate mutated
peptide fragments from this ligand and cyclic peptides designed by new machine learning tools. Our specific
aims are to: Aim 1) Assess and optimize claudin-4 peptides in vitro. Aim 2) Evaluate 64Cu and 68Ga-labeled
claudin-4 peptides in cell culture and mouse models of pancreatic cancer Aim 3) Evaluate claudin-4 peptides
labeled with lutetium-177 in 3A) cell culture, 3B) xenograft, transgenic and PDX mouse models and 3C)
combination therapy with immunotherapy.

## Key facts

- **NIH application ID:** 10995214
- **Project number:** 1R01CA289924-01A1
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Katherine W Ferrara
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $637,798
- **Award type:** 1
- **Project period:** 2024-06-01 → 2029-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10995214

## Citation

> US National Institutes of Health, RePORTER application 10995214, Development of a theragnostic radiopharmaceutical for pancreatic cancer (1R01CA289924-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10995214. Licensed CC0.

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