# Opening the Therapeutic Window for PSMA-Targeted Molecular Radiotherapy

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2022 · $366,376

## Abstract

PROJECT SUMMARY –
 This application addresses critical needs and deficiencies in prostate cancer (PCa) patient management.
The five year survival rates for localized primary PCa are excellent, but sadly fall to below 1 in 3 for those with
metastatic disease. The deluge of academic and clinical efforts to harness targeted agents for imaging of
Prostate Specific Membrane Antigen (PSMA), widely overexpressed on prostate cancer tissues, for improved
detection represents a sea change in how malignant disease will be monitored. Advancing close behind is a
systematic evaluation of therapeutic variants of these agents that deliver an ionizing radiation dose to PSMA-
expressing sites of disease.
 There is considerable interest in alpha particle (α-particle) emitting radionuclides for this targeted
radiotherapy as the high linear energy transfer imparts 5-8 MeV in a dense track that is only several cell diameters
in length. Unfortunately, widespread background-organ expression of PSMA results in untoward side-effects of
absorbed dose to normal tissues. Off-target toxicity places limitations on the activity dose which may be
administered; the patient population eligible for the treatment; the requirements for involved long term care of
comorbidities; and ultimately the overall impact this treatment will have in the clinic.
Here, we propose a strategy that enables organ specific reduction in absorbed dose without affecting
tumor targeted uptake. We focus on the salivary glands and kidneys; radiosensitive organs that demonstrate
intense PSMA-ligand targeting in pre- and clinical imaging and treatment studies. We have developed and
acquired significant insight into a novel prodrug, Tris-POC-2-PMPA that is preferentially deliverd to the kidneys
and salivary, and selectively cleaved in these organs, to release the high affinity PSMA inhibitor, 2-PMPA. Our
Preliminary Data demonstrate the potential to ensure that tumor specific ablation without toxicity can be achieved
while sparing kidney and salivary tissue. Taking advantage of a hybrid imaging and therapy approach, we will
define the optimal treatment course required for tumor control, without normal organ toxicity, in multiple small
animal xenograft and in an advanced genetically engineered model that most closely recapitulates human
disease.
 This application is being undertaken by a multidisciplinary team composed of experts in radiochemistry,
medical physics, pathology, drug development and clinical molecular imaging. This group of investigators and the
strength of our data addressing key issues in alpha particle emitting radiopharmaceutical development
demonstrate that this application has the potential to realize the transformative capabilities of molecularly targeted
radiotherapy for cancer patients.

## Key facts

- **NIH application ID:** 10394232
- **Project number:** 5R01CA229893-04
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Daniel Lyndon Jaffe Thorek
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $366,376
- **Award type:** 5
- **Project period:** 2019-05-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10394232

## Citation

> US National Institutes of Health, RePORTER application 10394232, Opening the Therapeutic Window for PSMA-Targeted Molecular Radiotherapy (5R01CA229893-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10394232. Licensed CC0.

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