# Minimizing salivary gland and renal toxicity arising from PSMA-targeted alpha therapy

> **NIH NIH R01** · SLOAN-KETTERING INST CAN RESEARCH · 2022 · $687,250

## Abstract

ABSTRACT
Metastatic castration-resistant prostate cancer (mCRPC) is a lethal, incurable disease that will kill ~33,500
patients in the US in 2020. Responding to the urgent need for novel treatments that are safe and efficacious,
and leveraging the high expression of prostate specific membrane antigen (PSMA) in mCRPC lesions, several
small-molecule-based targeted radionuclide therapies (TRTs) have been developed. Among them, targeted
alpha therapy agent (TAT) with [225Ac]-PSMA-617 in particular has demonstrated striking responses in the
treatment of refractory patients — even achieving complete and durable responses in a subset of patients.
However, many responding patients have discontinued treatment due to non-target toxicity. Salivary gland
toxicity (irreversible xerostomia) and potential renal toxicity place hard limits on patient eligibility, maximum dose
and maximum number of doses, severely restricting the use of [225Ac]-PSMA-617. As such, there is an urgent
and unmet need to develop strategies that can reduce the unwanted side effects of these treatments without
compromising treatment efficacy. We in turn are proposing a simple method to reduce salivary gland and kidney
toxicity by reducing the effective specific activity (ESA) of [225Ac]-PSMA-617 by addition of PSMA-11. In our
preliminary studies, reducing the ESA of [68Ga]-PSMA-11 and [177Lu]-PSMA-617 with PSMA-11 led to
significantly reduced salivary gland and kidney uptake without compromising tumor uptake in mouse models of
prostate cancer. We have assembled a highly qualified and collaborative team of researchers — including
radiochemists, medical physicists, nuclear medicine physicians, genitourinary oncologists, veterinary
pathologists and toxicologists — to unequivocally demonstrate the efficacy of our methodology for reducing the
salivary gland and renal radiation dose of [225Ac]-PSMA-617 or other PSMA-TRT agents in clinically relevant
mouse and rat models. As part of our proposal, we will determine the range of ESAs that will reduce salivary
gland and kidney dose of [225Ac]-PSMA-617 by > 75% without compromising tumor radiation dose in mice and
rats; demonstrate that salivary gland and renal function are maintained long-term(~2 years post-treatment) while
eliminating tumor burden; demonstrate the methodology’s applicability to other PSMA-TRT agents; conduct a
GLP toxicology study of PSMA-11 at required doses (5–10 mgs/patient) to establish its safety; and make the
data available to all researchers in order to facilitate clinical trials. The experiments are being conducted as IND-
enabling studies for near-term clinical translation. Once established, our simple but innovative approach will
refine treatment with [225Ac]-PSMA-617 and other PSMA-TRT agents by reducing toxicity to salivary glands and
kidneys without compromising treatment efficacy and help to extend the lives of mCRPC patients while
maintaining their quality of life.

## Key facts

- **NIH application ID:** 10446375
- **Project number:** 1R01CA262675-01A1
- **Recipient organization:** SLOAN-KETTERING INST CAN RESEARCH
- **Principal Investigator:** Nagavarakishore Pillarsetty
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $687,250
- **Award type:** 1
- **Project period:** 2022-05-01 → 2027-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10446375

## Citation

> US National Institutes of Health, RePORTER application 10446375, Minimizing salivary gland and renal toxicity arising from PSMA-targeted alpha therapy (1R01CA262675-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10446375. Licensed CC0.

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