# Targeted inhibition of metabolic pathways to enhance radiopharmaceutical therapy

> **NIH NIH R21** · JOHNS HOPKINS UNIVERSITY · 2022 · $191,383

## Abstract

Glutamine is a major nutrient involved in several aspects of cancer metabolism. Glutaminase1 (GLS1) initiates
that process by converting glutamine to glutamate that is subsequently used in multiple reactions that support
tumor cell survival. Accordingly, GLS1 inhibition is a promising approach to treat tumors dependent on glutamate.
Here we focus on targeted inhibition of GLS1 to provide a new strategy to enhance the effect of prostate-specific
membrane antigen-based radiopharmaceutical therapy (PSMA-RPT) to treat metastatic clear cell renal cell
carcinoma (mRCC). mRCC is lethal, with a 5-year survival of only 12%. Although immunotherapy with checkpoint
inhibitors has demonstrated improved overall survival, only a minority of patients reliably respond. PSMA
displays high expression within the neovasculature of aggressive mRCC, and is a negative prognostic indicator.
Because tumor neovasculature is an established target for approved therapies for mRCC, we hypothesize that
PSMA-RPT can be a new and effective anti-vascular radiotherapy.
Many cancer-associated mutations reprogram the metabolism of mRCC with increased glutamine utilization
through GLS1. Inhibition of GLS1 reduces DNA repair in mRCC through decreased nucleotide production and
reduces glutathione synthesis while independently making the tumor cells vulnerable to DNA damage. We
hypothesize that inhibition of GLS1 will enhance PSMA-RPT by inducing further DNA damage to the cancer
cells. Inhibition of GLS1 has not been evaluated with RPT in general, or in PSMA-RPT, specifically. The
availability of clinically tested GLS1 inhibitors and PSMA-RPT renders this combined approach rapidly
translatable. We discovered small-molecule PSMA targeting, particularly for imaging, and have developed the
corresponding radiotherapeutic agents over many years. We recently translated an optimized 177Lu-labeled β-
particle-emitting compound (PSMA-R2/L1) for treating prostate cancer. While maintaining tumor uptake, our
compound showed significantly lower salivary gland uptake than existing agents in human studies, suggesting
that PSMA-RPT with 225Ac-L1 will improve the therapeutic window of α-particle-based radiotherapy. We plan to
evaluate 177Lu-L1 and 225Ac-L1 because of the different radiobiologic effects of the particles, including DNA
damage activity in the hypoxic tumor microenvironment of mRCC. We have developed several mRCC cell lines
in vitro and tumor models with variable GLS1 and PSMA levels and a patient-drived tumor model for a proof-of-
concept study. Specific Aims: Aim 1. To access the efficacy of 177Lu-L1 or 225Ac-L1 in combination with a GLS1
inhibitor in vitro. Aim 2. To assess the efficacy of 177Lu-L1 or 225Ac-L1 in combination with a GLS1 inhibitor in vivo
in relevant tumor models in orthotopic implantation. If successful, our research may have a near-term and
significant impact on improving patient outcomes.

## Key facts

- **NIH application ID:** 10356588
- **Project number:** 1R21CA267374-01
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Sangeeta Ray
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $191,383
- **Award type:** 1
- **Project period:** 2022-03-01 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10356588

## Citation

> US National Institutes of Health, RePORTER application 10356588, Targeted inhibition of metabolic pathways to enhance radiopharmaceutical therapy (1R21CA267374-01). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10356588. Licensed CC0.

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