# Molecular Imaging Markers for Glutaminolysis in Breast Cancer

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2021 · $402,259

## Abstract

Tumor-specific metabolic alterations have been increasingly recognized as a driving
force of tumor growth. Glutamine (Gln) is the most abundant amino acid in the blood. Glucose
and Gln are two major nutrients utilized by cancers to meet the demand for energy production
and biosynthesis. Gln is metabolized through the glutaminolysis pathway, which is highly active
in many aggressive forms of human cancers, including triple-negative breast cancer (TNBC),
pancreatic and lung cancer, lymphoma and glioblastoma. The first and rate-limiting step of
glutaminolysis is catalyzed by mitochondrial glutaminase (GLS) that converts glutamine to
glutamate. Drugs targeting key steps of glutaminolysis pathway are being developed, and
promising inhibitors of GLS have advanced to early phase clinical trials. However, there are no
current clinically feasible methods to estimate the level of cancer glutamine metabolism, nor is
there a non-invasive marker that can report the pharmacodynamic (PD) effect of GLS inhibitors.
These unmet needs provide strong motivation to develop imaging-based methods to measure
cellular glutaminolysis in order to direct GLS-targeted therapy, the focus of this proposal.
 To interrogate in vivo glutamine metabolism in cancer, our Center has designed and
developed two positron emission tomography (PET) imaging probes: L-[5-11C]Glutamine
([11C]Gln) and (2S,4R)-4[18F]Glutamine ([18F]Fluoroglutamine or [18F]4F-Gln ). This project aims
to develop and validate quantitative analysis tools for [11C]Gln and [18F]4F-Gln PET using
human breast cancer xenografts. Based on our preliminary studies, we have designed studies
to test the central hypothesis that the distribution volume of [18F]4F-Gln is a marker of tumor
glutamine pool that is an indirect measure of glutamine metabolism, while flux through GLS
measured by [11C]Gln PET is an authentic marker of tumor GLS activity. The utility of these
markers to report the pharmacodynamic effect of novel glutaminase inhibitor will be developed
and validated using breast cancer xenograft models based on cell lines of different breast
cancer subtype with varied degrees of dependence on glutamine.
 The outcome of the proposed project will fulfill the unmet clinical needs for quantitative,
non-invasive tools capable of predicting and measuring response to glutamine-targeted
therapies. These tools will be ready for clinical trials upon completion of this project to play a
critical role in development and deployment of such therapies in patients.

## Key facts

- **NIH application ID:** 10056201
- **Project number:** 5R01CA211337-05
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** DAVID A. MANKOFF
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $402,259
- **Award type:** 5
- **Project period:** 2016-12-08 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10056201

## Citation

> US National Institutes of Health, RePORTER application 10056201, Molecular Imaging Markers for Glutaminolysis in Breast Cancer (5R01CA211337-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10056201. Licensed CC0.

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