# PET Imaging of Glutamine Metabolism and Glutamate Transport to Guide Metabolically Targeted Therapy in Triple-Negative Breast Cancer

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2024 · $496,614

## Abstract

Glutaminolysis, the cellular catabolism of glutamine, is an important metabolic pathway
for aggressive and treatment-resistant cancers, including many triple-negative breast
cancers (TNBCs). It is well accepted that glutamate produced from glutamine by
mitochondrial glutaminase (GLS) fuels the TAC cycle, which provides energy and
precursors for biosynthesis. Emerging data have revealed a less recognized but important
contribution of glutaminolysis in mediating oxidative stress introduced internally by active
growth of aggressive cancer cells and externally by treatments including chemotherapy
and immunotherapy. Targeting inhibitors of GLS to block glutaminolysis is a therapeutic
strategy that has been tested in clinical trials of breast and other cancers with acceptable
toxicity, but limited efficacy, owing in good part to a lack of clinical markers to guide patient
selection and assess target impact. Preliminary data from our lab have shown that dual
targeting of GLS and the plasma membrane glutamate transporter, xCT (SLC7A11),
resulted in dramatic sensitization of resistant TNBC to chemotherapy. We propose three
aims based upon an overall theme to develop a kinetic framework for non-metabolized
amino acid analog PET tracers to measure cellular pool sizes as an indicator of
catabolism and cellular transport. Specifically, we will (1) validate quantitative markers for
cellular glutamine pool size from dynamic [18F]fluciclovine PET; (2) develop and validate
markers for cytosolic glutamate pool size and transport using 4-(3-[18F]fluoropropyl)-L-
glutamic acid ([18F]FSPG) PET, and (3) determine the utility of combined [18F]fluciclovine
and [18F]FSPG PET for predicting and measuring response to dual-targeted treatment
designed to sensitize TNBC to chemotherapy. As part of this work, we will address
mechanistic questions regarding cytosolic glutamate transport from mitochondrial pools
and to/from extracellular fluid to guide the interpretation of PET tracer kinetics. We will
also test approaches to target TNBC metabolic vulnerabilities, specifically the
dependence glutamine metabolism and glutamate transport, guided by the PET methods
we develop and validate in our pre-clinical TNBC models. The proposed work will lead
to a deeper understanding of the mutual engagement between glutaminolysis and redox
homeostasis of cancer cells and will yield quantitative imaging methodologies ready to
translate to the clinic.

## Key facts

- **NIH application ID:** 10813766
- **Project number:** 5R01CA266285-03
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** DAVID A. MANKOFF
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $496,614
- **Award type:** 5
- **Project period:** 2022-05-19 → 2027-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10813766

## Citation

> US National Institutes of Health, RePORTER application 10813766, PET Imaging of Glutamine Metabolism and Glutamate Transport to Guide Metabolically Targeted Therapy in Triple-Negative Breast Cancer (5R01CA266285-03). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10813766. Licensed CC0.

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