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

Award Number: R01CA266285
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/19/2022
PERIOD OF PERFORMANCE END DATE: 04/30/2027

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


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $522,750 )
2026	2026	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Detection and Diagnosis Research	000	5	4/9/2026	NON-COMPETING CONTINUATION	$522,750
														Subtotal = $522,750

Issue Date FY: 2025 ( Subtotal = $522,750 )
2025	2025	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Detection and Diagnosis Research	001	4	5/23/2025	NON-COMPETING CONTINUATION	$52,275
2025	2025	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Detection and Diagnosis Research	000	4	4/24/2025	NON-COMPETING CONTINUATION	$470,475
														Subtotal = $522,750

Issue Date FY: 2024 ( Subtotal = $496,614 )
2024	2024	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Detection and Diagnosis Research	000	3	5/1/2024	NON-COMPETING CONTINUATION	$496,614
														Subtotal = $496,614

Issue Date FY: 2023 ( Subtotal = $517,072 )
2023	2023	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Detection and Diagnosis Research	000	2	3/22/2023	NON-COMPETING CONTINUATION	$517,072
														Subtotal = $517,072

Issue Date FY: 2022 ( Subtotal = $562,902 )
2022	2022	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Detection and Diagnosis Research	000	1	5/19/2022	NEW	$562,902
														Subtotal = $562,902

Grand Total All Awards = $2,622,088

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

Award Number: R01CA266285

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 05/19/2022

PERIOD OF PERFORMANCE END DATE: 04/30/2027

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