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Metabolic Imaging of Targeted Therapies in Cancer

Award Number: R01CA268601
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/17/2022
PERIOD OF PERFORMANCE END DATE: 12/31/2026

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Metabolic Imaging of Targeted Therapies in Cancer - Metabolic Imaging of Targeted Therapies in Cancer PROJECT SUMMARY/ABSTRACT Given the paradigm shift in cancer therapy including the ever-growing increase in the use of targeted therapies, foremost small-molecule kinase inhibitors in cancer therapy, there is an urgent need to develop reliable imaging techniques to detect and monitor the efficacy of such inhibitors in cancer patients. Because direct evaluation of cell signaling is practically not feasible and changes in tumor volume occur late after treatment initiation given the predominantly cytostatic effect of the inhibitors, we are proposing an alternative approach to monitor changes in tumor metabolism induced by kinase inhibition. This will be achieved in three stages: 1) analysis of gene expression/proteomic/phosphoproteomic to identify metabolic pathways perturbed by inhibition of the signaling pathway performed both in vitro and in vivo in the mouse xenotransplant models using patient derived cultured and primary cells (PDX), 2) metabolomic and metabolic fluxomic analysis of effect of kinase inhibition on metabolic pathways, also done in in vitro and in vivo settings, 3) analysis of biomarkers of inhibitor response validated by the above “-omics” studies by imaging techniques, preferably non-invasive, such as 1H MRS or chemical exchange saturation-transfer (CEST) with standard FDG PET imaging serving as control. In these proof-of-principle studies, we will focus on mTOR, the serine/threonine kinase hyperactive in the majority of cancer types, and employ direct and indirect inhibitors of mTOR, rapamycin/rapalog and Torin2, respectively, as index kinase/kinase inhibitor system. We will use diffuse large B-cell lymphoma (DLBCL) as experimental cancer model. In preliminary studies, we have demonstrated that rapamycin decreased concentrations of lactic acid in patient-derived lymphoma cell lines, both cultured in vitro and xenotransplanted into mice, as detected by unique 1H MRS imaging-based detection pulse sequences developed by us and our collaborators. The rapamycin-induced decrease in glycolytic metabolism correlated with and, importantly, markedly preceded inhibition of tumor cell growth, strongly supporting the notion that image-based evaluation of the key metabolic response is predictive of biological tumor cell response to the inhibition. The response also correlated with and, hence, was at least in part attributable to decreased expression of hexokinase II, other glycolytic enzymes and enzymes from other key metabolic pathways including phosphoribosyl-amidotransferase and other enzymes involved in glutaminolysis. Utilizing 13C MRS and 13C LC-MS, we have confirmed mTOR control of glycolysis and also noted decreases in fatty acid and sterol metabolism as well as inhibition of the pentose phosphate shunt and the TCA cycle. We anticipate that the proposed studies will extend our knowledge of the impact of mTOR inhibition on malignant cell metabolism and, ultimately, set the stage for future clinical evaluation of MRS or other imaging method(s) for monitoring response to inhibitors of mTOR and other cell-signaling kinases in DLBCL and other types of cancer.


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 = $548,869 )
2026	2026	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT STREET	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Detection and Diagnosis Research	000	5	12/15/2025	NON-COMPETING CONTINUATION	$548,869
														Subtotal = $548,869

Issue Date FY: 2025 ( Subtotal = $609,855 )
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	6/2/2025	NON-COMPETING CONTINUATION	$60,986
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	1/7/2025	NON-COMPETING CONTINUATION	$548,869
														Subtotal = $609,855

Issue Date FY: 2024 ( Subtotal = $579,363 )
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	2/2/2024	NON-COMPETING CONTINUATION	$548,869
2024	2024	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Detection and Diagnosis Research	001	3	4/22/2024	NON-COMPETING CONTINUATION	$30,494
														Subtotal = $579,363

Issue Date FY: 2023 ( Subtotal = $597,658 )
2023	2023	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Detection and Diagnosis Research	001	2	5/15/2023	NON-COMPETING CONTINUATION	$0
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	1/26/2023	NON-COMPETING CONTINUATION	$597,658
														Subtotal = $597,658

Issue Date FY: 2022 ( Subtotal = $625,478 )
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	1/17/2022	NEW	$625,478
														Subtotal = $625,478

Grand Total All Awards = $2,961,223

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Metabolic Imaging of Targeted Therapies in Cancer

Award Number: R01CA268601

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/17/2022

PERIOD OF PERFORMANCE END DATE: 12/31/2026

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