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Human metabolic variation as a window into cancer initiation and progression

Award Number: R35CA220449
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/04/2017
PERIOD OF PERFORMANCE END DATE: 08/31/2030

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Human metabolic variation as a window into cancer initiation and progression - PROJECT SUMMARY/ABSTRACT Metabolic reprogramming is a hallmark of malignancy and potential source of therapeutic targets. Recent work indicates that metabolic liabilities change as cancer progresses, meaning that the pathways most relevant to advanced cancers may not be apparent in locally-invasive, treatment-naïve tumors at the site of origin. Recognizing the dearth of direct information about human cancer metabolism, we developed an approach to probe the metabolic network of intact human tumors by infusing patients with stable isotope-labeled nutrients (e.g. 13C-glucose) during tumor resection or biopsy. By measuring isotope labeling in metabolites extracted from tumor samples and following the outcomes of patients who underwent this procedure, we identified metabolic properties associated with poor survival. Of hundreds of metabolic features, 13C labeling in tricarboxylic acid (TCA) cycle metabolites was the most predictive of cancer progression and early death. In non-small cell lung cancer (NSCLC), patients whose tumors have high labeling of these metabolites succumb much earlier than patients with low labeling, and blocking this pathway in mouse models of NSCLC suppresses metastasis. In clear cell renal cell carcinoma (ccRCC), TCA cycle labeling is low when tumors are localized to the kidney but much higher in metastatic tumors, and activating the TCA cycle promotes metastasis in mice. Therefore, in both kinds of cancer, data from patients lead us to conclude that oxidative mitochondrial metabolism, particularly the TCA cycle, electron transport chain (ETC) and oxidative phosphorylation (OxPhos), promote cancer progression. The success of these experiments prompts us to further study the metabolic basis of human cancer progression in the hopes of developing new insights and therapies. We propose three general directions. First, using a combination of approaches in humans and mice, we will thoroughly examine how mitochondrial metabolism stimulates metastasis to identify discrete metabolic dependencies that could be safely targeted in patients. Second, we will develop approaches to discover new metabolic liabilities in human tumors. Strategies include a pipeline to probe viable tumor explants with a series of isotope-labeled nutrients under physiological conditions to choose the most informative tracers for isotope infusions in patients; and dynamic imaging methods to observe and quantify informative aspects of metabolic flux in tumors in real time. Third, we will use the orthogonal approach of studying human inborn errors of metabolism (IEMs) to discover why some metabolic anomalies prime cells to become malignant. This approach capitalizes on a clinical cohort of over 1,000 subjects, including patients with IEMs associated with highly penetrant cancers, and will provide unique insights into cancer initiation and progression. Altogether these efforts will build on our long-standing productivity in human cancer metabolism by uncovering new mechanisms governing the metabolic basis of cancer progression and producing new methodologies to understand and treat lethal malignancies.


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: 2025 ( Subtotal = $949,015 )
2025	2025	THE UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Cancer Biology Research	002	9	7/17/2025	NON-COMPETING CONTINUATION	$949,015
2025	2023	THE UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Cancer Biology Research	001	7	2/18/2025	COMPETING CONTINUATION	$251
2025	2022	THE UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Cancer Biology Research	000	6	2/18/2025	NON-COMPETING CONTINUATION	-$251
														Subtotal = $949,015

Issue Date FY: 2024 ( Subtotal = $903,713 )
2024	2024	THE UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Cancer Biology Research	000	8	8/2/2024	NON-COMPETING CONTINUATION	$903,713
														Subtotal = $903,713

Issue Date FY: 2023 ( Subtotal = $967,027 )
2023	2023	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Cancer Biology Research	001	7	8/8/2023	COMPETING CONTINUATION	$967,027
2023	2022	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Cancer Biology Research	000	6	7/14/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $967,027

Issue Date FY: 2022 ( Subtotal = $924,299 )
2022	2022	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Cancer Biology Research	000	6	8/12/2022	NON-COMPETING CONTINUATION	$924,299
														Subtotal = $924,299

Issue Date FY: 2021 ( Subtotal = $943,806 )
2021	2021	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Cancer Biology Research	000	5	8/20/2021	NON-COMPETING CONTINUATION	$943,806
														Subtotal = $943,806

Issue Date FY: 2020 ( Subtotal = $944,432 )
2020	2020	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Cancer Biology Research	000	4	8/13/2020	NON-COMPETING CONTINUATION	$944,432
														Subtotal = $944,432

Issue Date FY: 2019 ( Subtotal = $916,690 )
2019	2019	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Cancer Biology Research	000	3	8/21/2019	NON-COMPETING CONTINUATION	$916,690
														Subtotal = $916,690

Issue Date FY: 2018 ( Subtotal = $945,631 )
2018	2018	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Cancer Biology Research	000	2	8/10/2018	NON-COMPETING CONTINUATION	$945,631
														Subtotal = $945,631

Issue Date FY: 2017 ( Subtotal = $961,705 )
2017	2017	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Cancer Biology Research	000	1	9/4/2017	NEW	$961,705
														Subtotal = $961,705

Grand Total All Awards = $8,456,318

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Human metabolic variation as a window into cancer initiation and progression

Award Number: R35CA220449

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/04/2017

PERIOD OF PERFORMANCE END DATE: 08/31/2030

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