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Mechanisms of metabolic reprogramming by PIK3CA oncogenic mutations

Award Number: R01CA196643
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/17/2024
PERIOD OF PERFORMANCE END DATE: 12/31/2028

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Mechanisms of metabolic reprogramming by PIK3CA oncogenic mutations - The goal of this competitive renewal is to interrogate a paradigm-shifting hypothesis that a combination of CB- 839, a glutaminase inhibitor, and 5-FU induces neutrophil extracellular trap (NET) in PIK3CA mutant colorectal cancers (CRCs), which in turn kills these cancer cells. NETs are extracellular web-like structures of cytosolic and granule proteins assembled on de-condensed chromatin. NETs trap and kill bacteria, fungi, viruses, and parasites. Although some studies implicate NETs in tumor metastasis, whether NETs can kill cancer cells is largely unexplored. This proposal is built on the novel findings that we made during the current funding period: 1) PIK3CA mutations render CRCs more dependent on glutamine; 2) CB-839 preferentially inhibits xenograft growth of PIK3CA mutant CRCs; 3) the combination of CB-839 with 5-FU induces xenograft tumor regression of PIK3CA mutant CRC in nude mice; 4) the combination of CB-839 and 5-FU preferentially induces NETs in PIK3CA mutant CRCs; 5) depletion of neutrophils in nude mice significantly attenuates the efficacy of the drug combination; 6) disruption of NETs by DNase I treatment in xenograft tumors also attenuates the efficacy of the drug combination. These exciting observations lead us to hypothesize that NETs induced by the drug combination kill PIK3CA mutant CRCs. Two aims are proposed to test this exceptionally novel hypothesis. Aim 1 will determine if the combination of CB-839 and 5-FU induces NETs in immune-competent mice and human CRC patients. Aim 2 will elucidate the mechanisms by which NETs kill PIK3CA mutant CRCs. Although we focus on colon cancer in this proposal, our proposed studies may have a broader impact beyond colorectal cancer because PIK3CA is mutated in ~ 20% of all human cancer. Moreover, the mechanisms identified in the study may also apply to other NET-related diseases.


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 = $402,500 )
2025	2025	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Cancer Biology Research	001	7	6/12/2025	NON-COMPETING CONTINUATION	$40,250
2025	2025	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Cancer Biology Research	000	7	12/5/2024	NON-COMPETING CONTINUATION	$362,250
														Subtotal = $402,500

Issue Date FY: 2024 ( Subtotal = $402,500 )
2024	2024	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Cancer Biology Research	000	6	1/17/2024	COMPETING CONTINUATION	$402,500
														Subtotal = $402,500

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2020	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Cancer Biology Research	000	5	9/23/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $379,817 )
2020	2020	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Cancer Biology Research	000	5	4/22/2020	NON-COMPETING CONTINUATION	$379,817
														Subtotal = $379,817

Issue Date FY: 2019 ( Subtotal = $366,673 )
2019	2019	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Cancer Biology Research	000	4	4/12/2019	NON-COMPETING CONTINUATION	$366,673
														Subtotal = $366,673

Issue Date FY: 2018 ( Subtotal = $383,725 )
2018	2018	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Cancer Biology Research	000	3	4/24/2018	NON-COMPETING CONTINUATION	$383,725
														Subtotal = $383,725

Issue Date FY: 2017 ( Subtotal = $389,328 )
2017	2017	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Cancer Biology Research	001	2	6/7/2017	NON-COMPETING CONTINUATION	$38,933
2017	2017	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Cancer Biology Research	000	2	4/27/2017	NON-COMPETING CONTINUATION	$350,395
														Subtotal = $389,328

Issue Date FY: 2016 ( Subtotal = $394,667 )
2016	2016	CASE WESTERN RESERVE UNIVERSITY	2040 ADELBERT ROAD	CLEVELAND	OH	44106	CUYAHOGA	USA	Cancer Biology Research	000	1	5/19/2016	NEW	$394,667
														Subtotal = $394,667

Grand Total All Awards = $2,719,210

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Mechanisms of metabolic reprogramming by PIK3CA oncogenic mutations

Award Number: R01CA196643

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/17/2024

PERIOD OF PERFORMANCE END DATE: 12/31/2028

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