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Signaling importance of ‘functionless’ lyso-PAF, an inactive form of platelet activating factor, in melanoma with mutant Nras

Award Number: R01CA140515
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/23/2010
PERIOD OF PERFORMANCE END DATE: 01/31/2027

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Signaling importance of ‘functionless’ lyso-PAF, an inactive form of platelet activating factor, in melanoma with mutant Nras - Project Summary/Abstract Although many human cancers share similar metabolic alterations, including the Warburg effect, it remains unclear whether oncogene-specific metabolic alterations are required for tumor development. We identified phospholipase A2G7 (PLA2G7) as a “synthetic lethal” partner of Nras Q61K/R mutants in melanoma cells, which is selectively important for cell proliferation and tumor growth potential of melanoma cells expressing mutant Nras, but not in cells expressing BRAF V600E. PLA2G7 (a.k.a. platelet-activating factor acetylhydrolase (PAF-AH)) is a secreted enzyme produced by leukocytes including macrophages, T cells, and mast cells, which catalyzes the degradation of phospholipid platelet activating factor (PAF) and production of a biologically inactive phospholipid product Lyso-PAF, blocking PAF-induced inflammation and vascular permeability. Mechanistically, we found a surprising intracellular signaling function of PLA2G7. Knockdown of PLA2G7 results in decreased S338 phosphorylation of Raf-1 in cells, which is crucial for Raf-1 activation and consequently essential for mutant Nras-dependent MAPK activation, but dispensable for MAPK activation by BRAF V600E, which bypasses Raf-1. This explains the selective importance of PLA2G7 only in mutant Nras-expressing cells. Moreover, Lyso-PAF, a biological inactive form of PAF that has been suggested to be “functionless”, may contribute to p21-activated kinase 2 (PAK2)-dependent S338 phosphorylation of Raf-1, through direct binding to PAK2, likely in the catalytic cleft, leading to enhanced PAK2 kinase activity by stabilizing ATP binding. Thus, we hypothesize that “functionless” Lyso-PAF has an intracellular and signaling role that is selectively important for mutant Nras transformation by contributing to PAK2-dependent S338 phosphorylation of Raf-1, and PLA2G7 represents an alternative therapeutic target to selectively treat melanoma cells expressing mutant Nras. We have identified and validated a compound Succimer as a selective and potent PLA2G7 inhibitor. Three specific aims are proposed: (1) To determine the selective importance of the PLA2G7-Lyso-PAF axis in the proliferative and tumor growth potential of melanoma cells expressing mutant Nras, which is “bypassed” in cells expressing BRAF V600E, using diverse human melanoma cell lines and “isogenic” cell line pairs. (2) To explore the molecular and structural mechanisms by which Lyso-PAF contributes to PAK2-Raf-1 axis through directly binding to PAK2 catalytic cleft and consequently stabilizing ATP binding. (3) To evaluate PLA2G7 as an alternative target to selectively attenuate proliferative and tumor growth potential of mutant Nras-expressing melanoma cells in vitro, and in patient-derived xenograft (PDX) models of melanoma in vivo, respectively, using our newly identified PLA2G7 inhibitor, Succimer, and elucidate the underlying structural mechanism for further structure-activation relationship (SAR) studies.


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 = $358,791 )
2026	2026	UNIVERSITY OF CHICAGO	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Cancer Biology Research	000	16	1/6/2026	NON-COMPETING CONTINUATION	$358,791
														Subtotal = $358,791

Issue Date FY: 2025 ( Subtotal = $398,657 )
2025	2025	UNIVERSITY OF CHICAGO	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Cancer Biology Research	002	15	6/2/2025	NON-COMPETING CONTINUATION	$39,866
2025	2025	UNIVERSITY OF CHICAGO	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Cancer Biology Research	001	15	2/13/2025	NON-COMPETING CONTINUATION	$0
2025	2025	UNIVERSITY OF CHICAGO	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Cancer Biology Research	000	15	1/6/2025	NON-COMPETING CONTINUATION	$358,791
														Subtotal = $398,657

Issue Date FY: 2024 ( Subtotal = $378,725 )
2024	2024	UNIVERSITY OF CHICAGO	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Cancer Biology Research	001	14	4/16/2024	NON-COMPETING CONTINUATION	$19,934
2024	2024	UNIVERSITY OF CHICAGO	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Cancer Biology Research	000	14	1/12/2024	NON-COMPETING CONTINUATION	$358,791
														Subtotal = $378,725

Issue Date FY: 2023 ( Subtotal = $405,834 )
2023	2023	UNIVERSITY OF CHICAGO	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Cancer Biology Research	000	13	1/31/2023	NON-COMPETING CONTINUATION	$405,834
														Subtotal = $405,834

Issue Date FY: 2022 ( Subtotal = $407,027 )
2022	2022	UNIVERSITY OF CHICAGO, THE	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Cancer Biology Research	001	12	2/10/2022	COMPETING CONTINUATION	$407,027
2022	2019	UNIVERSITY OF CHICAGO	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Cancer Biology Research	000	11	10/29/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $407,027

Issue Date FY: 2021 ( Subtotal = $0 )
2021	2019	UNIVERSITY OF CHICAGO, THE	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Cancer Biology Research	004	11	3/30/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2021	2019	EMORY UNIVERSITY	201 DOWMAN DR	ATLANTA	GA	30322	DEKALB	USA	Cancer Biology Research	003	10	3/30/2021	NON-COMPETING CONTINUATION	$0
2021	2019	EMORY UNIVERSITY	201 DOWMAN DR	ATLANTA	GA	30322	DEKALB	USA	Cancer Biology Research	002	10	1/25/2021	NON-COMPETING CONTINUATION	$0
2021	2019	EMORY UNIVERSITY	201 DOWMAN DR	ATLANTA	GA	30322	DEKALB	USA	Cancer Biology Research	000	10	1/22/2021	NON-COMPETING CONTINUATION	-$156,974
2021	2019	UNIVERSITY OF CHICAGO, THE	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Cancer Biology Research	001	11	1/22/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$156,974
														Subtotal = $0

Issue Date FY: 2019 ( Subtotal = $362,052 )
2019	2019	EMORY UNIVERSITY	1599 CLIFTON RD.	ATLANTA	GA	30322	DEKALB	USA	Cancer Biology Research	000	10	7/25/2019	NON-COMPETING CONTINUATION	$362,052
														Subtotal = $362,052

Issue Date FY: 2018 ( Subtotal = $373,250 )
2018	2018	EMORY UNIVERSITY	1599 CLIFTON RD.	ATLANTA	GA	30322	DEKALB	USA	Cancer Biology Research	000	9	7/23/2018	NON-COMPETING CONTINUATION	$373,250
														Subtotal = $373,250

Issue Date FY: 2017 ( Subtotal = $373,250 )
2017	2017	EMORY UNIVERSITY	1599 CLIFTON RD.	ATLANTA	GA	30322	DEKALB	USA	Cancer Biology Research	000	8	7/12/2017	NON-COMPETING CONTINUATION	$373,250
														Subtotal = $373,250

Issue Date FY: 2016 ( Subtotal = $373,250 )
2016	2016	EMORY UNIVERSITY	1784 N DECATUR RD,S 530 NDBLDG	ATLANTA	GA	30322	DEKALB	USA	Cancer Biology Research	000	7	6/21/2016	NON-COMPETING CONTINUATION	$373,250
														Subtotal = $373,250

Issue Date FY: 2015 ( Subtotal = $387,250 )
2015	2015	EMORY UNIVERSITY	1784 N DECATUR RD,S 530 NDBLDG	ATLANTA	GA	30322	DEKALB	USA	Cancer Biology Research	001	6	7/27/2015	COMPETING CONTINUATION	$387,250
2015	2014	EMORY UNIVERSITY	1784 N DECATUR RD,S 530 NDBLDG	ATLANTA	GA	30322	DEKALB	USA	Cancer Cause and Prevention Research	000	5	7/22/2015	NON-COMPETING CONTINUATION	$0
														Subtotal = $387,250

Issue Date FY: 2014 ( Subtotal = $305,027 )
2014	2014	EMORY UNIVERSITY	1784 N DECATUR RD,S 530 NDBLDG	ATLANTA	GA	30322	DEKALB	USA	Cancer Cause and Prevention Research	001	5	4/16/2014	NON-COMPETING CONTINUATION	$22,012
2014	2014	EMORY UNIVERSITY	1784 N DECATUR RD,S 530 NDBLDG	ATLANTA	GA	30322	DEKALB	USA	Cancer Cause and Prevention Research	000	5	11/20/2013	NON-COMPETING CONTINUATION	$283,015
														Subtotal = $305,027

Issue Date FY: 2013 ( Subtotal = $296,324 )
2013	2013	EMORY UNIVERSITY	1784 N DECATUR RD,S 530 NDBLDG	ATLANTA	GA	30322	DEKALB	USA	Cancer Cause and Prevention Research	000	4	11/30/2012	NON-COMPETING CONTINUATION	$157,620
2013	2013	EMORY UNIVERSITY	1784 N DECATUR RD,S 530 NDBLDG	ATLANTA	GA	30322	DEKALB	USA	Cancer Cause and Prevention Research	001	4	6/6/2013	NON-COMPETING CONTINUATION	$138,704
														Subtotal = $296,324

Issue Date FY: 2012 ( Subtotal = $315,144 )
2012	2012	EMORY UNIVERSITY	1784 N DECATUR RD,S 530 NDBLDG	ATLANTA	GA	30322	DEKALB	USA	Cancer Cause and Prevention Research	001	3	4/20/2012	NON-COMPETING CONTINUATION	$31,514
2012	2012	EMORY UNIVERSITY	1784 N DECATUR RD,S 530 NDBLDG	ATLANTA	GA	30322	DEKALB	USA	Cancer Cause and Prevention Research	000	3	12/30/2011	NON-COMPETING CONTINUATION	$283,630
														Subtotal = $315,144

Issue Date FY: 2011 ( Subtotal = $315,053 )
2011	2011	EMORY UNIVERSITY	1784 N DECATUR RD,S 530 NDBLDG	ATLANTA	GA	30322	DEKALB	USA	Cancer Cause and Prevention Research	000	2	1/7/2011	NON-COMPETING CONTINUATION	$292,316
2011	2011	EMORY UNIVERSITY	1784 N DECATUR RD,S 530 NDBLDG	ATLANTA	GA	30322	DEKALB	USA	Cancer Cause and Prevention Research	001	2	5/18/2011	NON-COMPETING CONTINUATION	$22,737
														Subtotal = $315,053

Issue Date FY: 2010 ( Subtotal = $324,703 )
2010	2010	EMORY UNIVERSITY	1784 N DECATUR RD,S 530 NDBLDG	ATLANTA	GA	30322	DEKALB	USA	Cancer Cause and Prevention Research	000	1	2/23/2010	NEW	$326,936
2010	2010	EMORY UNIVERSITY	1784 N DECATUR RD,S 530 NDBLDG	ATLANTA	GA	30322	DEKALB	USA	Cancer Cause and Prevention Research	001	1	3/1/2010	NEW	$0
2010	2010	EMORY UNIVERSITY	1784 N DECATUR RD,S 530 NDBLDG	ATLANTA	GA	30322	DEKALB	USA	Cancer Cause and Prevention Research	002	1	4/12/2010	NEW	-$2,233
														Subtotal = $324,703

Grand Total All Awards = $5,374,337

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Signaling importance of ‘functionless’ lyso-PAF, an inactive form of platelet activating factor, in melanoma with mutant Nras

Award Number: R01CA140515

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/23/2010

PERIOD OF PERFORMANCE END DATE: 01/31/2027

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