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Targeted Sphingolipid Metabolism for Treatment of AML

Award Number: P01CA171983
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/10/2013
PERIOD OF PERFORMANCE END DATE: 05/31/2026

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Targeted Sphingolipid Metabolism for Treatment of AML - PROJECT SUMMARY Through three inter-related and inter-dependent Projects and four essential Cores, our team will continue to define the biological basis of dysfunctional sphingolipid metabolism in AML, and in that process, validate new therapeutic targets for pharmacological treatment approaches. The premise of the renewal P01 application is that targeting enzymes responsible for dysfunctional sphingolipid metabolism will lead to new clinical options in AML. The overall hypothesis to be tested by all projects is that increasing endogenous pro-apoptotic ceramide species, while diminishing pro-survival phosphorylated or glycosylated ceramide metabolites, will yield efficacious treatments for AML. The overall premise of this renewal application are the exciting results from the first-in-man clinical trial of ceramide nanoliposomes for solid tumors (NCT02834611), demonstrating the lack of dose-limiting toxicities at doses where stable disease is observed. Exciting preliminary and published in vivo data provide the rationale for nanoscale delivery vehicles for exogenous ceramide as an adjuvant therapy to support standard of care therapy (low-dose AraC and venetoclax) in a phase Ib/IIa clinical trial for relapsed/refractory AML (Project 1, CAV trial, UVA Protocol Review Committee approval #5414, pre-IND 142902). In addition, preliminary and published data are provided demonstrating that selective inhibitors of ceramide metabolism (Projects 2-3) increase the clinical utility of agents that raise levels of pro-apoptotic ceramides. A common scientific theme of all Projects is the mechanistic investigation of drug resistance and programmed cell death, which can be directly altered with sphingolipid-based therapeutics. The major innovation of our P01 is to utilize a bioinformatic and systems biology approach to integrate genomics, sphingolipidomics, and proteomics data from molecularly defined patient samples to reveal susceptible populations for testing innovative sphingolipid-targeted therapeutics in state-of-the-art patient-derived xenografts, genetically engineered murine models, and most importantly, a clinical trial. The major goal of this proposal is to develop new sphingolipid-targeted therapeutics for AML. The interdisciplinary team includes leaders in the fields of leukemia (specifically AML), nanoscale delivery systems for bioactive lipids, programmed cell death, and the biochemistry and biophysics of sphingolipids. This major goal will be accomplished through the following overarching five Specific Aims that are shared by all Projects and Cores: 1) Evaluate the efficacy of therapeutics that elevate exogenous or endogenous levels of pro-apoptotic ceramide species in animal and clinical trials; 2) Obtain preclinical and clinical PK, bio-distribution, and toxicology data to support and/or expand our FDA-IND for sphingolipid-based AML therapeutics; 3) Define the biochemical, biophysical, and molecular mechanisms underlying the synergies obtained with agents that target dysfunctional sphingolipid metabolism; 4) Understand the molecular basis defining variable dysfunctional sphingolipid metabolism for heterogeneous AML; 5) Define and validate lipid-based biomarkers as diagnostic or prognostic indicators.


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 = $0 )
2025	2024	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 EMMET ST N	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Cancer Treatment Research	000	10	2/28/2025	NON-COMPETING CONTINUATION	$0
2025	2024	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 EMMET ST N	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Cancer Treatment Research	001	10	7/28/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $1,894,532 )
2024	2024	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 EMMET ST N	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Cancer Treatment Research	000	10	6/12/2024	NON-COMPETING CONTINUATION	$1,894,532
														Subtotal = $1,894,532

Issue Date FY: 2023 ( Subtotal = $1,954,358 )
2023	2023	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Cancer Treatment Research	001	9	6/23/2023	NON-COMPETING CONTINUATION	$1,954,358
2023	2022	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Cancer Treatment Research	000	8	2/7/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $1,954,358

Issue Date FY: 2022 ( Subtotal = $1,954,358 )
2022	2022	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Cancer Treatment Research	000	8	7/6/2022	NON-COMPETING CONTINUATION	$1,954,358
														Subtotal = $1,954,358

Issue Date FY: 2021 ( Subtotal = $1,995,479 )
2021	2021	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Cancer Treatment Research	000	7	6/15/2021	NON-COMPETING CONTINUATION	$1,995,479
														Subtotal = $1,995,479

Issue Date FY: 2020 ( Subtotal = $2,054,089 )
2020	2020	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Cancer Treatment Research	002	6	5/8/2020	COMPETING CONTINUATION	$7,209
2020	2020	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Cancer Treatment Research	001	6	5/7/2020	COMPETING CONTINUATION	$2,054,089
2020	2017	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Cancer Treatment Research	000	5	2/18/2020	NON-COMPETING CONTINUATION	-$7,209
														Subtotal = $2,054,089

Issue Date FY: 2017 ( Subtotal = $2,019,502 )
2017	2017	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Cancer Treatment Research	000	5	8/4/2017	NON-COMPETING CONTINUATION	$2,019,502
														Subtotal = $2,019,502

Issue Date FY: 2016 ( Subtotal = $2,019,502 )
2016	2016	UNIVERSITY OF VIRGINIA	P.O. BOX 400195	CHARLOTTESVILLE	VA	22904	CHARLOTTESVILLE CITY	USA	Cancer Treatment Research	000	4	8/19/2016	NON-COMPETING CONTINUATION	$2,019,502
														Subtotal = $2,019,502

Issue Date FY: 2015 ( Subtotal = $2,077,502 )
2015	2015	UNIVERSITY OF VIRGINIA	P.O. BOX 400195	CHARLOTTESVILLE	VA	22904	CHARLOTTESVILLE CITY	USA	Cancer Treatment Research	000	3	9/18/2015	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$2,077,502
														Subtotal = $2,077,502

Issue Date FY: 2014 ( Subtotal = $1,929,328 )
2014	2014	MILTON S HERSHEY MEDICAL CENTER	500 UNIVERSITY DRIVE, POB 850	HERSHEY	PA	17033	DAUPHIN	USA	Cancer Treatment Research	000	2	8/29/2014	NON-COMPETING CONTINUATION	$1,929,328
														Subtotal = $1,929,328

Issue Date FY: 2013 ( Subtotal = $1,988,999 )
2013	2013	MILTON S HERSHEY MEDICAL CENTER	500 UNIVERSITY DRIVE, POB 850	HERSHEY	PA	17033	DAUPHIN	USA	Cancer Treatment Research	000	1	9/10/2013	NEW	$1,988,999
														Subtotal = $1,988,999

Grand Total All Awards = $19,887,649

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Targeted Sphingolipid Metabolism for Treatment of AML

Award Number: P01CA171983

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/10/2013

PERIOD OF PERFORMANCE END DATE: 05/31/2026

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